Targeted Oncology
Targeted Oncology
Targeted Oncology

Sunitinib Versus Pazopanib in Renal Cell Carcinoma

Robert J. Motzer, MD
Published Online:3:53 PM, Mon February 18, 2013


Debu Tripathy, MD, Co-Leader, Women's Cancer Program, Norris Comprehensive Cancer Center, University of Southern California, discusses two important trials in breast cancer looking at extended hormonal therapy.

It is understood now that 10 years of tamoxifen is superior to 5 years in premenopausal patients with high-risk, early-stage disease. However, Tripathy says, most patients are postmenopausal and see benefit when treated with aromatase inhibitors. The question remains as to whether these patients could see benefit when treated with 10 years of an aromatase inhibitor compared to 5 years.

While these results may not be the most scientifically interesting, Tripathy says, they will surely affect many patients.

Clinical Pearls



  • For patients who are premenopausal with high-risk, early-stage breast cancer, 10 years of tamoxifen has shown superiority to 5 years of tamoxifen
  • In postmenopausal women, aromatase inhibitors have demonstrated superiority and a better side effect profile
  • Two large studies look to answer the question as to whether extended use (10 years) of aromatase inhibitors will show benefit compared to 5 years


ASCO2013



Myeloma



MM-003: A phase III, multicenter, randomized, open-label study of pomalidomide plus low-dose dexamethasone (LoDEX) versus high-dose dexamethasone (HiDEX) in relapsed/refractory multiple myeloma (RRMM)

Jesùs F. San-Miguel, MD, PhD

Pomalidomide + LoDEX significantly extended PFS and overall survival vs. HiDEX in patients who failed lenalidomide and bortezomib. Pomalidomide + LoDEX should become a standard of care in relapsed/refractory multiple myeloma patients who have exhausted treatment with lenalidomide and bortezomib.

Breast Cancer



PrECOG 0105: Final efficacy results from a phase II study of gemcitabine and carboplatin plus iniparib (BSI-201) as neoadjuvant therapy for triple-negative and BRCA1/2 mutation-associated breast cancer
Melinda L. Telli, MD
Preoperative gemcitabine and carboplatin plus iniparib is active in the treatment of early-stage triple-negative and BRCA1/2 mutation-associated breast cancer.

Gastrointestinal (Noncolorectal) Cancer



Results of a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas with PET and CA19-9 correlates

Daniel D. Von Hoff, MD

MPACT was a large, international study performed at community and academic centers. nab-paclitaxel + gemcitabine was superior to gemcitabine across all efficacy endpoints, had an acceptable toxicity profile, and is a new standard for the treatment of metastatic PC that could become the backbone for new regimens.

Developmental Therapeutics - Immunotherapy



A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors
Roy S. Herbst, MD, PhD
MPDL3280A was well tolerated, with no pneumonitis-related deaths. Durable responses were observed in a variety of tumors. PD-L1 tumor status appears to correlate with responses to MPDL3280A.


Nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with advanced solid tumors: Survival and long-term safety in a phase I trial.

Suzanne L. Topalian, MD

Nivolumab produced sustained survival with a manageable long-term safety profile in advanced melanoma, NSCLC and renal cell carcinoma, supporting its ongoing clinical development in controlled phase III trials with survival endpoints.

A phase II study of NPC-1C: A novel therapeutic monoclonal antibody (mab) to treat pancreatic and colorectal cancers
Preliminary results with NPC-1C show signs of clinical activity based on stable disease in heavily pretreated patients with pancreating and colorectal cancer. Safety has been established at the 1.5 mg/kg dose. A new lot of NPC-1C, produced with improved sterility and purification procedures and demonstrating no red cell agglutination, has been manufactured under GMP conditions. We plan to introduce this new lot at the current 1.5 mg/kg dose level. If there are no dose limiting toxicities, we plan to dose escalate to a higher MTD at which we will re-evaluate clinical efficacy.

Lung Cancer

A phase III study of pemetrexed (Pem) plus carboplatin (Cb) plus bevacizumab (Bev) followed by maintenance pem plus bev versus paclitaxel (Pac) plus cb plus bev followed by maintenance bev in stage IIIb or IV nonsquamous non-small cell lung cancer (NS-NSCLC): Overall and age group results

Mark A. Socinski, MD

Overall survival was not significantly different in any of the age subgroups. PFS was significantly longer in pemetrexed arm overall and for patients ≤70, but was similar for patients >70, >75 yrs. Toxicity profiles differed; subgroup safety data paralleled overall data.

Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC)
David R. Spigel, MD
Treatment with MPDL3280A was well tolerated, with no pneumonitis-related deaths. Rapid and durable responses were observed. PD-L1 tumor status correlated with response to MPDL3280A.

Prostate Cancer



CA184-095: A randomized, double-blind, phase III trial to compare the efficacy of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer

The primary endpoint is overall survival; secondary endpoints include progression-free survival, time to pain progression, time to non-hormonal systemic therapy and safety characterization. The accrual goal is 600 patients randomized.

Outcomes in patients with liver or lung metastatic castration-resistant prostate cancer treated with the androgen receptor inhibitor enzalutamide: Results from the phase III AFFIRM trial.
In the phase III AFFIRM trial, patients with lung mCRPC had higher median overall survival than patients with liver mCRPC. Enzalutamide resulted in higher response rates in both liver and lung mCRPC patients. Overall survival and radiographic progression-free survival were also improved in both patient groups treated with enzalutamide.


Design of the AFFINITY study: A randomized phase III study of a novel clusterin inhibitor, custirsen, plus cabazitaxel/prednisone (CbzP) versus CbzP alone as second-line chemotherapy in metastatic castration-resistant prostate cancer (mCRPC)

The primary efficacy measure is overall survival. The secondary measure is proportion of patients alive without disease progression at Day 140 post-randomization.

Genitourinary (Nonprostate) Cancer



Rates of dose adjustment in patients treated with tivozanib versus sorafenib in the phase III TIVO-1 study.
Lower rates of dose adjustment due to related AEs were observed in patients with metastatic RCC who received tivozanib compared to sorafenib


Phase III randomized sequential open-label study to evaluate the efficacy and safety of sorafenib followed by pazopanib versus pazopanib followed by sorafenib in the treatment of advanced/metastatic renal cell carcinoma (SWITCH-2 study).

The primary endpoint of this study is to evaluate if total PFS of sorafenib followed by pazopanib is non-inferior to pazopanib followed by sorafenib.

A phase III comparative study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus everolimus in patients with advanced or metastatic renal cell carcinoma previously treated with antiangiogenic therapy.
The primary endpoint is overall survival. Secondary endpoints include PFS, ORR, OR duration, adverse events, overall survival in PD-L1 positive or negative subgroups, and patient-reported outcomes. The trial is open and enrolling patients.

Gynecologic Cancer

A randomized double-blind phase III trial comparing vintafolide plus pegylated liposomal doxorubicin (PLD) versus PLD plus placebo in patients with platinum-resistant ovarian cancer (PROCEED).

The primary objective is to assess PFS based on investigator assessment (RECIST v1.1) in folate receptor positive patients. Secondary objectives include overall survival, safety/tolerability, overall response rate, and disease control rate. Enrollment to the study is currently ongoing.

Exploratory analysis of nibrin in advanced ovarian cancer (AOC) patients treated in the phase III OVA-301 trial.
The results point out the potential importance of nibrin expression in the clinical outcome of patients with advanced ovarian cancer. In particular, high protein expression of nibrin seems to be associated with a worse clinical outcome. Prospective clinical trials evaluating the clinical usefulness of this marker with other standard of care treatments are warranted.


<<< View all coverage from the 2013 ASCO Meeting

Darrin Stuart, PhD

Darrin Stuart, PhD

Results of a preliminary study presented at AACR 2013 suggest that using an intermittent dosing strategy with vemurafenib instead of continuous dosing has the potential to overcome the development of resistance in patients with melanoma treated with the drug.

“When vemurafenib was introduced, it was exciting to witness the translation of the discovery of BRAF mutations in melanoma into an effective therapy. However, it was disappointing to see patients stop responding to such a promising therapy after 6 to 8 months of treatment,” said Darrin Stuart, PhD, senior research investigator at the Novartis Institutes for Biomedical Research in Emeryville, California.

BRAF mutations occur in more than 50% of melanoma patients, and vemurafenib extends survival for these patients. However, most of these patients will relapse with lethal drugresistant disease, Stuart said.

A previous study by Stuart and colleagues found that xenografts of melanoma tumors expressing BRAF mutations implanted in experimental mouse models developed resistance to vemurafenib; moreover, the tumors exhibited dependence on vemurafenib to sustain their growth. When the drug was stopped, tumor growth was suspended, and some tumors regressed in the mouse model.

Stuart and colleagues sought to determine whether the tumor drug dependency observed in experimental animal models was also present in humans. They studied 42 patients with vemurafenibresistant tumors. CT scans were available for 19 of these patients who were taken off treatment; 14 of the 19 demonstrated a decrease in the rate of tumor growth once they were no longer taking vemurafenib.

“This is the first evidence that the drug-addicted state that we observed in mouse models may also occur in humans,” he said.

The next step was to implant xenografts of patient-derived BRAF-positive tumors in mice and treat them with vemurafenib either on an intermittent schedule of 4 weeks on/4 weeks off, or on continuous treatment. None of the animals in the intermittent dosing group developed drug resistance.

Continuous dosing maintained the selective pressure required for the few surviving tumor cells to develop resistance, and alternating the selective pressure through intermittent dosing appeared to prevent the evolution and expansion of resistant cells, Stuart said.

At a press conference, Stuart was asked whether the next step for Novartis will be to study intermittent dosing and compare it with continuous dosing in patients. “Novartis is interested in testing multiple approaches that include trying different dosing regimens to using different combinations of drugs with vemurafenib,” he said. “I am not at liberty to say what the company is planning, but I can say we are enthusiastic about the findings I reported at this meeting. Patients derive a clinical benefit from vemurafenib and then develop resistance. Some sort of drug holiday makes sense. I hope people will study this clinically.”


Reference

Thakur MD, Fisher R, Salangsang F, et al. Modeling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Presented at: the AACR Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract LB-144.


Tumor tissue samples

Tumor tissue samples await analysis for cancer-related genes at the Center for Advanced Molecular Diagnostics at Brigham and Women’s Hospital in Boston.

As the cost of sequencing and analyzing genetic data continues to fall, the nation’s leading cancer centers keep unveiling ambitious new clinical programs and research projects that will change the way every cancer specialist practices. Dana-Farber Cancer Institute, along with Brigham and Women’s Hospital, has launched one of the biggest research programs to date, in which the Boston, Massachusetts, centers seek to make the tumors of every patient with cancer a subject of genetic research.

Other cancer centers, while not broadening the research pool so widely, have deepened it by analyzing multiple tumor samples from each patient or conducting full-genome sequencing of both tumor samples and healthy tissue in tested patients.

These research projects supplement rapidly evolving protocols for clinical care. The tumors of most patients at most major facilities now receive some form of genomic testing to guide treatment. And that testing keeps getting more detailed.

For oncologists, hematologists, and other specialists who treat patients with cancer outside academe, these trends portend more than just an avalanche of studies that will have to be read. They portend a whole new age, albeit one that’s still a bit hazy.

Gordon B. Mills, MD, PhD

Gordon B. Mills, MD, PhD

“Genetic analysis has already changed cancer care at every practice, and we’ve only seen the tiniest tip of the iceberg,” said Gordon B. Mills, MD, PhD, who chairs the Department of Systems Biology and holds the Olga Keith Weiss Distinguished University Chair for Cancer Research at The University of Texas MD Anderson Cancer Center in Houston.

“But I think we have a little work to do before we know how we can best use these new tools,” he said. “Different cancer centers are trying different things, which will help us figure out what works and what doesn’t, and what all cancer specialists should eventually be doing.”

Sequencing Costs Plummeting



Ever since the Human Genome Project resulted in the full sequencing of the first human genome in 2003, technological advances have increasingly enabled researchers to explore the genetic underpinnings of cancer at a decreasing cost.

“The ability to sequence an individual’s entire genome as well as the patient’s tumor genome is now a feasible enterprise at a cost and speed that was unthinkable even five years ago,” noted Boris Pasche, MD, PhD, of the University of Alabama in Birmingham, and Devin Absher, PhD, of the HudsonAlpha Institute for Biotechnology in Alabama, in an editorial in the Journal of the American Medical Association last year.1

Indeed, it took 10 years and more than $2 billion to sequence the first human genome. Today, whole-genome sequencing costs from approximately $10,000 to $35,000 per human genome, and the National Institutes of Health (NIH) $1000 genome target is within the realm of possibility.2Meanwhile, the nation’s network of cancer centers has been gearing up to make the most of the new technology, both individually and with federal leadership. After the genomic changes that occur in gliobastoma and ovarian cancers were successfully mapped, the NIH launched The Cancer Genome Atlas project in 2009. More than two dozen institutions throughout the country are working on characterizing, sequencing, and analyzing the genomes of more than 20 cancers.3

As part of that effort, the University of California, Santa Cruz, has established the Cancer Genomics Hub, intended to serve as a repository and portal for an anticipated deluge of data. Research for the atlas currently generates about 10 terabytes of data each month—far more than the 45 terabytes of data the Hubble Space Telescope gathered in its first 20 years, according to a press release announcing the first supercomputer milestone in May.4

A researcher at the National Human Genome Research Institute uses a pipette to prepare DNA for sequencing.

A researcher at the National Human Genome Research Institute uses a pipette to prepare DNA for sequencing.

Research Reveals Complexities



Amid this bounty of information, those in the forefront of such research are striking notes of caution about how quickly genomic knowledge can translate into clinical advances.

Much of the uncertainty stems from continuing discoveries about cancer’s true complexity. Mills’ colleagues at MD Anderson, for example, recently made a particularly dispiriting discovery that has already transformed cancer care at MD Anderson and other hospitals.

Cancer, they found, mutates so quickly that metastasized tumors often vary genetically from and within primary tumors. In some cases, tumor genes can vary by 40%. Even a single large tumor can vary genetically from one side to another, an unnerving fact in an age when tests of tumor genes taken from a single biopsy are supposed to tell doctors the proper course of treatment, Mills noted.

MD Anderson has responded by performing genetic testing on several different tumor samples from patients with cancers that are likely to mutate. If the tests show several different strains of cancer, the hospital responds by treating them all. Even so, in those tumor types that MD Anderson has studied, changes between the primary tumor and the metastases correlate strongly with bad outcomes, so the cen-ter is working to develop new treatment strategies.

“The discovery of these tumor mutations should be a big step forward in making good treatment decisions—a real advance that doctors everywhere should be thinking about—but it will probably delay efforts to do full genome analysis on every patient and every tumor,” Mills said.

“Not only will there be the extra cost of full sequencing for a handful of samples from every patient, the extra data add astronomical complexity to the analysis of what all those genes do,” he said.

Technology Terms in Cancer Genomics

The following institutions are the major research centers participating in the TCGA. The project is scheduled to receive $175 million through the American Recovery and Reinvestment Act and $50 million each from the National Cancer Institute (NCI) and the National Human Genome Research Institute.

Term Description
Whole-Genome Sequencing Consists of 3 phases: sample preparation, where genome target is broken into fragments; physical sequencing, where bases in each fragment are identified in order; and reconstruction, where bioinformatics software is used to align overlapping reads from each fragment.
Targeted Genome Sequencing Refers to strategies that enrich the input for DNA regions such as whole exome or cancer genome.
Cancer Genotyping Involves use of multiplex assays and microarrays to analyze hundreds to millions of germline, somatic mutations, gene copy number variations, and other alterations affecting gene expression. Detects only known variants that have been selected for analysis.
Bioinformatics Applies statistics and computer science to biology through information management and algorithm development.

Tran B, Dancey JE, Kamel-Reid S, et al. Cancer genomics: technology, discovery, and translation [published online ahead of print January 23, 2012]. J Clin Oncol. 2012;30(6):647-660. doi:10.1200/JCO.2011.39.2316.

Project Focuses on Full Genome

Nevertheless, at least one institution is moving ahead with full genome analysis, not with all patients, but in at least one large research study.

Doctors at the Mayo Clinic in Rochester, Minnesota, have initiated the Breast Cancer Genome Guided Therapy Study (BEAUTY) for 200 women with locally advanced breast cancer. The goals: to discover why some women do not respond fully to neoadjuvant chemotherapy and to speed the development of treatments targeted to nonresponders.

Researchers will perform full genome analysis not only on every woman’s tumor, but also on a healthy blood sample from each participant. The information from the normal or germline sample should help illustrate which human genes lead to what tumor genes, and whether variations in patients’ DNA lead to varying responses to treatment, even when tumor genes are similar.

All tumor samples will be kept alive and grown inside mice, so that fully sequenced live human tumors will be forever available for research and testing.

Matthew P. Goetz, MD

Matthew P. Goetz, MD

“The ultimate goal here is to speed drug development by determining which genetic variations determine who responds to a given treatment, and to develop novel therapies for women whose tumors are resistant to standard chemotherapy. Currently, every woman receives a standard course of treatment, and it fails to completely eradicate tumors in a substantial number of patients,” said Matthew P. Goetz, MD, associate professor of Oncology and Pharmacology, at Mayo’s College of Medicine.

“Preserving the human tumor as mouse xenografts will provide the ability for us to partner with pharmaceutical companies in order to test new drugs, with the focus being on those tumors not eradicated with standard chemotherapy. These are fully human tumors but because they’re preserved as xenografts, you can experiment with treatments in a way you obviously cannot when humans are involved.”

Actually, the ultimate goal is far more ambitious than identifying relevant genetic variations and developing new drugs for this one form of cancer.

Judy C. Boughey, MD

Judy C. Boughey, MD

“This is a flagship study at Mayo. If successful, we would plan to replicate this approach for different types of cancer,” said Judy C. Boughey, MD, associate professor of Surgery at Mayo’s College of Medicine. “Multiple other solid organ tumors, such as lung or pancreas, would be appropriate for similar studies.”

Taking a Look at Many Tumors



Unlike Mayo’s study, which will provide extraordinarily deep information about 200 women and 200 tumors, the flag-ship genomics effort at Dana-Farber will only provide a few hundred data points on every tumor examined. But Profile, as the program is called, will provide that detail on the overwhelming majority of patients at the hospital—an estimated 10,000 new cases of cancer per year.Every patient who walks in the door at Dana-Farber and at Brigham and Women’s is asked to participate and, to date, about 70% of them have agreed, said chief scientific officer Barrett J. Rollins, MD, PhD, who is one of the architects of the program and is the Linde Family Professor of Medicine at Harvard Medical School.

Barrett J. Rollins, MD, PhD

Barrett J. Rollins, MD, PhD

Participation requires no extra biopsies or other procedures. Researchers simply perform extra tests on the tumor samples they naturally take.

Investigators also are analyzing the archived tumor samples of patients who give consent. In theory, they could go back decades because the hospital stores samples indefinitely, but financial considerations have stopped the team from going back further than two years.

The analysis, for both new and pre-existing patient samples, is similar. Rather than looking for the handful of genetic variations that are understood well enough to influence treatment of any particular cancer, the lab examines 471 alleles of 41 genes suspected of playing some role in cancer.

All of that information goes into a massive database, where sophisticated software will look for relationships between tumor genes, disease progress, and response to treatment.

This automated data mining constitutes just one of several major uses for all of the information that is collected.

Investigators will also have access to the data, stripped of any information that identifies the patient. Researchers who become curious about how a certain genetic variation affects the course of a particular cancer will be able to simply look it up in the Profile database, rather than have to set up a study to collect the information from scratch—a process that Rollins said is often the most costly and time-consuming aspect of a particular study.

The Cancer Genome Atlas (TCGA) Research Network

The following institutions are the major research centers participating in the TCGA. The project is scheduled to receive $175 million through the American Recovery and Reinvestment Act and $50 million each from the National Cancer Institute (NCI) and the National Human Genome Research Institute.

Center Specialization Institution
Biospecimen Core Resources International Genomics Consortium, Phoenix, AZ
The Research Institute at Nationwide Children’s Hospital, Columbus, OH
Genome Characterization Centers Baylor College of Medicine, Houston, TX
Brigham & Women’s Hospital and Harvard Medical School, Boston, MA
British Columbia Cancer Agency, Vancouver, Canada Broad Institute, Cambridge, MA
University of North Carolina, Chapel Hill, NC
University of Southern California, Los Angeles
Johns Hopkins University, Baltimore, MD
Genome Sequencing Centers Baylor College of Medicine, Houston, TX
Broad Institute, Cambridge, MA
Washington University School of Medicine, St. Louis, MO
Genome Data Analysis Centers Broad Institute, Cambridge, MA
Institute for Systems Biology, Seattle, WA
Lawrence Berkeley National Laboratory, Berkeley, CA
Memorial Sloan-Kettering Cancer Center, New York, NY
University of California, Santa Cruz, Santa Cruz, CA
University of North Carolina at Chapel Hill, Chapel Hill, NC
University of Texas MD Anderson Cancer Center, Houston, TX
Data Coordinating Center NCI Center for Bioinformatics, Bethesda, MD

Quick facts. The Cancer Genome Atlas website. http://cancergenome.nih.gov/newsevents/ forthemedia/quickfacts. Accessed May 7, 2012.
Perhaps more importantly, organizations that want to test drugs on people who have rare combinations of genes and tumors will be able to find a large group of potential patients, already identified, rather than having to find a full cohort of patients by themselves. This step alone could cut development times by years for some drugs.“Even analyzing 10,000 tumors a year, it’s going to take several years for this study to bear fruit, but there are enormous advantages to a study with these numbers. Many relationships are impossible to see in individual patients or dozens of patients or even hundreds of patients, but they will emerge clearly when you’re studying tens of thousands of patients,” said Rollins.

“Such a project would have been impossible even a couple years ago, but the cost of sequencing genetic samples has fallen so rapidly and the computing power available to analyze the data has gotten so fast, that we can finally do this,” he said. “At some point, every doctor’s office may be participating in studies like this.”

Rollins said the cost per patient for the 471-allele test has already fallen to just $500, and it continues to fall so quickly that Dana-Farber may soon sequence whole exons rather than just the alleles. Still, even with costs falling so fast, the Profile team is looking hard for financing, either research money from outside sources or data that translate some of their efforts from research to treatment and allows them to charge insurers.

Treading Cautiously to the Clinic



But the jump from pure research to improved treatment will be a cautious one, no matter how fast the computers start spotting fascinating correlations. “We won’t be changing treatment protocols based directly on correlations we find with Profile. We think that such a massive observational study will give us countless ideas to test, but observations can never take the place of controlled tests, no matter how compelling they look,” Rollins said. “Aside from those patients who end up in clinical trials because their records are in our database, participation in Profile probably will not end up changing what care patients receive.”

Rollins believes that the 70% participation rate—for a research project that probably won’t benefit patients who en-roll—demonstrates how far the medical profession has come in convincing patients of both the importance of genetic research and the efficacy of privacy safeguards. Patients are rapidly becoming more comfortable with the underlying issues.

Looking forward, moving beyond single-hospital initiatives like Profile to ones that collect patient data from several, and eventually most, facilities will likely take some time.

Not only would such studies require even greater technology, they’d also need enormous amounts of coordination (and, given the fact that many doctors have yet to switch to electronic records, probably persuasion), either from the government or some industry group, experts said. Most powerhouse cancer centers say they’re still at least a year or two away from trying a single-building effort like Profile, observers said. Some even believe it may be too early for even limited genetic testing on all cancer patients.

“At Vanderbilt, we are taking a disease-specific approach, with the goal of trying to build a sustainable model for mutational profiling,” said William Pao, MD, PhD, director of Personalized Cancer Medicine at Vanderbilt University Medical Center in Nashville, Tennessee.

William Pao, MD, PhD

William Pao, MD, PhD

Sequencing Center

The Cancer Genome Atlas (TCGA) Research Network includes three large-scale sequencing centers.

Unlike many cancer centers that are trying to perform some genetic analysis as part of clinical care for all cancer patients, Vanderbilt currently has routine screens for three tumor types: lung, breast, and melanoma. They expect to add systematic colon cancer screens later this year, and other tumor types can be profiled by request.

Pao believes that the genetic makeup of individual tumors should be considered to help prioritize treatment for all oncology patients. In order to help facilitate an informed approach to cancer medicine and to identify appropriate genotype-driven clinical trials for patients, he and his colleagues have developed an online tool, MyCancerGenome (www.mycancergenome.org), freely available to all.

“We’ve worked with colleagues around the world to build a knowledge base about tumor mutations and how they affect cancer responses to targeted therapies. We put all the information online in a way that’s easy for every doctor to access, to understand and, when appropriate, to act upon,” said Pao, speaking of MyCancerGenome.org. “All this research needs to be accessible or doctors won’t be able to take full advantage of it.”


References



  1. Pasche B, Absher D. Whole-genome sequencing a step closer to personalized medicine [editorial]. JAMA. 2011;305(15):1596-1597.
  2. Tran B, Dancey JE, Kamel-Reid S, et al. Cancer genomics: technology, discovery, and translation [published online ahead of print January 23, 2012]. J Clin Oncol. 2012;30(6):647-660. doi:10.1200/JCO.2011.39.2316. [Erratum: J Clin Oncol. 2012;30(10):1149].
  3. Quick facts. The Cancer Genome Atlas website. http://cancergenome.nih.gov/newsevents/forthemedia/quickfacts. Accessed August 22, 2012.
  4. Stephens T. UC Santa Cruz builds national data center for cancer genome research [news release]. Santa Cruz, CA: University of California Santa Cruz Public Information Office; May 1, 2012. http://news.ucsc.edu/2012/05/cancer-genomics.html. Accessed August 22, 2012.




Pamela Crilley, DO, medical oncologist, Cancer Treatment Centers of America, Eastern Regional Medical Center, explains the benefits and downfalls of prescribing TKIs for the treatment of CML.

While a TKI is less invasive than a bone marrow transplant, the toxicity of TKIs remains a factor, especially considering the length of time a patient must be treated. Research is being conducted to analyze the outcome of CML patients based on the rapidity of which they reach milestones.

Clinical Pearls



  • TKI treatment is less invasive than a bone marrow transplant but still has downfalls
  • CML is a chronic disease and TKI treatment must be consistent and long
  • The toxicity of a TKI affects a patient's and physician's decision
  • Research is being conducted to analyze the rapidity of which patients reach milestones in the treatment of CML


Oncology Fellows features articles written by practicing physicians, clinical instructors, researchers, and current fellows who share their knowledge, advice, and insights on a range of issues.

Healthcare Reform and the Future of Oncology

Publish or Perish

Introducing Humanities Into the Oncology Curriculum

Starting a Smoking Cessation Clinic

Five Steps to Financial Security


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
View the full PDF of this issue




Mark D. Pegram, MD, a professor of medicine at Stanford University Medical Center and the director of the Breast Cancer Program at the Stanford Cancer Institute, describes research into the antibody-drug conjugate T-DM1 (trastuzumab emtansine), following its FDA approval in February as a treatment for HER2-positive metastatic breast cancer.

T-DM1 was approved following treatment with HER2-targeted and taxane-based therapies based on results from the phase III EMILIA trial comparing it to the combination of capecitabine and lapatinib. Overall, treatment with T-DM1 in the EMILIA trial resulted in a significant improvement in overall survival, progression-free survival, and response rates. This high degree of response for patient with advanced disease suggest the agent will also be beneficial in earlier lines of treatment, Pegram believes.

As such, researchers are examining T-DM1 in the neoadjuvant and adjuvant setting for patients with HER2-positive breast cancer. The phase III MARIANNE trial is looking at the agent as a first-line treatment for HER2-positive metastatic breast cancer with or without the addition of pertuzumab compared to the standard of trastuzumab plus chemotherapy. The second trial will examine T-DM1 in the adjuvant setting in combination with standard chemotherapy and pertuzumab.

Clinical Pearls



  • T-DM1 was approved following treatment with HER2-targeted and taxane-based therapies based on results from the phase III EMILIA trial
  • T-DM1 is being looked at in the neoadjuvant and adjuvant setting for patients with HER2-positive breast cancer


LungsNearly three-fourths of patients with previously untreated advanced non-small cell lung cancer (NSCLC) with specific mutations of epidermal growth factor receptor (EGFR) experienced one full year of progression-free survival (PFS) when given the investigational therapeutic agent dacomitinib. Patients with a human epidermal growth factor receptor 2 (HER2) mutation also appeared to experience a similar benefit when given the same drug. Preliminary study results were presented at the European Society of Medical Oncology (ESMO) 2012 Congress in Vienna, Austria.

Dacomitinib is an irreversible pan-HER inhibitor. It is designed to bind to three separate kinase-active members of the HER family: EGFR/HER1, HER2, and HER4. While it has been compared to other similar agents, dacomitinib has yet to be studied in great detail in terms of the benefits observed in patients with these specific mutations.

In the results of an open-label phase II study presented at ESMO, patients were divided into an EGFR cohort and a HER2 cohort. Patients in the EGFR cohort (n=89) had stage IIIB/IV adenocarcinoma and had smoked for less than 10 pack years or had a known EGFR mutation. Many of the patients in this cohort had EGFR deletions at either exon 19 (n=25) or exon 21 (n=21). Patients in the HER2 cohort (n=17 at time of reporting data) had known HER2 amplifications or mutations and could have received any number of prior lines of therapy.1

Among the patients with EGFR deletions at exons 19 and 21, the partial response (PR) rate was 74% (95% confidence interval [CI], 59%–86%). At 12 months, the preliminary results showed that 74% of patients had achieved PFS (95% CI, 59%–85%), and the median PFS was 17 months (95% CI, 13–24). Among the 16 patients in the HER2 cohort for whom response data were available, 2 achieved a PR.

Another study presented at ESMO showed that dacomitinib could be combined with the ALK inhibitor crizotinib, and that the combination has a manageable toxicity profile. Dose limiting toxicities at various dosage combinations included mucositis, diarrhea, elevated alanine transaminase (ALT) levels, and nausea. The study is currently ongoing, but 2 unconfirmed partial responses were identified among 28 evaluable patients, while 14 had stable disease, 6 had progressive disease, and 6 had intermediate disease.2


References



  1. Janne PA, Kris M, Goldberg Z, et al. Dacomitinib (PF-00299804), an irreversible pan-HER tyrosine kinase inhibitor (TKI), for first-line treatment of EGFR-mutant or HER2-mutant or -amplified lung cancers. Presented at: European Society of Medical Oncology 2012 Congress; September 28–October 2, 2012; Vienna, Austria. Abstract 1228.
  2. Janne PA, Shaw AT, Giaccone G, et al. Phase I trial of irreversible pan-ERBB inhibitor dacomitinib (DAC) in combination with ALK/MET inhibitor crizotinib (CRIZ) in previously treated advanced non-small cell lung cancer (NSCLC). Presented at: European Society of Medical Oncology 2012 Congress; September 28–October 2, 2012; Vienna, Austria. Abstract 1290.




Michael J. Morris, MD, medical oncologist, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, comments on the use of biomarkers in prostate cancer clinical trials.

The goal in prostate cancer is to develop clinical trials endpoints that can be used instead of hard endpoints (such as overall survival or clinical benefit). If this can be achieved, clinical trials can be shortened and drug development can be accelerated, Morris says.

Clinical Pearls



  • The aim in prostate cancer is to develop clinical trial endpoints that can be used instead of hard endpoints such as overall survival
  • New biomarkers are being analyzed to find a relationship with clinical outcome


Oncology Fellows features articles written by practicing physicians, clinical instructors, researchers, and current fellows who share their knowledge, advice, and insights on a range of issues.

What I Have Learned Since Fellowship: Tips for professional success and happiness

Learning to Deliver Bad News

Help Prevent Costly Malpractice Suits

Finding Hope Amid Cancer's Destruction


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
View the full PDF of this issue


Oncology Fellows features articles written by practicing physicians, clinical instructors, researchers, and current fellows who share their knowledge, advice, and insights on a range of issues.

City Oncologist, Country Oncologist: What to consider when choosing to practice in a rural setting

Being Your Own Advocate

The Collaboration of Oncologists and Nurses

Day in the Life of a Pediatric Oncologist


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
View the full PDF of this issue


Oncology Fellows features articles written by practicing physicians, clinical instructors, researchers, and current fellows who share their knowledge, advice, and insights on a range of issues.

What You Can Expect: A year-by-year look at a fellowship program

Defusing the Student-Loan Debt Bomb

Achieving Career Success in Academic Oncology

The Importance of Mentoring


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
View the full PDF of this issue


The first few years after medical school can seem financially suffocating for young physicians. Who can think about saving for long-term goals, such as buying your first home or planning for retirement, when you’re struggling with day-to-day bills and the equivalent of a mortgage in student loan debt? The good news is that fellows are earning more. The 2010 Postgraduate Fellowship Compensation Survey, produced by the American College of Healthcare Executives in Chicago, found that nearly 75% of fellows surveyed earned between $45,000 and $60,000 per year. Just 4% of those polled said they earned less than $40,000 a year, while 15% said they were paid $60,000 or more. (See “What Do Fellows Earn?” below.) Indeed, fellowship compensation has increased over the last 5 years; median base compensation rose 14% to $49,800 in 2010, from $43,604 in a similar survey conducted in 2006. “[T]here also has been a noticeable improvement in fringe benefits that are fully paid versus those [that are] partially paid. The improvements are most noticeable for medical, dental, and disability insurance,” according to the study’s authors. “For example, 43% of fellows in 2010 received fully paid disability insurance when in 2006 only 29% received this benefit.”

Still, even students at the high end of the fellowship pay scale must find the means to service enormous debt. The average educational debt for the Class of 2010 was $157,944, according to the Association of American Medical Colleges in Washington, D.C. (That’s just an average—students in certain medical specialties graduate with debt of $200,000 or more.)

“In the coming years, a lot of people will still be paying off their student loans when it’s time for their kids to go to college,” said Mark Kantrowitz, the publisher of financial aid information Web site finaid.org, in an interview with The New York Times.

On top of 6-figure education loans, many graduates have substantial high-interest credit card debt. On average, older graduate students (aged 30 to 59 years) had outstanding credit card balances of $12,593, according to a 2007 Nellie Mae survey, the most recent data available. That’s almost twice as much as their younger counterparts aged 22 to 29 years, who carried average credit card debt of $6479.

So what’s a struggling fellow to do? Don’t panic. By taking a methodical approach to managing your spending and your debt, you can get on the road to financial security. Just follow these 5 steps.

In the coming years, a lot of people will still be paying off their student loans when it’s time for their kids to go to college. ”

Choose the Right Repayment Plan



If you’re one of the lucky few young physicians with enough income to cover your monthly expenses and your debt payments, with money to spare for saving, choose a student loan repayment program with the shortest term. The standard federal loan repayment program extends payments out for 10 years. (Extended and graduate repayment programs allow graduates to expand payments up to 30 years.) If you have higher-interest private loans, pay the minimum owed on your federal loans and concentrate on making larger payments to pay down the higher-interest debt first.But if you’re neck-deep in debt, including high-interest credit card debt, and you expect your current meager salary to increase steadily over the next decade, consider enrolling in an income-based repayment (IBR) program. Graduates pay 15% of their income over 25 years, and after that the remaining balance (if any) is forgiven. (You can cut that down to 10 years if you work in public service, including jobs in government and nonprofit 501(c)(3) organizations, under the Public Service Loan Forgiveness plan.)

In 2010, the federal rules were changed to make the IBR rules more equitable for married couples. Previously, the formula that lenders used to calculate IBR payments did not combine a couple’s total student loan debt, leading to monthly payments that were up to twice the amount 2 single borrowers would have to pay, particularly if both spouses had advanced degrees. For married couples who file jointly, lenders now use a formula that factors in the couple’s total outstanding federal student loan debt and adjusted gross income to come up with the minimum monthly payment. Find out if you’re eligible for the IBR program by using this calculator: ibrinfo. org.

Can’t Afford Your Lifestyle? Change It



Many graduates in their late 20s have enjoyed living on their own for many years. When the time comes to finally start repaying those big monthly education bills, however, some may find themselves unable to make ends meet and be forced to make hard decisions about their living arrangements.

Moving back home with one or both of your parents can seem like a drastic—and humiliating—step for a young physician to take, but eliminating monthly housing costs can allow you to concentrate all your disposable income on repaying your high-interest debts. But don’t just show up on your parents’ front porch, laundry in hand. Instead, create a “rapid debt-reduction plan” that plots out how long it will take you to whittle down your debt to a manageable level, and sets a goal for when you plan to get back out on your own. (Vertex2.com, a site devoted to Microsoft Excel spreadsheets, has an excellent debt-reduction worksheet—based on the “snowball method” of paying the highest debts first— that can help you track your progress at bit.ly/15FuL.)

If moving home with your parents is not an option (or at least, not a palatable one), consider taking on a roommate to share your monthly household expenses, and perhaps even your commuting costs.

What Do Fellows Earn?

What Do Fellows Earn?

Source: 2010 Postgraduate Fellowship Compensation Survey, the American College of Healthcare Executives.

Save for a Rainy Day, Even When It’s Pouring



Once you’ve got the right loan repayment plan in place and you feel comfortable that you can afford your monthly household expenses, it’s time to focus on emergency savings. Yes, emergency savings is even more important than saving for retirement at this point. The fact is, small and even big financial crises—such as a major car repair or being unable to work because of accident or injury—do happen to people your age, and you need to plan for it.Conventional wisdom calls for saving between 3 to 6 months of monthly expenses in an emergency account, but even this amount can seem daunting when there are so many other pressing bills to pay. So start small—and stick with it. Open a high-interest online savings account and start socking away, say, $25 to $50 a paycheck, by having the funds automatically deposited each pay period. Then once a year, or sooner if your cash flow improves, increase that amount steadily until your savings would cover at least 3 months of expenses. Using an online account and cutting up your debit card to avoid easy access to the funds will help you avoid the urge to splurge.

Not Saving for Retirement Yet? Start



With your short-term financial cushion in place, it’s time to think about long-term savings. Younger workers are notorious for putting off saving for retirement early in their careers. In fact, a full one-third of workers aged 25 years and under do not contribute to employer-sponsored retirement plans, and only 4% of young workers are maxing out their workplace retirement plans, according to a recent survey by the tax-information publisher CCH Inc.

This is especially true for younger physicians and couples struggling to repay enormous student loan debt. Most do not realize, however, that even meager retirement savings in the first few years after medical school can contribute substantially to their retirement nest egg down the road. By the time retirement rolls around, they will have missed out on a lifetime of compounding.

The retirement age for those born after 1960 is 67, so a 27-year-old fellow has 40 years to build a nest egg before he or she is eligible for full Social Security benefits. For example, socking away $5000 a year over 40 years, with a relatively conservative 6% return, will generate savings of $871,667. But if you postpone retirement savings in just that first year alone, your account would end up with $51,429 less.

Again, if you’re struggling financially and even saving $5000 a year pre-tax seems too steep, try at the very least to contribute enough to get your employer’s 401(k) matching contribution. It doubles your return on savings before you even begin investing.

Thinking About Raiding Your Nest Egg? Stop



If you have already begun contributing to a retirement savings account—on your own with an individual retirement account (IRA) or a Roth IRA, or through your workplace’s defined contribution plan, such as a 401(k)—the temptation to tap into the savings to make ends meet may be strong. Nearly 1 in 5 Americans admitted raiding their retirement accounts during the past 12 months to cover household expenses, according to a recent report by consumer finance site Bankrate.com. Even worse, 60% of young workers cash out their 401(k) when changing jobs.

If you are considering tapping your retirement savings, don’t! After getting hit with taxes and penalties, you’ll end up with roughly 70 cents on the dollar. And as with the example above, spending even a few thousand dollars in savings early in your career can have dire consequences when you’re ready to retire. In fact, some may find themselves unable to retire because their savings fall short of their goals. Instead, search for other ways to cut back on spending and leave your tax-deferred retirement account alone.

By following these steps, and sticking with them—no matter how tough the going gets—you will shore up your finances, pay down your debt more quickly, and potentially save yourself thousands in interest costs.


Terri Cullen is managing editor of Physician’s Money Digest, a personal finance, financial news, and practice management resource exclusively for physicians. She has covered personal finance and financial planning topics for more than 15 years as an author and former writer and columnist for The Wall Street Journal.

This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
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woman writingIt seems that every year, the list of Accreditation Council for Graduate Medical Education (ACGME) requirements grows longer and more bewildering. That’s no surprise in oncology. Our patients are increasingly complex, our therapies are more numerous and more sophisticated, and the ACGME’s reach extends beyond medicine into patient safety, quality improvements, and understanding medical systems. In addition, there is the burgeoning list of required conferences, institutional demands, and the dawning of the electronic age, complete with electronic medical records, electronic admission, electronic discharge, electronic sign-in and sign-out, and electronic communication, all of which conspire to keep us at our laptops far longer than at the bedsides of our patients.

Add to this the stress of our clinical work. We try to satisfy the needs of our patients and their families, many of whom are facing life’s biggest crisis. They deserve more attention than our crowded and fragmented schedules will allow; this only heightens our stress. For the fellow, this stress can be still greater. There are the additional burdens of being less experienced, being less appreciated by families, struggling with difficult decision-making and poor outcomes, and managing the competing demands of patients, faculty, the fellowship program, and the fellow’s own family life.

Given the stresses and demands of our field, it is not surprising that the prevalence of burnout is high. Burnout is defined as emotional exhaustion, depersonalization (ie, treating patients as objects), and a low sense of accomplishment. However, there are many ways to maintain the deep satisfaction that comes with working with patients with cancer and their families and with our colleagues. Incorporating medical humanities into one’s medical practice and the fellowship curriculum is one such way. Medical humanities is simply application of history, literature, art, music, and other fine arts to the practice of medicine and the care of the patient.1

There is not much literature on this approach, particularly in oncology. Gilewski describes a forum for fellows at Memorial Sloan-Kettering Cancer Center that focuses on end-of-life care and the stresses of such care on fellows and other caregivers.2 Sands et al reported on a narrative training course, in which members of a pediatric oncology team wrote about their own personal experiences with their patients.3 The 19 participants in this course displayed improved perspective on their patients’ problems, higher empathy scores, and better teamwork.

‘Narratives in Oncology’ Seminar



In 2009, we introduced a seminar at the James P. Wilmot Cancer Center in Rochester, New York, titled “Narratives in Oncology,” which was designed for medical and pediatric oncology fellows and radiation oncology residents. Our goal was to introduce our trainees to literature, poetry, and essays in the lay press as well as in the medical literature that focus on the human side of patient care. We hoped that such literature would open the eyes of our fellows to a rich source of thought-provoking material on patient and physician perspectives on life, death, and medical care. We also hoped that discussion of these essays would stimulate dialogue among us about subjects we seldom discuss: what to tell (or not to tell) our patients, the challenges of communicating bad news, how to deal with difficult families, coping with loss, and our own personal stresses caring for so many medically and emotionally needy patients.The seminar was designed so that we would meet in a 1-hour session once a month for 6 months. The faculty preceptors and the fellowship director chose articles to review, and 1 week prior to each session 1 or 2 essays/articles were distributed to the fellows. We chose articles that provided the patient’s perspective and that highlighted common clinical dilemmas. For example, for our first session we read an essay by Stephen Jay Gould called “The Median Isn’t the Message,” which discusses how a patient might look at odds of survival very differently than would a physician.4 In another session, we read a Glamour magazine excerpt, “I Want My Life Back,” by Andrea Coller, a young patient with multiply recurrent Hodgkin lymphoma, and learned what it feels like to be 27 years old and go through intensive chemotherapy and how we physicians look from the perspective of a young adult. (It wasn’t pretty!)5 We read a painful essay called “Facing Our Mistakes” by David Hilfiker6 and watched Casey’s Legacy, a video of a physician who tearfully describes a mistake he made in caring for a child.7 For the last session, fellows were asked to write an essay about a moving interaction with a patient, and selected essays were read at that session.

The seminar was quite successful. Attendance ranged from 11 to 18 fellows and it was clear they had read the assigned material. Discussion was lively and almost all the fellows actively participated. Faculty preceptors guided the discussion, but little stimulation was needed to provoke conversation. Fellows frequently cited their own patient scenarios that related to articles we reviewed. They frequently brought up the unique aspects of being a fellow and dealing with stressful patient encounters. They cited such examples as not feeling comfortable with the attending physician’s communication skills, their own lack of experience when patients ask difficult questions, their discomfort when delivering bad news, and their unhappiness about knowing that, as a trainee, they cannot always speak freely. As the word spread about the seminar, we were joined by other faculty members, nurses, and nurse practitioners.

For the final session, fellows and faculty were asked to write a brief essay. One fellow wrote a moving piece about running into a very grateful couple in the grocery store and how he just could not remember who they were. He explained how embarrassed he was to have no memory of them. Was one a former patient? Were they bereaved family members? But at the same time, it made him realize that through his actions he can have a real impact on his patients’ lives. Another fellow wrote about her interactions with a demanding daughter, a hospital executive who tested the limits of the fellow’s patience. The fellow described how, tough as the executive in her power suit seemed, deep down she was scared of losing her mom, who eventually died of cancer. The fellow said that she knows how this feels because she, too, lost her mother.8At the conclusion of the seminar series, we formally surveyed the fellows for feedback on the course. Ten of the 11 fellows who returned the survey felt that the course was a useful part of their curriculum. The fellows “repeatedly cited the openness to discussion of issues that typically are not part of the traditional oncology curriculum, as well as the relevance of the specific articles chosen.”8 As one of the fellows said, the course “provided a forum in which we could discuss our experiences and explore difficult issues with others who have shared similar experiences.”8 Ten of the 11 fellows said the course had a positive impact on their interaction with patients, enabling them to have a more “humanistic approach,” be “more aware of patients’ feelings,” and hang on to empathy when it might otherwise have been lost. The majority of fellows felt that the writing exercise was useful, albeit difficult. It should be noted that 1 respondent did not find the course helpful at all; hence, a reminder that this is not an approach that is useful for everyone, and that we need to be sensitive to the needs of individuals who may choose to deal with patient care dilemmas more privately.

Overall, there was consensus among the fellows and faculty that the “Narratives in Oncology” seminar is a valuable part of the fellowship curriculum, and that the principles and practices we discuss can be incorporated into patient care, help to improve patient-physician communication, and make care of the patient with cancer more gratifying. As we move into year 2 of the seminar, we hope to expand to include other forms of artistic expression, such as art, music, and video, and perhaps expand our audience to other healthcare providers and other subspecialists.

*This article is adapted by the authors from: Khorana AA, Shayne M, Korones DN. Can literature enhance oncology training? A pilot humanities curriculum. J Clin Oncol. 2011;29:468-471.


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
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David N. Korones, MD, is professor of pediatrics, oncology, and neurology at University of Rochester School of Medicine and Dentistry in Rochester, New York. He is also a pediatric hematologist/oncologist and palliative care specialist.

Michelle Shayne, MD, is assistant professor of medicine and oncology at University of Rochester School of Medicine and Dentistry in Rochester, New York. She is a medical oncologist with expertise in breast cancer and is the Hematology/Oncology Fellowship Program director.

Alok A. Khorana, MD, is associate professor of medicine and oncology at University of Rochester School of Medicine and Dentistry in Rochester, New York. He is a medical oncologist with expertise in GI oncology and thrombosis.


References

  1. University of Rochester Medical Center. Medical Humanities Web site. http://www.urmc.rochester.edu/smd/medical-humanities. Accessed May 8, 2011.
  2. Gilewski T. The art of medicine: teaching oncology fellows about the end of life. Crit Rev Oncol Hematol. 2001;40:105-113.
  3. Sands SA, Stanley P, Charon R. Pediatric narrative oncology: interprofessional training to promote empathy, build teams, and prevent burnout. J Support Oncol. 2008;6:307-312.
  4. Gould SJ. Full House: The spread of Excellence From Plato to Darwin. New York, NY: Harmony Books; 1996:45-56.
  5. Coller A. Non-fiction contest winner: I want my life back. Glamour magazine Web site. http://www.glamour.com/magazine/2008/05/essay-winner-surviving-cancer. Accessed May 11, 2011.
  6. Hilfiker D. Facing our mistakes. N Engl J Med. 1984;310:118-122.
  7. Boyte WR. Casey’s legacy. Health Aff (Millwood). 2001;20:250-254.
  8. Khorana AA, Shayne M, Korones DN. Can literature enhance oncology training? A pilot humanities curriculum. J Clin Oncol. 2011;29:468-471.


About 13,300 new cases of acute myeloid leukemia (AML) are diagnosed yearly, and nearly 9,000 deaths occur in the United States. It is a rapidly progressive disease that results in the accumulation of immature, functionless cells in the marrow and blood, leaving the body unable to fight infections or produce enough normal red blood cells, white blood cells, and platelets. The disease primarily affects people age 60 and older and is the second most common form of leukemia in adults.

Almost two-thirds of AML patients over age 65 do not receive treatment for the disease because standard therapy can be risky. The traditional, harsh chemotherapy approach is difficult for anybody, but particularly so for older patients who don’t tolerate the “thunderbolt” of intensive chemotherapy well. Many patients are judged not to be candidates for any treatment at all because they likely would not survive the traditional, harsh chemotherapy approach. Furthermore, the AML seen in elderly patients is also more likely to have evolved from a prior hematologic disorder, and the leukemic blasts are more likely to have poor-risk structural and numeric cytogenetic abnormalities and expression of multidrug resistance protein (MRP1). These blast features have been associated with greater resistance to therapy, which makes the response rate lower, the risk of relapse higher, and the cure rates lower. On average, such patients survive only 1.7 months after diagnosis.

The development of a less toxic therapy has enabled such patients who would have never received treatment for their disease to actually benefit from prolonged remissions with improved quality and length of life, without paying the price exacted by intensive therapy regimens.

Researchers at Washington University School of Medicine in St. Louis and collaborating institutions found that decitabine might benefit older AML patients by reactivating genes that cancer cells turn off. It works by reducing the amount of DNA that is marked with a chemical tag called a methyl group. Scientists think that the excess methylation found in cancer cells inactivates genes that normally suppress tumor development.

The study published in the Journal of Clinical Oncology by Cashen et al was conducted at three sites: Washington University School of Medicine; the University of California, Los Angeles; and the City of Hope National Medical Center in Duarte, California. The researchers tested decitabine in 55 AML patients with an average age of 74 years. All patients received the same decitabine dose for five consecutive days every 4 weeks until their disease stopped responding to the drug and began progressing or until an adverse event occurred to prevent further participation. By comparison to standard chemotherapy and stem cell transplantation, the treatment was considered a low-intensity treatment and was more tolerable for elderly patients, especially those with accompanying medical problems. In 24% of the study participants, blood counts and bone marrow returned to normal, which is considered a complete response. It took 4.5 cycles of decitabine treatment on average to achieve a complete response. In those with a complete response, average survival time was 14 months. For all study participants, average survival time was 7.7 months. Treatment-related adverse events included low blood counts (red cells, white cells, and platelets), infection, fever, and fatigue. Almost half of the study participants had at least one serious adverse event. Seven patients discontinued treatment, and three patients died as the result of adverse events. In a different study, we looked back at our institution experience with decitabine as initial treatment for older patients with de novo AML and MDS-related AML and found that 45 patients met the criteria. About one-third of patients achieved complete response (CR/CRi) with maximum of 5 cycles of therapy and durable response of 13 months. The median overall survival for the whole cohort was about 9 months and for CR/CRi group was 19 months. Day 100 mortality was about 20%. The length of hospital stay averaged 20 days. Cytogenetics had no impact on response. No documented invasive infections were found, and only fatal bleed was reported.

Decitabine seems to have acceptable response rate, side-effect profile, and short hospital stay duration. At the same time, we have to wait for the results of further trials of decitabine to have a better estimate of the response rate and survival outcome compared to other low-intensity options for older adults.


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
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As a practicing pediatric oncologist at an academic institute, every morning begins with optimism and a quest to win the day. As I walk into my office, I see my nurse flagging me down to sign a bunch of papers including procedure orders, chemotherapy orders, and home-health laboratory test orders. I get a hot cup of coffee and take time to catch up on emails, communications from consultants, referrals, and patient reports. Next, I review the children admitted through the inpatient service and their blood test results from overnight. Often, this is also the ideal time to review updates on new clinical developments in oncology, or to read up and educate myself on clinical dilemmas and ongoing research. This helps to prepare me for my resident education on clinical bedside rounds.

Children admitted to our facility, a pediatric specialty service, are cared for by resident staff at night, in consultation with practicing oncologists. In the morning, I attend the inpatient service bedside rounds and discuss the children’s care with the resident staff. Academicians at most institutions have teaching responsibilities that may occasionally include additional lectures for residents or medical students. Investing time in teaching the residents often rewards me with fewer tortuous night calls, since the residents are usually better prepared to handle anticipated complications as a result.

Pediatric oncology is a stimulating field with a multitude of research opportunities and discoveries every day. The prognosis in several childhood cancers has improved tremendously thanks to novel drug therapies, drug delivery systems, and protocol-driven treatments that have helped standardize therapy across the U.S. and improve results. It is intellectually stimulating to discuss ideas and diagnoses with other consulting services or experienced colleagues in my field across the country. Doing so enhances the quality of care I provide and helps broaden my perspective and differential on a given case. Be prepared to be humbled, however, as discussing clinical experiences with other physicians makes you vigilant and allows for fewer errors. Also, while consulting services can add to the quality of care you provide, remember to advocate for your patients and keep possible diagnoses in perspective before heading down the path of ordering multiple tests or scans.

For example, I once saw a 6-year-old girl with Cushing’s syndrome and a hepatic mass suspected to be hepatoblastoma. The mass showed calcification on scans and her alpha-fetoprotein level was normal. The child had severe hypertension consequent to paraneoplastic syndrome, preventing us from taking her to surgery. We insisted on a biopsy before proceeding with any chemotherapy, although the majority of the consultants were convinced it was a hepatoblastoma. Ultimately, when the mass was excised, it was a rare “nested stromal tumor” of the liver.

Following up on your patients when they are admitted to another service, such as surgery or intensive care, helps you stay abreast of events and changes in their status. Being familiar with a child’s long-term medical illness also helps protect him or her when you advocate for their care. It is key to follow up on the children and their several tests as the day progresses, as each update has the potential to alter treatment plans that were made earlier in the day based on certain assumptions. I head to the hospital in-service as I begin the day. My resident team, pharmacist, and nurse practitioner are waiting and ready. We spend the morning seeing and discussing our inpatients. A simple case of scheduled chemotherapy, a sick child with fever and neutropenia, or a more involved case of a newly diagnosed child with acute leukemia or a new solid tumor keeps us engaged. The morning passes in a flash as we manage each issue and care plan. Some of the most enjoyable moments involve the exchange of knowledge between myself, residents, pharmacists, nursing staff, child life services, and social services because it helps me render comprehensive care for my patients. Unfortunately, not every day is a breeze. We have challenging days where we spend considerable time discussing and resolving more complicated issues such as end-of-life care, palliative therapy, pain control, and optimal quality of life for our less fortunate children with terminal disease.

Communicating with parents and children is a skill. It is also a predominant part of my job description and of my professional day. Training in how to communicate bad news and discuss end-of-life care or options such as pain relief, hospice care, and resuscitation choices with parents is often initiated during fellowship and fully mastered in practice when you are responsible for the care of each child whom you manage. Prudency is in realizing that each situation is unique, showing true empathy to the needs of children and parents, and being prepared to listen. As much as you would like to be outlining plans, taking the time to listen to the concern of a child or parent can help get you through difficult situations. Remember to include the children in decisions and discussions.

Next, I head to the outpatient clinic and infusion center. The aura is lighter and less somber. Scheduled outpatient chemotherapy follow-up, outpatient procedures like spinal tap with instillation of medications, bone marrow procedures, postchemotherapy follow-up, and health surveillance for our cancer survivors fill the afternoon. Seeing a cancer survivor cheerfully return to the clinic with tales of school or summer vacation, or witnessing young teens recount their camp experience or academic success brings true satisfaction. Those days, I succeed in my quest to win the day.

I end the day with some more paperwork, including billing for services rendered. Coding and billing is an integral part of practicing medicine. Detailed and time-intensive care planning is often accompanied by paperwork, and an efficient team of personnel including nurse, patient liaison, social worker, and home-health services is an invaluable asset. I check back on issues pending for the day and make sure my hospital patients are well cared for before I head home for the night. While every day is not a winning day as an academic oncologist, optimism can provide hope for winning every day!


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
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I was drawn to medical oncology because it combines science and humanism. I am witness to my patients’ most vulnerable, challenging, and genuine moments. That said, the most lasting memories I have from internship involve the fear, shock, and failure that I felt as I cared for ill or dying oncology inpatients. I decided that if I was to become a medical oncologist and be entrusted to care for patients with a life-threatening illness, it was my responsibility to be as well trained as possible in physical symptom management, communication, and nonphysical distress. I would follow them from diagnosis to either cure or death and never abandon them. Training in palliative medicine as well as medical oncology felt like honoring the saying: “To cure sometimes, to relieve often, to comfort always.”

I am just finishing up a 2-year medical oncology fellowship after completing a hospice and palliative medicine fellowship and will be starting as an attending in both GI oncology and palliative medicine this summer. This dual training is becoming a much more frequent occurrence with medical oncologists,1 and some oncology training programs across the country have integrated medical oncology/palliative medicine into a 3-year ACGME-accredited fellowship similar to hematology/oncology. This article aims to recount my experience in this dual training, including the challenges I faced and the benefits I reaped. Hopefully, this will help better inform oncology fellows regarding whether or not this training suits them.

Benefits

I will never forget visiting a hospice patient as a palliative medicine fellow and talking with his wife. She felt their oncologist was wonderful, knowledgeable, and connected with them, but he had abandoned them since hospice enrollment. He didn’t call and was no longer involved in decision making. And believe me, there were decisions to be made. Should they continue tube feeds? What were the benefits and risks? What should they do about his secretions that were severely impacting his quality of life? When and how should they tell other family members? Most likely the oncologist “abandoned” his patient because he just didn’t know or have experience in caring for patients while they were dying. Just as I can advise the right chemotherapy regimen for treating metastatic cancer, I can also assure symptoms are managed right up until death or assure a patient is sedated if all other conventional methods fail.

This continuity of care is vital to helping patients transition as their cancer progresses. I have known them for months to years and have learned and elicited their values and goals throughout their course of cancer. They trust me because I know them intimately, what they have been through, and have fought beside them during their battle with cancer. Therefore, when I tell them we have come to a point where their life would be “better” (based on their own definition) without further chemotherapy, they believe me. They can accept their fate and begin to find other sources of hope to sustain them for the time they have left.As oncologists, we gather to discuss challenging clinical quandaries in conferences, but we do not discuss how emotionally draining it is to care for certain patients or families and grieve their loss. In hospice and palliative care, emotional coping and strategizing is a crucial piece of the multidisciplinary meeting time with chaplains, social workers, psychologists, nurses, and physicians. Oncologists are prone to burnout2 and having the experience of a true multidisciplinary support network in cancer care and learning emotional resilience3, such as that learned in hospice and palliative medicine, can help improve job satisfaction and prevent this burnout.

Solid malignancy services can be heavily burdened with patients who have suffered complications from chemotherapy or their cancer. A palliative medicine training can assure that I can always make an impact on the patient’s care and on the residents’ and fellows’ education whether I am titrating medications to relieve refractory nausea or pain, navigating tricky goals of care issues with challenging families or young patients, or helping coworkers and residents grieve their dying patients.

Lastly, improved end-of-life care, including decreased spending and better symptom management, are hot button topics. In an era when research money is tight and innovation is valued, having insight into strategies that could reduce aggressive care at the end of life while respecting patients’ values and goals could allow for a successful, independently funded research niche.

Challenges

One potential issue is the worry that oncologists trained in palliative medicine may not be as aggressive and would encourage patients to seek comfort care despite there being further therapy available. Interestingly, after my palliative care training, a mentor has joked that I am far more aggressive in some situations than she would be. For example, after getting a sense of the value a patient places on quality of life and extension of life, I explain how potential therapies may impact each of these points. If a patient chooses an aggressive therapy in order to reach a goal that I think is possibly achievable despite significant potential toxicity, then I will likely treat. It is one thing to treat aggressively as a rule and another to tailor your aggressive therapy based on a patient’s prognosis, values, and goals.

A second challenge is whether a physician can wear both an “oncologist hat” as well as a “palliative medicine hat.” The answer varies depending on the situation. Many of my oncology patients are thrilled that I am trained in palliative medicine because they feel assured that no matter what happens with their cancer, they will not be left to suffer and will have guidance if they have to face the dying process. On the other hand, patients who view palliative medicine as equivalent to hospice may not trust me to make aggressive decisions for them. In addition, I need another practitioner to “share the load” when caring for patients who have extreme and/or refractory symptoms. Lastly, I had not anticipated just how difficult it would be for me to watch a patient progress from diagnosis to death. A 50-year-old man with metastatic pancreatic cancer was admitted to the inpatient hospice unit for pain and delirium management 8-9 months after I had met him, a healthy-looking man. It had been a few months since I had last seen him, but when I walked into his hospital room I had to leave and check that I had entered the right room. He was no more than skin and bones. I felt like a proxy family member watching from beginning to end as the cancer consumed him. In that moment I realized, at least in part, why medical oncologists may not be fully present during a patient’s death… it is very, very hard to bear witness to. I feel lucky that I have been formally palliative medicine-trained, so those emotions don’t keep me from being there for my patients and their families at the end.

On a practical note, a hospice and palliative medicine fellowship after oncology training will break up your oncology experience by a year and may make restarting this oncology career more challenging. This must be weighed against the depth this training adds to your experience.

Conclusions

Medical oncology is a complex field, rich in basic science, mechanism of actions, and cutting-edge clinical investigation but also physical, emotional, social, and existential distress for the patient. The field of hospice and palliative medicine is well suited for training oncologists in the science of compassion and communication, which can significantly improve the experience of cancer patients. A push for some palliative medicine training in all oncology fellowships would be extremely appropriate, but for individuals who feel this aspect of oncologic care is what gives them job satisfaction and is an essential part of their practice, I would strongly recommend a year-long ACGME accredited hospice and palliative medicine fellowship. I sleep well at night.


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
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Navigating the First Year of Fellowship

For an incoming first-year hematology/oncology fellow, July 1st is when you are once again the new kid on the block. Whether you are starting a fellowship at your home institution or in a new city, July 1st marks the beginning of the final phase of training that we have worked so hard to arrive at. Although completing fellowship at your home institution may give you a leg up on finding the bathroom, it will not, unfortunately, lessen the learning curve inherent to the most challenging year of training. And although you may initially still perceive yourself as a third-year resident mastering the skills of hypertension and diabetes management, to your patients, you are now their oncologist.

The field of hematology/oncology is unlike many other medical sub-specialties in that there is very little exposure to it during residency. During the earlier part of your first year, you will rattle-off chemotherapy side effects and tell patients and their families “what they can expect.” At that point, however, you may barely be able to pronounce the drug, let alone provide patients the knowledge they need to prepare for toxicities. I spent my first year of fellowship studying the “hallmark” articles and memorizing National Comprehensive Cancer Network (NCCN) guidelines. I imagined myself going home after work to sit and read about each of my clinic patients. As the demands of first-year fellowship became obvious, however, I realized that this was not how I was going to gain my knowledge. Between learning to write orders, performing bone marrow biopsies, and running the oncology services, there were many days when I was glad to have an opportunity to eat lunch, let alone absorb the latest Journal of Clinical Oncology article.

Most of the knowledge I attained during the first year of fellowship came from interacting with patients and learning how to take care of them. As you make your way through the first year, you’ll realize that you are no longer memorizing a list of side effects, but rather explaining to your patients the toxicities that you have actually witnessed. As the initial feelings of being overwhelmed wear off, you will slowly become comfortable with this “new language” of oncology.

As I entered fellowship, I prepared myself for the academic challenge and even cleared my weekends in anticipation of spending most of my time at the hospital. I studied NCCN guidelines and tried to read everything that I thought would prepare me. It was the emotional toll of learning how to be an oncologist, however, that proved to be the most challenging. No matter how hard I searched, I could not find an algorithm that explained how to tell my 21-year-old patient and his family that his cancer had progressed and he was dying. This part of the job did not become easier for me emotionally during the first year. As I learned the natural history of diseases, however, I became more comfortable with these difficult conversations.

What surprised me about these encounters was the fulfillment and great satisfaction I found in supporting my patients through their treatment journey, whether it meant receiving more chemotherapy or making the difficult decision to transition to hospice. I was fascinated by the fact that cancer is the ultimate equalizer—it disregards race, gender, and socioeconomic status, and gives patients the same hopes and fears. As the year progressed, I grew to appreciate that fact that although the victory of remission is obvious, the less obvious victories such as controlling pain or nausea truly impact our patients’ quality of life.The first year of fellowship was more challenging for me than any other time during my training. At this point in our lives, many of us have families and other obligations that may seem incompatible with being a first-year fellow. After finishing clinic most days, I would frantically run to to pick up my two-year-old daughter from daycare by 6:00 pm. While balancing family and fellowship is not easy, it is possible to juggle both with careful planning, support from your family, and prioritization. In my experience, a personal support system—from a spouse, family member, friend, or coworker—is crucial during the first year of fellowship. Caring for patients with cancer requires you to give yourself both academically and emotionally, and having a support system is very important as you learn how to handle the death and dying of your patients.

Another key to surviving your first year of fellowship is relying on the second- and third-year fellows for help as you navigate the first few months. Although senior fellows may seem like they have everything figured out as they diligently work on research projects and quote data from hallmark articles, remember that they started out just like you. The worst mistake you can make is not asking for help when needed. The senior fellows and attendings would rather be asked the important questions than have serious mistakes made.

As you settle into your first year, you will become comfortable performing bone marrow biopsies and will not be scared every time your pager goes off. You will inevitably become more comfortable with the never-ending thrombocytopenia consults and will start thinking about your future as an oncologist. Finding a meaningful mentor that understands your clinical and research goals will be important to establish early. Many times, these relationships happen naturally as you get to know the faculty and learn about their interests. On the other hand, you may find yourself intrigued with a certain research topic and need to seek out people in the department. Either way, a good mentor will help develop your interests and open up opportunities.

It is now July 1st of my second year, and although I can fully recognize how much I have learned about the science of oncology and the art of treating patients, I still cannot pronounce all of the chemotherapeutics and need to look up the staging systems of some malignancies. After so many years of learning general medicine, you have finally arrived at your specialty of choice. As you battle your way up the learning curve, it may feel at times that you are simply trying to survive. Rest assured that you will approach July 1st a resident, but leave your first year of fellowship as an oncologist.

Sheetal Kircher, MD, completed her first year of fellowship at Northwestern Memorial Hospital in June 2010.

Solidifying Clinical Knowledge

By Josephine Feliciano, MD

During my first year of fellowship in a combined hematology and oncology program, I spent much of the year trying to balance my clinical obligations with my life outside of the hospital. My first year involved 11 months of inpatient ward training in malignant hematology, solid oncology, and stem cell transplant rotations, interspersed with inpatient consult in benign hematology and oncology. In addition to the rigorous inpatient schedule, I also spent three half-days in disease-specific outpatient clinics. While the learning curve was steep, the bigger challenge was balancing work demands with a husband and toddler at home. I anticipated that the second year of fellowship would be the time to catch my breath, and in many ways, this was true.Although I felt an incredible sense of relief after the clinical marathon of first-year fellowship, my second year has been busy in a different way, with a shift in focus toward pursuing clinical, translational, or basic science research. The daily schedule during my second year provided me with a mental and physical breather. Holding a pager six days per week during the first year created a mental “bond” to the hospital; even when I was physically away from the hospital, it was hard to truly “exhale” and reflect. During my second year, I finally felt that I could exhale. Upon reflection, it became clear that although the first year of fellowship was intense, I had gained an immeasurable amount of knowledge in a short time. I also gained a sense of confidence and pride knowing the myriad challenges I overcame. As a second-year fellow, I was able to counsel the incoming first-year fellows and reassure them that the first year would not only be survivable, but also an incredible chance to lay a strong foundation for their career. Perhaps one of the biggest distinctions between the first and second year is that the second year was a time to solidify my clinical knowledge, build my resume, and prepare for the process of applying for jobs, which will begin relatively early during the third year.

Much of the second and third years of fellowship are designed to allow time for research pursuits, particularly for physicians who are interested in an academic career. For those who hope to pursue a career in academic medicine, most agree that a successful and productive second year of fellowship begins with identifying the right mentor. Ideally, mentorship should begin during the first year of fellowship, although expectations for research productivity should be modest. If nothing else, establishing a mentor or network of mentors during the first year and meeting on a regular basis can help create the framework for a productive relationship and enable you to “hit the ground running” at the beginning of your second year. This is especially true for those who begin fellowship with a particular disease focus or interest, or who develop one early on. An ideal mentor is someone whom you respect; who is experienced and academically successful; and who is approachable, available, and invested in your own success.

Many mentors may have projects that are near completion or in various stages of development, and a fellow is the ideal candidate to complete them. Faculty are usually very receptive to fellows who are interested in helping complete projects. This can be an opportunity for fellows to gain skills that will be applicable in the future, even if their disease focus or interests change with time. Such a situation is a “win-win” for both parties—the mentor benefits from the outside help, while completed projects can help fellows “build” their resumes and provide them with an opportunity to present at conferences and meetings. Although projects that are initiated during fellowship often take years to complete and may continue beyond fellowship, they can provide fellows with valuable skills that can transcend their professional career.For fellows interested in pursing a career in academic oncology, the second year of fellowship is an important time to consider applying to programs such as the American Society of Clinical Oncology (ASCO)/American Association for Cancer Research or the American Society of Hematology (ASH) Clinical Research Training Institute workshops to gain further skills useful in clinical research. These workshops focus on teaching fellows and junior faculty the various methods of clinical trial design and technical writing, and tend to take place in July and August, with application deadlines as early as December. If you are interested in applying for these programs, it is helpful to know about them ahead of time in order to identify a project for the application process. Furthermore, the second year of fellowship is a time to consider applying for fellow training grants that are available through various organizations, such as the ASCO Young Investigator Award or the ASH Fellows training awards. This is also an ideal time to begin projects that could be used when you apply for these awards during the third year of fellowship.

The second year provides plenty of time to broaden your knowledge and solidify everything learned during the first year. Most fellowship programs have numerous conferences and tumor boards that can be more consistently attended during the second and third years. During your first year of fellowship, it can be a challenge to attend all of the didactic opportunities that are available while simultaneously balancing your clinical responsibilities. The second year may also provide more time to read the primary data in order to support your clinical decisions. Most fellowship programs have physicians continue in one or more clinics during the second year of fellowship while scheduling less inpatient service. This is crucial for developing and strengthening the clinical skills necessary for going into practice after fellowship, especially for those who may be interested in clinical practice.

Whether you are pursuing an academic or clinical position post-fellowship, being productive during your second year is important. The time to start applying for jobs comes sooner than imagined (or at least sooner than I had imagined). Most faculty advised me that for academic jobs, resumes are sent as early as July through October. Since the job search begins early in the third year of fellowship, the latter part of my second year was also dedicated to updating my resume, completing projects that could be included in my resume, and asking for letters of recommendation and references. I personally chose to start the process quite early because I knew that I would be on maternity leave when I would need to send resumes to various institutions. If you know very early which particular institutions or geographic locations you prefer, the annual ASCO meeting is a good venue to begin to make some contacts for the job search.

While the first year of an oncology fellowship may be the most physically and emotionally demanding, the second year is crucial for training and preparing physicians for their career post-fellowship. For me, the second year of fellowship was a time to really get involved with clinical research to prepare me for an academic career and improve my skills as a clinician.

Josephine Feliciano, MD, completed her second year of fellowship at Northwestern University Feinberg School of Medicine in June 2010.

A Light at the End of the Tunnel

By Sairah Ahmed, MDCongratulations—you’re a third-year fellow and there’s finally a light at the end of a long, dark tunnel. Suddenly “the real world” is a tangible reality. After years of training, you are entirely capable of dealing with the science of medicine, from looking up NCCN guidelines to treating solid and hematologic malignancies, from writing review articles to talking to patients about goals of care. An acute leukemia at 3:00 am no longer strikes fear in your heart. But nothing in training has prepared us for the next steps—looking for a job, navigating contracts, and trying to decide where you will be happiest for the rest of your professional career. Scary thought, huh?

One of the first decisions to be made is whether to pursue a career in academia or private practice. While some decided this long ago, the choice isn’t so black and white for the rest of us. So why choose private practice over academia? The obvious answer is monetary compensation, but ultimately, it’s about personality. Being part of a practice provides a great deal of control over where, when, and for whom you work. You are the master of your fate and captain of your soul—how many times has that happened before? After years of self-discipline, finally what you want matters; how much it matters may be up for debate!

On the other hand, why choose academia over private practice? Teaching, clinical and translational research, and subspecializing in a specific malignancy are all included in the mix, but again, it’s personality. Those who choose academia like to be constantly challenged and crave the feeling of juggling several balls at the same time. They focus on multiple problems while trying to advance scientific knowledge, always hoping that one of those balls won’t go splat at the wrong moment!

Below is my advice for navigating the details after the private practice vs academia decision is made.

Private Practice: Once the geographic area is decided, start networking with friends, colleagues, and physicians in the area—both in other specialties and your own. Determine which practices you’re interested in, whether they’re hiring, and send out interest letters and your curriculum vitae (CV). An extremely important asset are your faculty; the connections they have within the community and across the country is an invaluable tool—USE THEM!

By September, actively gather information about where to apply, and by November, send out CVs and set up interviews. Winter and spring will be an interview merry-go-round. Ask the questions you never asked in residency or fellowship interviews: What is the base salary? Are there bonuses? How does partnership work? How is vacation decided? What is the call schedule? What are the details of the non-competence clause? The list is endless and will reflect what is most important to you. Remember to trust your instincts and pay attention to the intangibles—all the things that make you love your work environment. Don’t underestimate the importance of these factors.

Before accepting the final offer, make sure a lawyer reviews the contract. The devil is in the details, and your responsibilities should be clear prior to signing on the dotted line.

Academia: Geographic location, a specific research interest, or treating a particular tumor type may drive your choice. Sometimes having more than one goal makes it harder to find a perfect fit. Again, talk to faculty, as they will have the inside track on open positions or cancer centers that are hiring. Former fellows and colleagues are great resources to tap as well. Use ASH and ASCO to network; it may lead to interviews later.In September, start sending out letters of intent with CVs attached. Don’t limit the search to institutions with open positions—include all institutions you’re interested in. Sometimes the job you want isn’t being offered yet, but it never hurts to ask. Gently having faculty mentors call or email can also help open the door to an interview.

Academic interviews usually include a job talk, which may entail discussing the clinical research you’re involved in or detailing the time spent in a basic or translational lab. THE most important aspect of the talk is your grasp of the subject matter. From the mundane to the most technical, you want to impart to the audience how intimately involved in the project you were, not that the post-docs in your lab did most of the work and you can’t tell the difference between a Western blot and a microarray. If you’re discussing a clinical project, know how the information was collected and how to interpret the statistics, and be able to explain the hypothesis behind the study. No one expects entirely independent data; however, if you can’t intelligently discuss your project, it’s very hard to be taken seriously. Confidence and the ability to answer queries serenely will make you stand out from the rest of the crowd.

The tricky part is making sure the job they offer is the one you want. Is there enough research time? How does the tenure track work? How many clinics during the week? How many service months? How is salary determined (RVUs vs grants)? And finally, if your heart is set on lung cancer but the open position is in lymphoma, are you willing to compromise? Once more, get a lawyer to review the contract, although most institutions have basic stipulations that are set in stone.

Last but not least, if you’re slightly insane, follow me down the path to yet another fellowship. There are a few options if you haven’t tired of a training salary and want to attain PGY-8 status. I chose a stem cell transplant fellowship, but there are others in transfusion medicine or pharmacogenomics. The application process was circumspect compared to a job hunt or even prior training positions. There are a very finite number of institutions that offer these positions and interviews are the same flavor as before, just longer.

In the words of George Burns, “I look to the future because that’s where I’m going to spend the rest of my life.” After the stress and confusion wear off, you’ll realize that the hardest part is over and now begins the start of your career!

A few words of wisdom for incoming first-year fellows:

• This is toughest year of training you’ll ever experience. You will learn an immense amount, but there will be days (lots and lots of days) that you want to give up. Don’t! It will get better and you will sleep again.

• Ask questions. You’re in fellowship to learn; the aim is for you to be taught and trained well.

• Remember internship and the mantra “Eat when you can, sleep when you can, and just get through today.” Relearn the mantra.

• It’s hard to tell people they are dying and you can’t change that reality. Burnout is real and you have to avoid it. Use everything you can to keep centered— family, friends, co-fellows, sports, alcohol…ok, I was kidding about the alcohol! But expect the emotional roller coaster; we all get on the ride but aren’t ready for the sudden fall.

Understand that difficult patients (and families) are often a manifestation of fear and loss of control. It’s seldom personal and they don’t really hate you. Avoid saying, “I understand what you’re going through” unless you’ve experienced the same. Try, “I can’t imagine what you’re going through,” and then just listen….a lot.Sairah Ahmed, MD, completed her third year of fellowship at Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, in June 2010. She is starting a stem cell transplant fellowship at MD Anderson Cancer Center in July 2011.


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
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Since the time of Hippocrates, practicing the art of medicine has involved the passage of knowledge and experience from one generation of practitioners to the next. Unlike other fields of study in the sciences and humanities, the process of educating physicians tends to involve a much more intimate relationship between the instructors and trainees. While the earliest years of medical school education are usually carried out in the classroom, there is an early transition to education in small teams, often led by the attending and residents. During the latest years of residency (most often during subspecialty training), the relationship between instructors and trainees gains sufficient permanence; instructors will usually know the trainees well enough to provide detailed guidance in educational and career development. In this aspect, the fellowship training period provides the most intimate one-on-one training in a clinical setting. And, perhaps, the most developed form of this relationship is that of the mentor and mentee.

What is mentorship?

Mentorship has been defined as “a dynamic, reciprocal relationship in a work environment between an advanced career incumbent (mentor) and a beginner (protégé), aimed at the development of both.”1 Strictly speaking, “mentorship” indicates a personal developmental relationship in which a more experienced (often more senior) individual helps a less experienced or knowledgeable individual who is usually newer to that particular organization. Mentorship should not be confused with similar methods of imparting knowledge, such as tutoring (or instructing, which is the dissemination of knowledge), coaching (which dwells on the development of skills), or serving as a role model (in which one provides examples of specific behaviors). Mentorship incorporates these aspects, but builds upon them with the addition of guidance in career development.

While formal mentorship programs were first launched in corporate America in the 1970s as a way to develop junior staff, they weren’t officially introduced into medical education until the 1990s.2 The mentoring process is now considered to be an essential responsibility of medical school faculty in an effort to enhance the educational mission, and is clearly helpful in encouraging career satisfaction and success.3,4 Despite its inherent added value, mentorship is often not deemed important by the institution (such time is not billable, after all) and thus, is often beset by the competing demands of clinical care and research on both the mentor and mentee. Although not all institutions may have a formal mentorship program in place, it should not deter fellows from being proactive and seeking out mentors in areas of common interest.

The benefits of having a mentor

Mentorship can accord significant potential benefits to fellows, such as providing access to networking, which may be one reason why those who are mentored tend to do well in institutions.1 Multiple studies have shown that having a mentor has a positive influence on overall career enhancement; one study even demonstrated that those who received mentoring were more than twice as likely to receive a promotion.5 Mentoring has also been associated with improvements in research, teaching, and patient care.6A mentoring relationship can be very helpful when deciding on which specialty and subspecialty to pursue. Two of the major decisions that fellows must make are whether to specialize in hematology, oncology, or both; and whether to pursue a career in academics, private practice, or industry. The two decisions are actually closely related. For example, if one desires to enter into a private practice setting, it would be reasonable to become double board certified in hematology and oncology. While there is a move among larger practices to develop some tumor or disease-specific expertise and local recognition, most private practitioners must still function in a fairly general manner.

By itself, hematology as a discipline is more or less restricted to academic centers and larger hospitals, especially nonmalignant hematology. If such arrangements are made between a private practice and either a university or consortium of practices, it may also be possible to participate in “bedside” teaching of students and residents, as well as larger phase II (proof of concept) and phase III (confirmation of activity or benefit) trials, although there may be very little time, infrastructure, or opportunity to initiate and support one’s own clinical research interests. On the other hand, a career in academic clinical research affords many of these opportunities, though usually with somewhat smaller patient loads, protected time to carry out research and teaching, and a lesser amount of financial compensation than seen in private practice.

Those who are more interested in basic research will find an outlet in either academics or private industry, usually with a pharmaceutical company. However, the options in industry also involve the initiation and conduct of clinical trials (though it usually involves little or no patient interaction), while also requiring more than a little business savvy during the process of drug development. Regardless, a mentor can help fellows choose a career track by assisting them in identifying and focusing on their strengths and academic interests, while constructively illustrating any potential areas of weakness and developing methods to seek improvement.

A reciprocal relationship

Mentorship is a bidirectional relationship, with benefits accrued by the mentor as well as the mentee. For example, mentoring enables an individual to demonstrate leadership among his or her peers. The very act of providing personalized guidance in a field in which the mentor is passionate about is invigorating and often positively stimulates the mentor’s teaching and research efforts. Finally, there is the intangible satisfaction that one achieves by the act of “giving something back” and seeing one’s protégé succeed, based in part on the mentor’s efforts. In this respect, established faculty (especially those in mid-career or later) should also actively seek out fellows and newly-minted junior faculty and work closely with them to provide guidance that will enhance not only the careers of their charges, but their own as well.

Leaving the lines of communication open

Fellows must remember that mentorship is a process, not an end in itself. A successful relationship with a mentor may last a lifetime, and he or she will often be willing and able to offer insightful guidance long after the fellowship has been completed. Such relationships can provide myriad benefits to the fellow in the development and direction of their early career, providing access to resources, experience and insight that would not readily be available to fellows on their own. Ultimately, having a mentor can be an invaluable resource for young physicians and provide a measurable boost to their career development and overall success.Dennie V. Jones, Jr., MD, FACP, is a professor of medicine; medical director of the New Mexico Cancer Care Alliance; medical director of the Clinical Protocol, Data Management and Informatics Group; and chief of the section of thoracic medical oncology in the division of hematology/oncology at the University of New Mexico Cancer Center in Albuquerque.

References

1. Sambunjak D, Straus SE, Marusic A. Mentoring in academic medicine: a systematic review. JAMA. 2006;296(9):1103-1115.

2. Buddeberg-Fischer B, Herta KD. Formal mentoring programmes for medical students and doctors—a review of the Medline literature. Med Teach. 2006;28(3):248-257.

3. Gray J, Armstrong P. Academic health leadership: looking to the future. Proceedings of a workshop held at the Canadian Institute of Academic Medicine meeting Québec, Que., Canada, Apr. 25 and 26, 2003. Clin Invest Med. 2003;26(3):315-326.

4. DeAngelis CD. Professors not professing. JAMA. 2004;292(9):1060-1061.

5. Wise MR, Shapiro H, Bodley J, et al. Factors affecting academic promotion in obstetrics and gynaecology in Canada. J Obstet Gynaecol Can. 2004;26(2):127-136.

6. Illes J, Glover GH, Wexler L, Leung AN, Glazer GM. A model for faculty mentoring in academic radiology. Acad Radiol. 2000;7(9):717-724.

Finding a Mentor and Maximizing Your Relationship

By John Rhee, MD

Why should I obtain a mentor?

A successful career path in oncology is not accomplished alone. Whether your ultimate aspirations are in academic medicine, community practice, or industry, having one or more mentors during your fellowship is of vital importance.

A mentor can be an invaluable source of practical knowledge; as you have probably realized, the management of patients with cancer is complex and involves as much art as science. A mentor can provide insight on the nuances of oncology that are not learned from textbooks or journals. When needed, he or she can also aide in stress management.

Perhaps the most obvious role of a mentor is to assist in research. It is unrealistic for a fellow to accomplish much research without substantial guidance. A research mentor can help write protocol, as well as generate, present, and publish data.

Lastly, a mentor can help you choose between various oncology careers. If your mentor has been in both academic medicine and private practice, he or she will be especially suited to give you the pros and cons of each. Near the end of your fellowship training, a phone call from your mentor can make the difference in obtaining a faculty position at a prestigious institution or landing a private practice job in the location of your choice.

How do I find a good mentor?

While many training programs have a formal mentor assignment process, finding a good mentor will take some initiative. A first step may be to ask yourself where you see yourself in five to 10 years. Ascertain your interests— are you more interested in patient care or research? Do you want to pursue clinical or basic science research? Does your ideal career involve working with a specific tumor type such as lung cancer or lymphoma, or in a discipline such as immunology or pharmacology? Most likely you are undecided right now, but identifying your interests can help you determine which mentor may be the best fit.The next step is to identify potential mentors. Review faculty profiles and read some of their publications. Speak to the senior fellows or junior faculty for recommendations (certain faculty members may have a track record as successful mentors). Look for mentors who have published with current or previous fellows. A mentor who is on the editorial board of a journal is a bonus, but certainly not mandatory. If you are interested in community practice, strongly consider identifying some of the clinical faculty as potential mentors. For those who plan to go into private practice, a community practitioner who is affiliated with an academic institution typically has a keen interest in teaching and can be an outstanding mentor.

There are pros and cons to working with senior versus mid-career versus junior faculty. While senior faculty may have national and international reputations, they likely will have less time to commit to mentoring fellows. Junior faculty members may lack experience and may be more driven in advancing their own careers. Mid-career faculty, then, may be best suited to be mentors.

When I was a fellow, one particular faculty member had at least three fellows and residents under his wing during any given year. Being the fourth or fifth mentee creates a less favorable ratio. A good mentor has sufficient time and interest in your career and is someone you feel comfortable talking to about your career goals.

Finally, make contact with potential mentors. You may be lucky to connect with the perfect mentor during a consult month, clinic assignment, or ward rotation. Otherwise, send an email or call the faculty or his or her administrative assistant. It is a compliment to faculty to hear that you are interested in their research or in rotating through their clinic.

How do I maximize my relationship with my mentor?

As always, communication is paramount and being proactive will enable you to get the most out of your relationship. By mid-fellowship, you should be meeting periodically with your mentor and discussing your career aspirations. Naturally, academic faculty hope that you’ll follow in their footsteps, but are understanding if your interest lies in community practice. In the end, it’s your career and life.

Do you want to publish? If so, discuss your original ideas, but realize that it may be unrealistic to initiate a research study and publish during your fellowship. Ask to be involved in the interpretation of ongoing data and potentially assist in writing the manuscript. Mentors may receive invitations to write case reports or review articles or book chapters. Early in your fellowship, these assignments may be a source of satisfaction and pique your interest in a specific area.

The mentor/mentee relationship is a two-way street. Even if not specifically assigned, volunteer to rotate through your mentor’s clinic a half or full day per week throughout the year if your schedule will allow. While in clinic, be eager to complete dictations or contribute in other ways. These actions can gain your mentor’s favor in the future.

If you realize that you are not working with the right mentor, there’s no need to panic. You may realize that another faculty member’s research or clinical interests mirrors yours more closely. Or, if your mentor is too busy to be involved, you may seek career guidance or mentorship from someone else.Although I worked with a number of outstanding faculty during my fellowship training, a handful of mentors were key in my career development. A faculty member who was well renowned in an area of my interest initially served as my mentor. When he left our institution during my fellowship, I worked with a non-clinical faculty member doing laboratory research and quickly realized that research was not my calling. Soon after, I picked up several clinical mentors, one of whom had connections with a practice and helped me land a job there immediately after fellowship.

One last bit of advice—maintain communication with your mentors after you’ve finished your fellowship and moved on. After spending five years at my first position, I realized that I wanted to move back to where I trained for family reasons. An unsolicited telephone call from one of my mentors led to an interview with my current practice. Needless to say, I got the job!

John C. Rhee, MD, is an oncologist at UPMC Cancer Centers, Oncology Hematology Associates, in Pittsburgh, Pennsylvania.


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
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A career in oncology can be a tremendously fulfilling and a meaningful venture. Oncologists care for the sick, advance medical science, and mentor the next generation of medical professionals. Despite the value and importance of these pursuits, an expanding body of literature reports that physicians are experiencing increased personal distress and decreased satisfaction with the medical practice.1,2 Unlike many other professionals, physicians often experience extreme fatigue and emotional exhaustion at early stages in their careers during medical school and residency. High rates of burnout and poor mental health among physicians can have a profound impact on patients’ quality of care and threatens the sustainability of the health care enterprise.

What is burnout? Burnout is an emotional state seen in many individuals under constant pressure. It can be accompanied by a number of physical and behavioral signs and symptoms, such as exhaustion, perceived clinical ineffectiveness, impaired job performance, and lead to poor health, including hypertension, anxiety, and depression.3,4 The condition has been compared to a worker who has become separated or withdrawn from the original meaning and purpose of his work. Physicians experiencing burnout have been shown to have higher rates of divorce, suicide, job turnover, drug and alcohol abuse, and a shorter life expectancy.3

The risk of burnout increases in individuals who consistently experience work overload and a perceived lack of control. Simendinger et al suggested a three-degree model of burnout.5 The third, or most severe degree, is characterized by major physical and/or psychological breakdown including mental illness, heart attack, and ulcers.5 These individuals find their work unrewarding, believe they are treated unfairly, experience insufficient personal rewards (eg, loss of mentor support and intrinsic satisfaction) and are confronted with conflicting values.

Sources of burnout

Several factors such as decreased autonomy, increased administrative tasks and paperwork, less time with patients, and difficulty balancing personal and professional responsibilities can contribute to burnout. Oncologists in academia may face additional stressors such as declining levels of funding to support their scientific research, and changes to the structure of fellowship that have increased their clinical responsibilities and decreased time for traditional academic pursuits such as research and education.6 As a result, physicians may not always have the opportunity to focus on the areas that they view as most personally meaningful.

Interestingly, a study by Einhorn et al found that daily interaction with suffering and dying patients was not the greatest source of stress for oncologists.7 Rather, increased claims documentation requirements (such as those for Medicare) and bureaucratic hassles, which for many resulted in longer working hours, was the greatest concern among oncologists. Board certification may be modestly positively associated with satisfaction,and being a foreign medical graduate may be modestly negatively associated with satisfaction, although this is limited to few studies.8

Burnout among oncologistsAlthough burnout affects many individuals under constant pressure, oncologists in particular are frequently overloaded with the demands of their profession. The stressors of caring for ill patients, responding to the needs and questions of families, and experiencing limited treatment success and the constant loss of patients can exert an emotional toll on oncologists. In a 2003 survey, Allegra et al found that the rate of burnout among oncologists in the U.S. exceeded 60%.9 The seeds of burnout may be sown in residency and fellowship training, during which fatigue and emotional exhaustion are often the norm. By mid-career, the momentum of burnout may be subtly reinforced by the fact that your peers perceive you as a hard worker who places service to others before self-care. As a result, some physicians may deny major negative aspects of their work considering their commitment to become a well-trained medical oncologist.

Fellows coping with the demands of their practice by working harder and longer may experience severe inefficiency, psychological impairment, and poor patient care. Fellows’ expectations are often their greatest source of stress, and few spend time reflecting on themselves or attending to their own needs. Even so, fellows might be reluctant to recognize or talk openly about psychological problems resulting from their professional experiences to avoid having a psychological diagnosis or a “weak fellow” label pinned on themselves. The nature of medical training can reinforce false beliefs in one’s immunity to difficulties and prevent recognition of serious psychological problems.

When physicians suffer from burnout, negative effects on patient care and increased medical errors can result. A study by Isen et al found that third-year medical students with positively primed emotions and in whom positive affect had been induced arrived at an accurate diagnosis more efficiently and with greater curiosity and less disorganization.10 Given the potential human costs of medical mistakes, the emotional impact of actual or perceived errors can be devastating for oncologists. It’s well documented that doctors with burnout get sued more often.11 Learning how to prevent burnout, then, is of great importance.

Preventing burnout

The intensity and scope of stressors facing physicians require healthy and successful coping strategies such as cultivating professional and personal relationships, maintaining control over in your career, and preserving your well-being.12,13

Cultivate relationships. Nourishing close relationships is perhaps the most important aspect of your balancing act. Good relationships with patients, relatives, and staff help promote professional status esteem, intellectual stimulation, and good management and organizational structure. An adequate support system can be a powerful source of strength and resilience for physicians, who over time may feel isolated in their careers. Such loneliness can be especially pronounced for physicians who begin to feel down or burned-out. Through socialization and sharing their feelings with others, oncologists can also more readily recognize indicators of stress and burnout in colleagues. In addition to personal and professional relationships, support can be found through professional organizations and groups settings.

Maintain control over your career. A sense of autonomy and control over work is important to ensuring job satisfaction. Control over your schedule, including interventions to improve the flexibility and predictability of work hours is the most important predictor of work–life balance and burnout. While such a goal may seem impractical given the increasing demands on physicians, studies have suggested strategies for increasing one’s sense of control and improving resilience.A study by Jensen et al found that a main aspect of physician resilience was setting limits in both professional and personal arenas.14 Setting limits means being able to know when to say “no” to avoid over-commitment and achieve balance. This may mean prioritizing responsibilities, reducing working hours, changing the way you practice (eg, solo vs group practices), and scheduling time for exercise and relaxation. Since saying “no” inherently involves a certain degree of confrontation, physicians may be reluctant to deny requests from others and consequently find themselves drained or resentful. Giving yourself permission to set limits can markedly improve your professional satisfaction. Physicians with a positive coping strategy know how to organize their work, delegate job duties, and be realistic as to what can be accomplished with available time and resources.

In a separate study by Dunn et al, interventions designed to increase physician control over the work environment, improve order in clinic functioning, and deepen the meaning physicians found in their work were examined.15 The study found that strategies such as soliciting physician input on the scheduling template and accommodating scheduling requests (eg, length of sessions) and other practice preferences (eg, case mix) contributed to decreasing their emotional exhaustion. The possibility for flexible working schedules via part-time and job share options can also be examined.

Given the diversity of career opportunities for a medical oncologist, it is increasingly important that fellowship training provide the diverse experiences needed to make informed career choices. It’s essential to begin your fellowship with an open mind. Fortunately, post-fellowship career choices are usually reversible, and the opportunity exists to switch practice settings. Many oncologists have successfully transitioned from academia to nonacademia and vice versa, for example.

Preserve well-being. Preventing burnout necessitates the promotion of your well-being. Physicians must be guided from the earliest years of training to cultivate methods of personal renewal, emotional self-awareness, connection with social support systems, and a sense of mastery and meaning in their work. Enjoying vacation or personal time will help alleviate burnout, while thinking positively can transform individuals for the better, making them healthier, more socially integrated, knowledgeable, effective, and resilient.

A fellow’s greatest strength is a generally positive outlook. Thinking positively isn’t necessarily easy, but it’s essential. It would benefit fellows to realize early on that there are always going to be difficult situations during training; there is always going to be stress, and another fellow may get sick or need to leave and you will have to cover the call. It’s simply a part of life. Successful fellows dwell on the good times and not on the bad. At the end of each day, reflect on the positives and focus on what you learned. What went right and why?

Mentorship programs are a valuable resource for supporting junior physicians in their career development and helping them navigate professional challenges.15 A mentor may also be able to detect dissatisfaction and help physicians reevaluate their interests and career paths. Opportunities for personal development, whether through medical education, personal hobbies, or sabbatical programs, can help physicians gain perspective and broaden their horizons. Spickard et al. emphasized that the principle “do no harm” is at the core of the medical profession and not incidental to physicians.2 As he put it, “doing no harm begins with one’s self.”Mohamed Abdel Khalek, MD, is a clinical research fellow at Tulane Cancer Center in New Orleans, Louisiana. Emad Kandil, MD, FACS, is an assistant professor of surgery and medicine; adjunct assistant professor of otolaryngology; and chief of the endocrine surgery section in the division of endocrine and oncological surgery at Tulane University School of Medicine in New Orleans, Louisiana.


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
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References

1. Ramirez AJ, Graham J, Richards MA, Cull A, Gregory WM. Mental health of hospital consultants: the effects of stress and satisfaction at work. Lancet. 1996;347(9003):724-728.

2. Spickard A Jr, Gabbe SG, Christensen JF. Mid-career burnout in generalist and specialist physicians. JAMA. 2002;288(12):1447-1450.

3. Gundersen L. Physician burnout. Ann Intern Med. 2001;135(2):145-148.

4. O’Connor PG, Spickard A, Jr. Physician impairment by substance abuse. Med Clin North Am. 1997;81(4):1037-1052.

5. Simendinger EA, Moore TF. Organizational burnout in health care facilities: Strategies for prevention and change. Rockville, MD: Aspen Syst Co; 1985.

6. Campbell EG, Weissman JS, Blumenthal D. Relationship between market competition and the activities and attitudes of medical school faculty. JAMA. 1997;278(3):222-226.

7. Einhorn LH, Levinson J, Li S, Lamar L, Kamin D, Mendelson D. American Society of Clinical Oncology 2001 Presidential Initiative: impact of regulatory burdens on quality

cancer care. J Clin Oncol. 2002;20(24):4722-4726.

8. DeVoe J, Fryer Jr GE, Hargraves JL, Phillips RL, Green LA. Does career dissatisfaction affect the ability of family physicians to deliver high-quality patient care? J Fam Pract. 2002;51(3):223-228.

9. Allegra CJ, Hall R, Yothers G. Prevalence of burnout in the U.S. oncology community: results of a 2003 survey. JOP. 2005;1(4):140-147.

10. Isen AM, Rosenzweig AS, Young MJ. The influence of positive affect on clinical problem solving. Med Decis Making. 1991;11(3):221-227.

11. Crane M. Why burned-out doctors get sued more often. Med Econ. 1998;75(10):210-212, 215-218.

12. Novack DH, Suchman AL, Clark W, Epstein RM, Najberg E, Kaplan C. Calibrating the physician. Personal awareness and effective patient care. Working Group on Promoting Physician Personal Awareness, American Academy on Physician and Patient. JAMA. 1997;278(6):502-509.

13. Myers DG. The funds, friends, and faith of happy people. Am Psychol. 2000;55(1):56-67.

14. Jensen PM, Trollope-Kumar K, Waters H, Everson J. Building physician resilience. Can Fam Physician. 2008;54(5):722-729.

15. Dunn PM, Arnetz BB, Christensen JF, Homer L. Meeting the imperative to improve physician well-being: assessment of an innovative program. J Gen Intern Med.

2007;22(11):1544-1552.

Translating medical nomenclature into language that is easily understood by patients can be difficult: how do you explain the pathology of cancer or the benefits of myeloablative chemotherapy in patient-friendly terms? Your ability to do so, however, can impact treatment adherence, health outcomes, and the perception of physician empathy during a patient’s bleakest moment. The use of analogies, long recognized in medicine as a way to facilitate physician-patient communication, can help get your message across.

I still vividly recall the elderly Vietnamese male patient in the busy emergency room of Harborview Medical Center. He seemed to be dazed at the frenetic pace of activity around him as he laid on a gurney in a room created by curtains, grimacing in pain. Family members spanning four generations surrounded him and looked up at me as I approached and gently bowed in respect. There I was, a busy hematology/oncology consult fellow, who had to announce his diagnosis of metastatic pancreatic cancer and answer a multitude of questions that would likely make no sense to anyone. I’m certain that many of my peers have been in a similar situation countless times, in which translating clinical information into “human” terms proves difficult. In my experience, the effective use of analogies when communicating with patients has been an invaluable tool that is often met with a sigh of relief and a nod of understanding.

While I have improvised analogies to cater to the educational background of patients and family members, I prefer to use basic analogies, as rudimentary explanations are best for even the most educated of individuals when it pertains to issues of life and death. Most patients appreciate this sort of explanation, and more often than not, the analogies generate a smile during even bleakest situations.

Some of my most useful analogies have been as follows:

Chemotherapy: I often explain to new patients who are about to start the first of many chemotherapy regimens that they are embarking on a marathon; the physician is the coach and the health care team, composed of the nursing staff and pharmacists, are track coordinators monitoring their well-being. Many patients ask about nail changes with chemotherapy. I often tell them that just like the annual circles in the cores of trees that demonstrate their age and reflect the harsh times they have experienced, each hyperpigmented nail line indicates the chemotherapy insult that they have received, and that normal nail usually develops once they discontinue chemotherapy.

Blood counts: I communicate the importance of blood cell counts by telling patients that white blood cells, red blood cells, and platelets represent the armed forces, the Navy, and the Air Force. All three are needed to fight disease and stay in homeostasis; inadequate levels of any of them can render the patient’s health in major jeopardy.

Neutrophils: Mostly needed to prevent infection, they are like policemen that curtail offenders (ie, microbial pathogens). When there is unrest (ie, infection) there is always an increased number of troopers (ie, leucocytosis); neutropenic patients are therefore vulnerable to infection due to less policing.

Lymph nodes and metastasis: Lymph nodes are like security guards at multiple checkpoints or roadblocks in the body. When there is disorder and mayhem, the security guards radio for backup to swell their numbers. Similarly, lymph nodes enlarge when they become involved in an irregularity upstream, thus preventing it from dissipating downstream. If they are overwhelmed, metastases occurs.Myeloablative chemotherapy: This is like winter, in which the cold weather causes the grass to die and take on a pale hue. When new growth appears in small pockets during the spring, it is difficult to ascertain if it is fresh grass or tainted with weeds (ie, disease). Oftentimes in patients with leukemia who have undergone induction chemotherapy, a day 14 marrow aspiration is performed to identify the persistence of blasts (ie, weeds), and another marrow aspiration and biopsy is performed on day 28 to identify if the new growth is devoid of blasts (ie, weeds in the grass). Another similar analogy is the effect of a powerful weed killer on grass.

GI malignancies: Using the analogy of drilling though a timber frame wall is helpful to explain the stage of disease. If the cancer has penetrated most of the muscularis mucosa and serosa (ie, the insulation and sheathing of the home’s wall), its chance of metastasizing is high (ie, through the outside brick). The more the cancer has spread through its confining walls, the greater the chance that the cancer will disseminate.

Proper hydration: Although need for proper hydration in patients with cancer is essential, many do not consume enough fluids due to chemotherapy-associated nausea, anorexia, and changes in taste. Such patients often have dark-colored urine indicating high urinary concentration and poor oral fluid intake. I use the analogy of a few drops of a blue coloring agent changing the color of water in a small glass, but not of a tub of water. Volume does matter. After hearing this analogy, they often return to tell me that their urine is mostly clear now, which is very gratifying!

Non-malignant hematology patients: In patients who are mostly well, I cannot over-emphasize that the need for regular medical follow-ups is imperative for their well-being. Many patients do not keep their appointments or do so only when they need medication refills. I ask these patients how often they change the oil in their cars. It is like a light bulb turning on when patients see the connection between the maintenance of their vehicle and their body.

Analogies are extremely useful when used in the proper way. If they are misused and misunderstood by the patient, it could lead to confusion and discontent. The central message is to use familiar concepts to help patients understand unfamiliar or complex issues to help ease their anxiety. One must always gauge the level of understanding of the patient and avoid overusing analogies. Always bear in mind the rule that analogies are like cars—if driven too far, they will inevitably break down! 

Jaideep Shenoi, MD, is a third-year senior hematology/oncology fellow at the University of Washington/Fred Hutchinson Cancer Research Center in Seattle, Washington.



This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
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The field of oncology has undergone a significant transformation in the last few years. In this era of individualized medicine, we are learning new ways to tailor treatment based on the molecular pathways of the tumor. There has never been a more exciting time to be in the field of oncology, especially in academic oncology. In addition to the ability to develop a disease-focused clinical career, an academic oncologist can also build a research, educational, or administrative career (as, for example, a cancer center medical director or a department section chief). Academic oncologists have a critical role as opinion leaders and shape the future of cancer care by research and training future oncologists, residents, and medical students.

Applying for an academic job

If you are planning to pursue an academic career, make sure you have a mentor who can guide you through the application, interview, and selection processes. Generally speaking, there are usually many academic oncology practices in universities and cancer centers that actively search for young talent to build their department or join their established staff. A fellow should start looking for an academic job opportunity before the end of the second year of fellowship or during the early part of third year. A good place to start is with advertisements in major oncology journals or postings at national meetings such as the American Society of Clinical Oncology or the American Society of Hematology Symposium.

Preparing an adequate curriculum vitae (CV) is probably the most important step in the job application process. The CV should include the following information in a clear and organized manner: contact information, academic background and training history, research experience, grants and publication, awards, and voluntary work experience. Emphasizing teaching or mentoring experience and research skills (while avoiding falsifying information) will make a candidate more desirable for an academic job. A candidate should also identify mentors who know him or her well, and who are willing to write letters of recommendation or serve as references if needed.

The job interview process

Institutions that have great interest in a candidate will send an invitation for a job interview. This is an opportunity for the candidate to make a lasting impression and also take a closer look at the work environment. To prepare for the interview, the candidate should inquire about interviewees—including other cancer specialists such as radiation oncologists and surgical oncologists—and their clinical interests. This information can be used to emphasize potential areas of collaboration in the future. In general, the candidate is expected to give a presentation related to his or her work and research interest. It’s vital to tailor the depth of the presentation based on the audience’s clinical interest and background. For example, if your audience is predominantly clinicians, try to focus on the translational or clinical aspects of your research as opposed to basic science. The interview is also an opportunity to highlight individual strengths such as involvement with investigator-initiated clinical trials and prior publication.

Tenure versus non-tenure tracks

It is important to understand the different aspects of a tenure vs non-tenure academic oncology track, including the academic ranks and specific requirements for each. A proper understanding of the responsibilities associated with a specific academic position, as well as the culture and expectations of the cancer center and department, is crucial for the candidate’s success in that environment.Usually, a candidate who has recently completed fellowship is accepted as an assistant professor or, in some cases, as a tutor or clinical instructor. In general, the candidate is offered a position in either tenure track or non-tenure track. In the past, tenure track meant guaranteed, permanent job appointment and benefits. The definition, however, varies from one institution to another. It is very important to find out if you are interviewing for a position in the tenure or non-tenure track and what the specific requirements are for each track. The type of appointment and the requirements needed to achieve tenure status should be made clear in the offer letter.

A key factor to advancing the academic ladder is identifying a mentor who shares common clinical and research interests. On average, an assistant professor is usually eligible to be promoted to an associate professor rank after five to seven years. Each institution will have its own criteria for promotion, and new faculty should familiarize themselves with them. The promotion process involves a thorough review of performance in various aspects of the particular track the you are in. It is important to maintain a high level of academic, research, and clinical productivity.

Types of academic appointments

In general, there are three types of academic appointments in oncology: clinical track, scientist track, and clinician scientist track.

Clinical track: Academic oncologists in a clinical track spend most of their working hours (up to 90%) in direct patient care-related activities. This can involve an assigned number of outpatient clinics per week (sometimes up to four days of clinic), along with hospital setting or inpatient coverage. The remainder of the time is dedicated to teaching and some research. Since this is a primarily patient care-focused track, the research expectation is limited. However, the faculty member is strongly encouraged to enroll patients in clinical trials and participate in national cooperative oncology group or industry-sponsored studies. A clinician track oncologist is rarely expected to write an investigator-initiated trial due to their limited time.

Scientist track: In this track, the emphasis is primarily on research (bench or translational). These oncologists can have up to 90% protected time for research, with less emphasis on patient care and teaching responsibilities. In general, academic oncologists in this setting are guaranteed lab space and initial funding to buy supplies and cover other overhead costs for the first one to two years. In addition, other ancillary services (eg, animal facilities and tissue banking) and access to other collaborative facilities (eg, clinical trial research units and statisticians) is provided. Academic oncologists are expected to eventually bring extramural support for research and mentor fellows with research interest. The patient care responsibility is usually minimal, consisting of one or two half-day clinics per week.

Clinician scientist track: Clinician scientists are usually translational investigators. They are the bridge between clinicians and basic scientists or oncologist in the scientist track. Clinician scientists are expected to write investigator-initiated trials and be principal investigator for national cooperative oncology group or industry-sponsored trials. Clinician scientists are also expected to acquire financial support through clinical trials or extramural funding. Usually, clinician scientists are in the clinic two or three days per week, with the rest of their time dedicated to research and clinical trial activities.

Financial compensation in academia The financial compensation for an academic oncologist is significantly less than an oncologist in a private practice. The starting salary for an academic oncologist is $160,000 to $200,000, compared with $175,000 to $300,000 for an oncologist in private practice. However, the financial risk in academia is less since academic oncologists work within the structure of university hospitals where the costs and profits are spread over multiple departments. Academic oncologists can choose to supplement their salary through research grants or by giving lectures at pharmaceutical-sponsored conferences.

Academic oncologists are not isolated from real-world medical-financial concerns; they will need to learn about the “ins and outs” of medical billing including, for example, assigning the correct Current Procedural Terminology code for Medicare patients. Familiarity with reimbursement measures such as Relative Value Units (RVUs) is essential since it is also used as a productivity indicator (ie, many practices set RVU goals based on the number of years in practice and assigned academic track).

All in all, finding your niche in academia and tailoring your career to suit your personal strengths and interests is instrumental. As Confucius said, “If you enjoy what you do, you will never work another day in your life.”

Sidebar: Keys to Success in Academic Oncology

• Thoroughly understand the expectations and goals of your track.

• Identify a mentor who is familiar with your career goals and who is willing to help you.

• Focus is essential for academic success; concentrate on your strengths and focus on your goals.

• Always try to be a good team player and treat others with respect.

• Take care of your patients, yourself, your family.

• Remember to keep a positive outlook and have fun!

Mohammed Almubarak, MD, is assistant professor of medicine in the hematology/oncology section of Mary Babb Randolph Cancer Center in Morgantown, West Virginia. Jame Abraham, MD, FACP, is Bonnie Wells Wilson Distinguished Professor and Eminent Scholar; co-leader of the Breast Cancer Program; chief of the hematology/oncology section; and medical director of the Mary Babb Randolph Cancer Center at West Virginia University in Morgantown.



This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
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Ifreke Williams, a third-year med student, stands in front of a camera holding a print-out of her outstanding student-loan debt to date, and the numbers are sobering: “Medical School Debt: $226,000 (Now)—$295,000 @ Graduation.”

Williams shared her story with HuffingtonPost.com to raise awareness of the staggering amount of debt many medical students face, along with the difficult career and life decisions that result from it.1 “The thought of starting life with such a huge debt is very frightening, especially since I plan on going into primary care and not a lucrative medical specialty or subspecialty,” she writes.

Medical student loan bill: $160,000

Medical students in the Class of 2009, including both public and private schools, graduated with a median student-loan debt of $160,000, according to a survey by the Association of American Medical Colleges (AAMC).2 But that figure is skewed by the number of students who receive financial assistance from their families, schools, scholarships or other forms of aid. Students like Williams who need to rely almost entirely on loans to pay their education costs often borrow far more: The AAMC survey found that 17% of private-school grads had incurred debt of $250,000 or more.

Students leaving med school with the equivalent of a mortgage in debt is severely limiting the choices young physicians can make—both in terms of their families and their finances. More residents burdened with six-figure debt are shunning family medicine and primary care, concerned with the relatively low pay and looming threat of sharp reductions in government Medicare payments. Physician shortages in primary care are the most pronounced in rural areas and in regions of the country where the cost of living is high. And, regardless of their chosen field, many young physicians find they must make sacrifices in their personal lives to service their debt, such as putting off buying a house or starting a family.

Policy makers are finally starting to take notice of the impact education debt is having on the U.S. healthcare system, and new legislation is being considered to help ease the burden. We’ll look at some new and existing government programs that are attempting to help physicians manage, or in some cases eliminate, their student-loan debt.

Married couples get a break with new IBR rules

Two important changes went into effect on July 1, 2010, that may make some physicians eligible for the Income-Based Repayment (IBR) plan that were not eligible before. A change in the way household income and debt is formulated could mean lower payments for married couples.

IBR is a payment option for federal student loans that keeps monthly loan payments affordable with payment caps based on the borrowers’ household income and family size. In most cases, loan payments are less than 10% of their adjusted gross income. Borrowers in the plans are also eligible for forgiveness of any remaining student-loan debt after 25 years—or just 10 years if they work in the public service sector, including jobs in government and nonprofit 501(c)(3) organizations. The program covers most federal loans. The 10-year payment period doesn’t have to be consecutive; so, for example, a borrower can work in public service for five years, go into the private sector for a few years, and return to complete the 10-year requirement when the time is convenient.Under the rules that went into effect in July, IBR eligibility will be based on either the balance when the loan first entered repayment or on the current loan amount—whichever is greater. So borrowers with loan balances that have increased due to accrued interest would be eligible to qualify based on what they actually owe. An online calculator available at www.ibrinfo.org/calculator.php, can tell you if you’re eligible for IBR under the new rules.

Up until July 1, married couples who both had federal student loans typically paid higher monthly IBR payments than single borrowers. For married couples who file jointly, lenders will now use a formula that factors in the couple’s total outstanding federal student-loan debt and adjusted gross income to come up with the minimum monthly payment. Previously, the formula didn’t combine the couple’s total student-loan debt, leading to monthly payments that were up to twice the amount that two single borrowers would have to pay.

If you’re married and your spouse has federal student loans too, contact your lender to ensure your payments reflect this new rule change.

Forgiveness programs on the rise

Physician shortages have vastly increased the number of national, state, and local loan-forgiveness programs offered to young physicians, most with the aim of boosting the number of physicians in primary care. Currently, there are a number of state and federal bills under consideration that would offer loan-forgiveness or partial-repayment programs to physicians who agree to work in certain fields or underserved areas of the country.

There are already a number of loan-forgiveness programs available for physicians. The most widely known is a program by the National Health Service Corps (http://nhsc.hrsa.gov), which makes loan repayments for physicians who practice for a certain number of years in areas of the country with severe physician shortages. Its full-time program starts with an initial award of $50,000 for two years of service, and a new part-time pilot project begins with an initial award of $50,000 for four years of service. Participants in the program may be eligible to extend their service until all of their debt is paid.

A growing number of hospitals and private healthcare systems are extending loan forgiveness to attract young physicians as well. A listing of hospitals and other organizations that offer loan forgiveness can be found at www.finaid.org/loans/forgiveness.phtml.

New ombudsman to resolve disputes with private lenders

Finally, the new provision of the 2010 financial reform bill creating new Federal Student Aid Ombudsman may help borrowers find relief in dealing with problems they encounter with private lenders. The ombudsman will be dedicated to helping students with private student loans resolve disputes and other problems with lenders. An ombudsman position already exists in the Education Department for federal student loans, but it excluded private loans.

The need for more oversight of non-government loans became abundantly clear over the last decade as the use of private student loans exploded: Between 2000 and 2008, total education borrowing with private loans soared from $6 billion to $24 billion, according to the College Board.3 In 2009, private loan borrowing was slashed in half, as access to credit dried up in the wake of the financial crisis.Often students who borrow with private loans do so because they’ve already maxed out the federal loan borrowing limits. Generally, there are no borrowing limits for private student loans, which can often lead students to overextend themselves. There are also no limits on private loan interest rates. With the exception of subsidized Stafford Loans, the rate on government loans is currently capped at 6.8%. Variable private loan rates can climb to 20% or more, and penalties for late payments can be equally steep.

The new ombudsman won’t have the authority to impose changes in the terms or conditions of individual student loans. Still, the office is designed to help find a fair and equitable solution for student problems.

If you are having a problem with a private lender, contact the ombudsman at http://fsahelp.ed.gov or call (877) 557-2575. You may also email a detailed letter explaining your problem to fsaombudsmanoffice@ed.gov, or write to the U.S. Department of Education, FSA Ombudsman, 830 First Street, NE, Fourth Floor, Washington, D.C. 20202-5144.

The new ombudsman’s office will also be responsible for issuing annual reports to congressional lawmakers on prevailing issues and trends within the private student loan industry, shining some much-needed light on practices that may be harming borrowers.

Sidebar: How Student Loans Affect Your Credit Score

For many graduates, taking out a student loan marks the beginning of their official credit history. Credit-rating companies consider student loans installment debt, in the same category as a mortgage or home-equity loan. Though you may have hundreds of thousands of dollars in debt, the size of your student loans isn’t as much of a factor in calculating your credit score as your ability to repay it. This is why it’s so important to never miss a payment to any lender.

Many students ding their credit scores quite by accident because they miss making their first student-loan payment—often because they weren’t aware it was due. Students move, addresses on file aren’t kept up to date, and payment notifications get lost in the mail. To avoid this, make sure you keep careful records on all of your outstanding student loans, and notify lenders when you move.

If you’re in a financial bind and you miss a payment, your credit score could drop by as much as much as 50 points. But if you enter a deferment or forbearance program with your lender, it shouldn’t adversely affect your score. Credit-scoring companies generally view these as temporary programs and so generally don’t factor them into the scoring. If you’re struggling to make payments, contact your lender to explore available debt-relief programs immediately before you miss a payment. To learn more about credit scores and how they’re formulated, visit MyFico.com (www.myfico.com).

Sidebar: Online Resources

FinAid

(http://finaid.org)

The most comprehensive source of up-to-the-minute student financial aid and student loan information, including advice and tools for parents, students, and graduates.

Student Loan Borrower Assistance Program

(www.studentloanborrowerassistance.org)

Run by the National Consumer Law Center, this site provides student loan borrowers with information on their legal options and rights, and has breaking news on government rules and legislation that may affect your loans.

IBRinfo

(www.ibrinfo.org)

A Web site with news, information, tools, and advice on the Income-Based Repayment (IBR) plan run by the Institute for College Access & Success.

First Facts

(www.aamc.org/programs/first/students/factsheets.htm)

Brief informational financial aid and student loan worksheets for help with repaying student loans from the Association of American Medical Colleges.



This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
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The story of the city mouse and the country mouse is a popular Aesop’s fable for children that concludes, “A modest life of peace and quiet is better than a richly one with danger and strife.” Is that the choice an oncologist makes when he chooses where to practice? Is the life of a country oncologist quieter and less intense, while the city oncologist’s life is noisier and more stressful?

First, it’s important to note that few oncologists have practiced in both an urban and a rural practice, so it is difficult to find one physician who can tell both sides of the story. I have practiced in Council Bluffs, Iowa, (population 60,000) for almost 25 years, and my office is about 20 feet from where I was born, so I can tell you what it is like to be a country oncologist.

The view from my “porch”

I practice in a five-physician group. We are not the only practice in town, but we are the largest. Sadly, oncologists rarely suffer from lack of patients, so it is probably just as easy to have a full patient roster in a small town as it is in New York City. Additionally, we have 10 satellite offices in the communities surrounding Council Bluffs.

Even in Corning, Iowa, the site of our farthest satellite, where the town population is about 2000, we have a local oncology-trained nurse who works with us and a local hospital to support our patients. The community is grateful for the care we provide, so treating those patients is especially rewarding. The other small communities we serve are similar in their support of the practice and the services available for patients. And for the patients who would never make the drive to Council Bluffs (a big city by their standards), providing local care is an ideal solution.

I regularly see my patients outside of the office. Almost once a day I run into a patient—at the gas station, post office, or a high school football game. If I am in the smaller communities, I’m almost guaranteed to cross paths with a patient. My life as a rural physician is not an anonymous one.

My longest commute is the three-hour drive to and from our farthest satellite office. I could have a driver and use the time for paperwork (though my nature would be to talk rather than work), but most often I drive myself and listen to books on tape. When I arrive home, I am rested; I no longer need to “decompress,” and the remainder of my day is mine. When my children, who are now in college, were younger, I did not miss a concert, sports event, or parent-teacher conference. I even have the option of flying my small plane to an outlying office, which likely would be a financial and logistical impossibility in an urban practice.

I consult with my partners when developing a treatment plan for a patient or when a patient is not responding as I had expected. With the advent of the Internet, imaging results online, and electronic medical records, I can also easily consult with a colleague hundreds or thousands of miles away.

My rotation on call is less frequent now, but it was not unreasonable even in the early days. I spoke recently with a colleague who is a solo practitioner in Wyoming. He has been on call for 8 years because he is the only oncologist in his town. When asked how disruptive it was to his family life, he remarked that it was a problem when he wanted a vacation. Beyond that, there were calls that came at inopportune times and calls that were no disruption at all.

Some patients in rural communities will travel to the large, famous cancer treatment facilities around the country, often for a confirming diagnosis. My experience has been that when a patient receives a confirmation of the diagnosis I have made, he or she is reassured, and our relationship improves. I have never felt minimized.

Lifestyle differences So then, if being an oncologist in the country or city is similar once the examination room door closes, what is the difference? The difference is lifestyle. In Council Bluffs, for example, a $250,000 house is a big house. Dinner for four at one of the better restaurants is under $100. The numbers may be smaller, but the life is not smaller. If you want to live on an acre or more of land but do not want the longer daily commute that it would require in Chicago or Denver, a rural practice may be for you.

However, I would be remiss if I didn’t mention that there are trade-offs. While on the popular culture front, books and magazines are as available in a small town as they are anywhere else, movies may open in the theater a week or two later, and finding legitimate theater may be a challenge. Regarding practical issues, worries about traffic, parking space availability, and long commutes are not daily concerns.

As mentioned, a physician practicing in a remote corner of America has easy access to the medical community far beyond his or her town via modern technology. The days of a rural physician being isolated are long gone.

A family decision

A professor once told me, “When you are deciding on where to practice, bring your spouse. You will close the door and could be anywhere, but your spouse will have to live each day in the community you choose.” That may be one of the more important lessons I learned in medical school. The choice of where to practice is a family decision, not an individual one.

Local education is a big consideration. It’s important to investigate the schools in a town that you’re considering relocating to if you have a family or plan to have one in the future. However, the days of small-town education being small or inadequate are gone. Medical schools are full of the sons and daughters of rural physicians who received a quality education at small-town high schools, attended first-class universities, and went on to some of the best medical schools in the country. My daughters are both at a nationally ranked university with plans to attend medical school; I have no doubt that they will get in. (I have not asked where they intend to practice, but I can guess.)

A bigger issue may be employment for a physician’s spouse. Depending on his or her field of expertise, this may present the most significant logistical issue. Fortunately, many universities are in smaller cities and towns, telecommuting has made working from a remote office a viable option, and opportunities are more plentiful than they once were. It was not the case for me, but I suspect that for some, asking one’s spouse to give up a career is a lot to ask. Perhaps too much to ask. I doubt that there are any hard data on the subject, but the high incidence of a spouse working as practice managers, at least in the early days, may represent a common solution to the career question.

Just as visibility for a physician in a small town is greater, so is visibility for a physician’s spouse and family. For my family, it’s simply been a fact of life that hasn’t had a negative impact on their daily lives. At least, not any that I’ve heard about!

Factors to consider

As you complete your fellowship, you’ll begin the process of determining where to practice. What factors should you consider?Economics can play a role. Many rural practices, especially oncology practices, are experiencing difficulties because of under-reimbursement and patients’ inability to pay deductibles and copays. These issues are compounded for an oncology practice because of the high cost of cancer drugs and can often be so severe as to threaten the financial survival of the practice. When finances interfere with the ability to deliver care or with a patient’s ability to pay for care, physicians can find themselves dealing with issues beyond that of a clinical nature. Recent healthcare reform legislation does not provide any relief to this problem.

I don’t need to tell you about interviewing the physician practice you may be considering; that is an obvious and important part of your decision. The culture of a practice is a product of the people and personalities within it, so you will need to project how you may see yourself interacting with them. Ultimately, your satisfaction and happiness will come as much from the practice environment itself as from the geographical location.

An important factor to consider is pace—the pace of your practice and the pace of your life. If you view rural/small-city oncology and rural/small-city living as slow, dull, and lacking more than it offers, it’s not for you. However, if city life leaves you feeling breathless and stressed, the nonurban option may be a good fit.

Get to know a town close up

Spend some time in the community you are considering beyond the time you would spend in the practice. Go to the schools, grocery store, hardware store, and department store. Check out the local movie theaters and libraries. Eat in the best restaurant in town and in the local diner. Read the local newspaper; better yet, subscribe for several months prior to visiting the community to see what’s going on around town. Find out how far it is to the nearest airport or Amtrak station. Check flight availability to the places you’ll likely want to travel. For example, Greenville, South Carolina, is a lovely rural community with a temperate climate and easy access to the Smoky Mountains. It is probably a great place to live. It is also one of the most expensive cities to fly to and from because of its limited air service.

This last suggestion is decidedly low-tech but still one of the most practical: Make a list of the pros and cons of each option. Make lists of what you will gain and what you will give up in small-town living. Make lists of what you want—shopping, nightlife, open land, or blue skies—and what you feel you cannot live without. Soon the choice will become obvious. If you choose rural oncology, good for you. And welcome!



This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
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I had never thought of myself as a political operative. I’ve been an oncologist in Billings, Montana, since 1995. When I was younger, there wasn’t much concern about getting reimbursed; you billed and you were paid. As far as my political involvement, it was nearly nonexistent. I never expected to walk the halls of Congress, meet with more than 50 members, and talk to my colleagues about the importance of traveling to Washington, DC, to make sure that our voices were heard. (I remember once bumping into Sen. Max Baucus [D-MT], now chairman of the Senate Finance Committee, in a cafeteria when he was running for re-election in 1996. I had to ask someone, “Isn’t that Senator Baucus?”)

However, as the current chairman of the Policy Committee and 2008-2010 past-president of the Community Oncology Alliance (COA), which represents more than 2500 oncologists at community cancer clinics, I am now an expert on the advocacy process, and I travel each month to the nation’s capital to advocate on behalf of oncologists and our cancer patients.

Why do I do this? Seven years ago, Congress passed the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA), which changed how doctors are reimbursed by the Centers for Medicare & Medicaid Services (CMS). When payments for chemotherapy administration were reduced, it forced oncologists to take on a new active role. We then established COA to mobilize the oncology community, including physicians, patients, administrators, nurses, and other healthcare providers, to increase awareness on Capitol Hill about how the law was affecting the cancer care delivery system. This has become an increasingly critical role now as oncologists are fighting for the lives of their patients and their practices—community cancer clinics, which treat 84% of Americans with cancer.

As the World Health Organization predicted, this year cancer overtook heart disease as the leading cause of death. About 7.6 million people died of cancer in 2008, and about 12.4 million new cases are diagnosed each year, according to a report by the American Cancer Society.1 The report further states that cancer costs more in productivity and loss of life than AIDS, malaria, the flu, and other diseases that are spread from person to person. Cancer’s economic toll was $895 billion in 2008, which is equivalent to 1.5% of the world’s gross domestic product.1

Although cancer is the number one killer of Americans under age 85, the good news is that cancer survival rates in the U.S. continue to improve. The e number of Americans living with cancer is likely to increase with the aging population, more screenings leading to earlier detection, and current treatments allowing patients to live longer. As a result, more oncologists will be needed in the future to administer the treatments to the growing population of patients. It is estimated that by 2020, the country will be 4800 oncologists short.2 Unfortunately, the state of physician reimbursement has disillusioned many practicing oncologists today about the Medicare system.

Physician reimbursement penalized Congress has failed to address the Sustainable Growth Rate (SGR), the formula used to calculate payments to physicians annually based on the economy. The intended purpose of this formula was to place constraints on the growth of Medicare. However, it appears that physicians alone are being punished for the increases in Medicare spending, despite the fact that physician reimbursement is a very small part of overall spending. Congress has blocked the cuts each year, and, in December, the seven-month patch will end again.

For the past 6 years, the SGR has reduced Medicare reimbursement for some of the most expensive drugs and services used to care for cancer patients. The CMS Physician Fee Schedule for 2010 cuts even deeper, reducing payment for chemotherapy administration services an additional 5% annually, and up to 20% by 2013. There are additional cuts for cancer diagnostic imaging and physician consultation services. Medical practices cannot continue to provide care when they lose money.

Many community oncology clinics treat patients who cannot afford supplementary insurance and are solely dependent on Medicare. This alone causes financial pressure for oncologists who are already losing money from inadequate reimbursements for drugs and chemotherapy administration, as well as other overhead expenses.

Before the MMA was passed there wasn’t as much concern with access to chemotherapy treatments as there is now. That law radically changed how we were paid for delivering cancer care. Now we’re seeing the full impact of the law, with practices decreasing services and the flight of community oncology clinics to merge with hospitals and larger groups. For some practices, the situation has become even more dire. In the past 3 years, 166 clinics have closed. Since January 2010, 39 community cancer clinics in 15 states across the United States have closed or are in the process of closing because of financial pressures from severe cuts in Medicare reimbursement for cancer care. By the end of the year, the number of clinic closings could double. A cancer clinic serving Selma, Alabama, for nearly 25 years was forced to shut its doors. Now those patients must travel an hour to obtain treatment at a community oncology center in Montgomery.

Practices depend on payments from private insurers to support their business. The COA conducted a study that showed that Medicare reimburses less than half of the cost of providing cancer treatment for patients. Practices take a financial loss every time they give a Medicare patient chemotherapy because of this poor reimbursement. This is not a sustainable business model. We need advocates to help convey to Congress that the cancer delivery system that has been built over the past two decades is quickly falling apart.

The mission of the Community Oncology Alliance

Meanwhile, there are a lot of conflicting and competing pressures. There is pressure from the government to hold down costs, and in the private sector, more pressure from insurance companies to contain costs. Oncologists, like other physicians, are frustrated by the entire process. Therefore, we must become our own biggest advocates. Someone has to stand up for patients’ access to chemotherapy drugs and the state of cancer care. The best ones to do that are physicians. In the last 7 years since COA was founded to advocate for patients and providers in community oncology clinics, there is a growing number of us who are doing just that. This brings us to the core of COA’s mission. While it is true that oncologists first, and foremost, are responsible for diagnosing and caring for patients with cancer and hematologic disorders, and second, for continuing to increase our knowledge about the disease through clinical and laboratory research, we now have another obligation that is equally as important: We must educate medical students, residents, fellows, and other trainees about how to advocate on behalf of our cause. This includes not only advocating for patients and their families, but advocating for our practices so that we can continue to save the lives of our patients.

COA’s mission is to protect patients’ access to quality, affordable cancer care across the country. We want to ensure that the nation’s cancer care delivery system remains the best in the world. Since COA was established, we have rallied the cancer community—physicians, staff , and patients—to take our message to Capitol Hill. Through political advocacy, we have made an impact.

It is vital that physicians take a leadership role when Medicare or Congress comes out with new rules that affect patient care. We must meet with our local officials and members of Congress. Elected officials, from the U.S. Congress to the state capitals, have a lot on their plates. They cannot be experts on every topic, particularly when it comes to healthcare concerns such as Medicare. They are looking to their constituents for advice, and who better to advise them on healthcare issues than physicians. We must speak up for our patients; if we don’t, no one else will.

Of course, here in Montana, it’s a lot easier to gain access to members of Congress because they have far fewer constituents than the more heavily populated states. We have senators who are willing to sit down over coffee and talk about the issues. But now I go to Washington, DC, practically every month to meet with members of Congress about issues that impact COA members across the country. I walk the halls of Congress to bring attention to COA’s causes.

Get involved in your community

To be an advocate, you don’t have to travel to the nation’s capital every month. There are many ways that an oncologist can help. COA has a petition, “Stop Cancer Care Cuts,” that was distributed to all of the offices of COA members for their patients, administrators, and staff to sign. Then they were to encourage their friends and families to sign. Another COA initiative, “Sit in My Chair,” has been embraced by oncologists. Oncologists invite their members of Congress to come to their clinics and observe patients being treated in an outpatient setting while actually sitting in the doctor’s chair. It is a very powerful tool. No single act drives home the importance of community cancer care than being there and seeing firsthand how patients are cared for.

To quote Bush Foundation vice president Pamela Wheelock as she spoke of the mission of their leadership program for medical fellows in October 2009, “Physicians have always been at the forefront of confronting community problems, whether it was by keeping its residents healthy through their daily work of seeing patients or by instituting new community programs—both related to health and with a broader emphasis… [fellows] “must put their courageous leadership skills to work on the questions that face our communities today and in the future.”3 It is easy to become politically involved in your own community, ranging from attending meetings with congressional staffers and political fundraisers to talking with your patients, family, friends, and neighbors about how the law is affecting Medicare reimbursement. We must spread the word about the negative impact that the MMA is having on cancer patients and their doctors. We must be our own best advocates


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
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Scenario 1   An inexperienced nurse receives an order that she believes was intended for a different patient. Rather than asking the oncologist directly, she goes to her nurse coworkers for direction. She “polls” the nurses and receives feedback on their interpretation of the order. She chooses to proceed without discussing the issue with the oncologist, and a medical error occurs.

The Institute of Medicine stated in its report, To Err Is Human, that medical errors account for between 44,000 and 98,000 hospital deaths per year in the United States.1 This information should not be new to anyone, as this report was released more than 10 years ago. What you may not know is why these errors occur. The Joint Commission suggests that organizational culture, availability of resources, staffing ratios, and education and training are top contributors to errors.2 It also identifies lack of communication or miscommunication as the number one root cause of sentinel events.

I have been a nurse for 15 years and have progressed from a novice new graduate nurse who did what I was told, to an experienced oncology nurse who thinks critically and asks questions. I have worked with oncologists who have discounted my knowledge, some who have yelled at me, and many who have collaborated with me as a peer to care for our patients. I have worked in healthcare facilities where the executive leadership team ignored unprofessional behavior from physicians, and I have worked in facilities where skilled communication and true collaboration have not only been encouraged, but expected and fully supported from the executive team.

I can personally reflect on these experiences and identify which were healthy and satisfying and which were not. I can also remember experiences that resulted in medical errors and those that were potential errors that did not reach the patient. I do not believe that it was coincidental that potential errors were caught when professional communication occurred within the interdisciplinary team—and when all roles were respected and valued.

The Danger of Not Communicating

In 2005, the American Association of Critical-Care Nurses (AACN) partnered with VitalSmarts, a corporate training organization, to conduct a study titled, Silence Kills: The Seven Crucial Conversations for Healthcare Professionals.3 The study found that healthcare professionals fail to have crucial conversations when there are broken rules, mistakes, lack of support, incompetence, poor teamwork, disrespect, and micromanagement. Other barriers to having crucial conversations were identified as lack of ability, belief of “it’s not my job,” lack of time, and fear of retaliation.3

Not having these conversations, or having the wrong conversations, can have an impact on medical errors, patient safety, quality of care, staff commitment, employee satisfaction, discretionary effort, and turnover. Improvement in communication could not only contribute to a significant reduction in errors, but also improve the quality of care. It seems simple: if we communicate effectively, we can improve patient safety and patient outcomes. So why are we not doing it? Why did the nurse in the first scenario not speak with the oncologist directly and question the order? There were several reasons, or “barriers”: the nurse was inexperienced, the oncologist had a reputation of yelling at nurses for “being stupid,” the oncologist was busy, the nurse did not want to bother him, and the organization did not support nurses questioning physicians.

Overcoming Barriers to Communication

As a result of those findings, the AACN made a commitment to actively promote the creation of healthy work environments that support and foster excellence in patient care wherever acute and critical care nurses practice. They identified six standards for establishing and sustaining healthy work environments4:

  • Skilled communication
  • True collaboration
  • Effective decision making
  • Appropriate staffing 
  • Meaningful recognition
  • Authentic leadership


Regarding the first two, skilled communication requires that nurses be as proficient in communication skills as they are in clinical skills. In order to have true collaboration, nurses must be relentless in pursuing and fostering true collaboration, and nurse managers and medical directors must be equal partners in modeling and fostering true collaboration.4

Scenario 2 reflects an effective oncologist-nurse relationship in which communication is clear, uninhibited, and encouraged—and directly affects the quality of patient care.

Scenario 2

An inexperienced nurse receives an order that she believes was intended for a different patient. She speaks to the oncologist and says, “I was looking over Mrs. Jones’s orders and noticed that she is scheduled for a head CT, but I wasn’t sure why. Also, when we rounded together this morning, you mentioned that Mrs. Smith needed a head CT today, but I didn’t see that ordered for her. Was this ordered on the wrong patient?” The oncologist responds, “No, both patients need a head CT. I must have missed ordering that on Mrs. Smith. Thank you for bringing that to my attention. Great catch. Now let’s talk about Mrs. Jones. You said you weren’t sure why it was ordered on her. Tell me what you see with her and why you think a head CT would or would not be important…”

The culture of the nurse-physician relationship has changed dramatically over the past years and is one of the most important drivers of a healthy work environment. Magnet research has demonstrated the importance of healthy nurse-physician relationships on outcomes for nurses, physicians, and patients.5 It is much easier to have a crucial conversation with someone with whom you have an established, respectful working relationship.

Policies, procedures, and workflow are essential in healthcare facilities to provide safe care of our patients. However, shortcuts will be taken, resources will be stretched, and emotions will run high. We will all make mistakes, and we will all see mistakes about to be made. How we respond to those situations will make or break our safety mechanisms and directly impact our patients. My advice to both nurses and oncologists is: Treat each other with dignity and respect, get to know your coworkers’ professional strengths and weaknesses, build off one another’s strengths to further your own professional development, and mentor others to increase their knowledge and expertise.


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
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Like most Americans, you’ve probably noticed a significant increase in the amount of credit card and rewards card offers you’ve received lately. That’s because the number of offers dispersed through the mail during the second quarter of 2010 exceeded 1 billion, more than double the 419 million for the same period in 2009, according to a report from Mintel Comperemedia, which tracks direct marketing.1 As a physician, you’re likely receiving more than your fair share.

Credit cards and rewards cards are a staple in today’s society, and have been for many years. According to “The Survey of Consumer Payment Choice,” published by the Federal Reserve Bank of Boston in January 2010, there were 176.8 million credit cardholders in the U.S. in 2008, with the average credit cardholder having 3.5 credit cards. About 60% of all consumers had a rewards credit card.2

What’s challenging, however, is wading through the sea of offers to select the credit card or rewards card that is right for you. The card you end up with should be a reflection of your needs, lifestyle, and purchasing habits—and that’s going to be different for every individual. But the process of card selection holds true no matter what your purchasing profile looks like.

Names and interest rates

There were 270 million Visa credit cards and 203 million MasterCard credit cards in circulation in 2009.3,4 The numbers for American Express and Discover credit cards pale by comparison, and stand at 48.9 million and 54.4 million, respectively.5,6 Those numbers, says Joel Ohman, CFP, founder of the Website CreditCardChaser.com, are an important consideration in the credit card selection process.

“A good rule of thumb is to have at least a Visa or a MasterCard, because they’re accepted in more places,” says Ohman, who admits that his favorite is an American Express cash back card. “But some places just don’t take it.” He explains that some merchants may not want to pay additional and/or potentially higher fee schedules for Discover or American Express, and rationalize that, given the lower number of consumers holding either of those two cards, they won’t be losing a lot of business by declining them.

As for interest rates, Christine Moriarty, CFP, president of Vermont-based MoneyPeace, Inc., says that should be less of a concern in your decision-making process, especially if you don’t plan on carrying any balances forward from month to month—a practice she strongly advocates.

“The only time it makes sense to carry the balance from month to month is for someone who gets reimbursed for business expenses,” Moriarty says. That’s because individuals who need to use their credit card for travel may receive their monthly statement prior to being reimbursed. “If they pay the bill in full, most will have to dip into savings or wreak havoc on their household financial system.”

Of greater importance, she says, is to remember that many credit cards, and quite a few rewards cards, carry annual fees, such as the American Express Premier Rewards Card, which comes with a $175 annual fee—another practice Moriarty frowns on. “I may be old-fashioned, but I’m also living in today’s world. And I say an annual fee is not necessary.”

Travel points or cash back? Are you a frequent traveler, either for business or pleasure? If so, Ohman says it makes more sense to obtain a card that helps you earn points or cash back toward airline tickets, or an affinity type program that offers higher average rewards if you travel on a select airline or stay at a specific hotel chain. Two of the more popular travel rewards cards are the PenFed Premium Travel Rewards American Express card, and the Simmons First Visa Platinum Travel Rewards card. The former awards five points for every dollar spent on airline tickets, and three points for every dollar spent on hotels and dining. The latter awards one point for every dollar spent, with 22,000 points needed to quality for an airline ticket.

For many, however, a basic cash back rewards card will suffice.

“I’m fairly average and I don’t travel a lot,” Ohman says. “If I had to pick, I’m very happy with my plain cash back card. I don’t have to worry about different formulas for calculating ratios and points. I know that if I spend X-amount, I’m going to get 1% or 2% back. People tend to like the cash back cards because of their simplicity.”

Speaking of keeping things simple, Moriarty cautions those shopping around for a credit or rewards card to be aware of credit card roulette, a practice whereby the rewards categories rotate periodically, sometimes quarterly, making it a little more challenging to keep track of which purchases are earning you the maximum amount of cash back. Moriarty tells her clients to steer clear of those types of cards.

“Take that same energy [used to keep track of changing categories] and put it into devising a payment plan to pay off your credit card,” she suggests.

Ohman agrees. He points out that there are two different types of people when it comes to rewards cards. There are certain people who like to be extremely frugal. They like to clip out coupons, they’ll comparison shop, and are the type of people who get the flyer brochures from their credit card company every quarter with the different cash back categories and they’ll schedule purchases, knowing they’ll use one credit card during one quarter for this type of purchase, and another card for another type of purchase the following quarter. But Ohman’s thought process, perhaps similar to that of many physicians, is different.

“For me, my time is money, so I’d prefer not to have to think about all these different categories, and get confused by different formulas and have to remember what to spend during what quarter,” he explains. “It’s hard to keep track of.”

Side-by-side comparisons

There are a wide range of websites that not only rate different credit and rewards cards, but also enable consumers to compare them side by side, in categories ranging from Introductory Period APR to earnings and rewards potential. These sites include Ohman’s CreditCardChaser.com, as well as LowCards.com, Credit.com, and CreditCards.com. Moriarty says the website she is most familiar with is BankRate.com, and points out that while these sites contain a lot of valuable information, it’s important to know that the source of that information is unbiased. Ohman says the information under the “Compare Cards” tab on CreditCardChaser.com is probably the most updated information imported directly from the different credit card companies. However, he stresses that “if someone is looking for the absolute gospel, these credit card holder agreements can change all the time.” He suggests that before applying for a credit card, consumers read through the disclosures that are required on every application to make sure they’ve applied for the card that’s best for them.

One category to be aware of when comparing credit and rewards cards is Credit Needed, or the minimum threshold of credit that’s required for obtaining that particular card. Some cards list that threshold as “Good,” while others carry a “Fair” or “Poor” indication. The reason for the low threshold is that some credit cards are specifically designed and marketed toward people with poor credit, giving them an opportunity to rebuild their credit. As such, unless you have less than good credit, it’s advisable to steer clear of those types of cards.

In addition, says Moriarty, the “Poor” rating under the Credit Needed heading could say a great deal about the company offering the credit or rewards card. “You want to stick with a big name company that’s going to be reliable for handling your debt and your money, and for reporting to the credit bureau. Know who you’re dealing with.”

Avoid the pitfalls

One of the biggest mistakes consumers make when they obtain a rewards card, says Ohman, is becoming so focused on the fact that they’re earning 2% cash back on their purchases that they forget to pay their balance in full each month. If your card carries an interest rate of 10% or 12%, failing to pay off the balance each month can negate your cash back rewards for several months. Some credit and rewards cards, however, offer a way to avoid that dilemma.

“My American Express card has a nice little feature where I can log in online and set up an auto pay for the full balance every month,” Ohman explains. “So when I make a purchase it’s just like using my debit card, only better, because I’m getting cash back.”

One very important element in selecting a credit or rewards card, says Moriarty, is to know oneself. “And knowing yourself may include not getting a rewards card. If you know you’re the impulsive type who will buy a lot of things just to get the rewards, you might actually end up spending more money in the long run.”


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
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using a smartphone to access medical recordsSmartphones are becoming the most transformational IT solution to ever impact healthcare. In developed countries they are in the process of changing the practice of medicine due to their ease of use and inherent portability. However, fellows face some challenges due to the learning curve involved in adapting to the smartphone’s digital delivery options. In fact, patients seem more adept at learning how to receive digital healthcare information than most physicians are at figuring out how to provide it.

The practice of healthcare lends itself well to smartphones, which provide a wide range of conveniences and workflow efficiencies that cannot be achieved with traditional tools such as notepads and pocket medical references. Smartphones allow physicians access to most updated information in the form of podcasts, smartphone apps, and more. They don’t need to carry tons of books or subscribe to dozens of hard copy journals. Podcasts are audio files that you broadcast or listen to on demand, and they usually have subscription options that allow updates to be automatically downloaded to smartphones. As for apps, for the iPhone alone there are currently almost 6000 medical-related apps in Apple’s App Store. Apps targeted to physicians include alerts, medical reference tools, diagnostic tools, and continuing medical education. Podcasts and apps give you the option of accessing only what you need, when you need it.

In the oncology world, protocols, interventions, and research change at a rapid pace, causing day-to-day variations in the ways that patients are treated. It is very important for an oncologist to have the most up-to-date information as soon as it is available. Smartphones are always connected to the information source and are capable of providing instant updates. For oncologists, the smartphone is able to access drug reference guides on the go, monitor a patient’s health conditions, and securely share electronic health records. Consequently, there is tremendous improvement in the time taken to make decisions. Healthcare is now a team effort, and using voice over IP (VoIP), unified communication tools, and instant messaging allow for effective clinical collaboration. If an oncologist receives an alert about a patient, he or she can call 2 colleagues instantly on a smartphone for a second opinion.

Oncologists are using their smartphones to hasten access to the most updated information and also to expedite the decision-making process. And you no longer see this pattern only among young oncologists; senior physicians are doing it as well. With advancing technology, more and more clinical data can be accessed, including NCCN guidelines and clinical articles from numerous medical journals. Not only are there apps for calculating prognostic scores to give survival estimates, but also apps to access the most recent clinical trials in progress. With such rapidly changing clinical practices and ongoing research, it is difficult for oncologists to stay up to speed on all the latest advances. But the apps that give access to the chemotherapy protocols, drug regimens, and the most updated research are an enormous information resource for oncologists.The access to online oncology communities such as Sermo.com and QuantiaMD has been made even easier with smartphones. You can post clinical questions and discuss them online with your colleagues and seek their expertise. Mobile technology, which includes iPads, is a revolutionary change for access to medical information. We can access these devices to show lab trends and imaging studies, as well as explain to patients—in a pictorial format—their diagnosis and its implications. The ease of access to this kind of information can save a lot of time and ensure faster delivery of quality care to the patients. The accessibility to the healthcare information at the point of care makes a huge difference in decision making, both for the patient and the oncologist. It can reduce the burdens of apprehension and anxiety associated with the diagnosis, treatment options, and prognosis for the patient and his or her family.

Epocrates is another popular app that is used by oncologists. Epocrates not only provides drug information but also dosages, adverse reactions, interactions with other medications, pricing, brand names, body surface area calculations, chemotherapy dosage calculations, and more.

In the past, such apps were used primarily on PDAs. However, with the advent of smartphones and other mobile devices, the apps can be easily installed and accessed on the phone at any time. Over the past few years, there has been an increasing trend of using smartphones and other mobile devices as sources for reference information. This is a big step forward from the days of PDAs and, further back, hard copy books and journals. With the rapidly changing clinical advances in oncology, the trend toward accessing resources via smartphone will only increase.


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
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I have just finished my 15th year on faculty and my 13th year directing the hematology/oncology fellowship program at the Medical University of South Carolina. Although none of what I have learned along the way is truly novel, I hope that a few observations born of experience in my professional life will help you achieve success and happiness in yours.  

Board Exams



Take ’em, Take ’em Early, and Keep On Taking ’em Until You Pass ’em

Take whatever boards you are eligible for as early as possible. A board exam covers the specialty’s full breadth, yet odds are good that once in practice you will quickly come to focus in some subset of the specialty. Do not be surprised if you quickly lose much of your knowledge, skills, and currency in any area in which you do not regularly practice. So take your exams at the earliest opportunity. For those training in combined hematology/oncology, do not wait to take the hematology exam until the year after taking the oncology exam. And if you feel you need extra study time, ask for it (ideally when negotiating your employment arrangements). Your employer wants you to obtain and maintain certification for all boards for which you are eligible, so a wise employer should grant you a reasonable amount of study time if you think you need it.

Experience Always Trumps Reading, but if Reading Is All You Can Do…

Unless you are convinced your knowledge in a particular area is deficient, do not bother studying much for your first attempt at the boards, with 1 exception: hematology/ oncology fellows should not forget that gynecologic oncology is on the oncology boards. In many adult medical oncology and hematology/oncology programs there is little opportunity to attend didactics in—let alone practice— gynecologic oncology, so this area of the boards can hurt you if you have not even read in this area. Remember that board questions are written carefully, and it has been my consistent observation across multiple exams that if you have seen a case of X within the last year or so, you will quickly know the right answer. Conversely, if you have never seen a case of X, you may be able to narrow it down to a couple of choices, but mere preparatory reading likely will not help you any more than a coin fl ip would. So if you fail an exam, actively seek opportunities to practice (and read) more in the areas in which you were deficient. (You will always learn far more from practice with reading than reading without practice.) Then take that exam again as soon as possible.

Do Not Waste a Year of Your Life

If you are in a combined adult hematology/oncology program and facing the prospect of not 1 but 2 (expensive) exams, just suck it up and take them both until you pass them both. It is silly to have spent an unrecoverable year of your life in exchange for a modest fellow’s salary and the right to take the hematology boards—and then end up not getting certified in hematology. (At that rate, you would have been far better off doing just 2 years of oncology training and going right out into practice.) So take ’em both until you pass ’em both. It makes an important statement to yourself, your colleagues, your institution, and, most importantly, your patients. And if you flunk the hematology boards on your first attempt but then are so focused on your oncology practice that you realize you need to take a hematology review course prior to retaking the hematology boards, then by all means take a hematology review course.

Your Next Board Exam Is Sooner Than You Think

Maintenance of certification (MoC) processes are far from perfect, but they are the best methods we have for assuring those around us of our continuing competency. You should keep abreast of the seemingly ever-changing MoC requirements and develop a plan to meet the requirements starting at the earliest possible point. Your practice and perhaps other work will quickly grow to consume your professional life, so if you have not developed and followed your MoC plan, you will find it needlessly challenging and anxiety-provoking to rush at the end to finish everything that must be done before you can once again sit for the boards.

Career Direction



Don’t Worry, Be Happy

Barring the grossest lapses of competence and professionalism on your part, you will always be highly employable— likely in the setting of your choice, too. Furthermore, as you age, you’ll increasingly appreciate how short life is, particularly the truly healthy portion. Therefore, the best advice I can give you is to know yourself and then, whenever possible, do what makes you happy. And, if your interests change in time—especially if you reach a point where, day after unending day, you get up in the morning not looking forward to what awaits you—be willing to change your work.

Loans? My Happiness Doesn’t Need No Stinking Loans

When you finish fellowship and enter practice, you will quickly earn enough to provide you and your family a good quality of life and still be able to pay back your student loans far faster than you might be able to believe right now. Therefore, I recommend you try to not let the size of your loan portfolio drive your choice of initial job. Select the position you feel you will enjoy the most rather than the one that will compensate you the most.

Making the Transition



I’m Really in Charge Now?

As recently discussed by William Wood,1,2 a regular contributor to HemOnc Today, the initial post-training stage of your professional life may be the most unnerving you will ever face, quite unlike the beginning of your internship or fellowship.Late in fellowship you will be pretty comfortable in your work due more to a growing base of experience than a growing base of knowledge. But another invisible factor contributes substantially to your comfort in training: you still are not responsible for what happens to your patients, at least not nearly to the extent that your faculty are. But as noted by Dr. Wood, suddenly one morning—and for the rest of your career—no one is more responsible for the consequences of your actions than you.

My recommendation: do not worry so much about being smart, and instead just be willing to work hard—and be humble. Quietly do what you are confident in doing, but when you realize you know less than would best serve the situation, admit it and seek help. Tell the patient you need time to review the latest literature. Step outside the exam room and ask your colleagues for advice. Present the case at tumor board. If there is not a tumor board where you practice, start one. Your peers and patients will be more impressed with you for your self-recognition of your deficiencies and your quest for self-improvement.

A Few Points for Success in Practice



The Toughest Decision: Doing Nothing

Advancements in medical science and in the evolving medicolegal and healthcare financing landscapes have created an often inappropriate sense of obligation, even a terrible temptation, to do things to patients. Early in your career, when your experience base is still relatively light, there can be insufficient appreciation of the potential for harm—medical, financial, and otherwise—posed by many interventions, both diagnostic and therapeutic. In 2011 cancer remains a bad disease, and though a majority now survive their disease,3 about a third still do not. Therefore, “first, do no harm” remains a terrific guiding principle.

"It fundamentally remains your choice in every encounter how much you will succumb to the ever-present pressures to minimize your time with the patient."

Patient History: The Hematologist’s Best Friend

Typically, different types of satisfaction are gained from addressing oncologic problems versus hematologic problems. In malignancy (solid or liquid), the diagnosis is rarely in question. (Do not be misled by the disproportionate share of unusual cases of diagnostic question that funnel into an academic center.) Thus, your satisfaction as an oncologist is largely derived from (1) identifying which treatment likely will off er the greatest benefit/cost ratio and (2) using your knowledge and skills to guide the patient through the treatment as effectively and comfortably as possible. After that, aside from further surveillance and prevention efforts, there is not much more for you to do than what your patient has been doing all along: hope for the best.

In nonmalignant hematology, though, the diagnosis is often the primary question. Toward that end, I will opine that the diagnostic hematologist’s best friend is almost always the patient’s history. Th e modern pressures impeding the physician’s ability to take a full history are apparent, but you will have a pretty good idea by the end of the evaluation what the correct diagnosis is if you (1) take a complete history and (2) always give preference to diagnoses that unify as many of the case findings as possible. Th e quickest route to erroneous diagnosis, futile (even harmful) diagnostic and therapeutic interventions, and dissatisfaction of all parties is skimping on history-taking and focusing exclusively on the patient’s hematologic issue.Most nonmalignant hematologic aberrancies are reactive, not primary. Make a point of figuring out the true root of the problem if you want the best outcomes. If you cannot figure it out at first (for lack of time or whatever other reason), do not give up. Revisit the situation soon and again think about the best unifying diagnosis. And if a few at-bats still do not yield the right answer, be humble and ask for help. Truly new, never-before-seen diseases are extremely rare, so it is far more likely that the situation indeed is diagnosable and just needs a fresh look—and the persistent use of readily available knowledge sources.

Normal Is Not Always Normal and Abnormal Is Not Always Abnormal

Look at every test result (there is a reason that a complete blood count includes more than just hemoglobin, leukocyte, and platelet counts) and try to at least briefly ignore the presence or absence of the High/Low flags, asking instead whether the result is Expected/Unexpected. (Oh, for a computer that could show “E/U” instead of “H/L”!) For example, try to train yourself not to reflexively think—let alone reflexively work up or treat—“iron deficiency” upon seeing microcytosis. Take a moment to trend the parameter and put it in context. For example, chronic stable mild microcytosis in a black person is far more likely to be alpha thalassemia than iron deficiency. Conversely, a newly “normal” mean corpuscular volume in a known thalassemic may bear as much significance as frank macrocytosis in a nonthalassemic.

What Patients Really Want From Their Physicians

Sure, your patients would like you to cure them, but they understand this often is not possible, so what they want even more is for you to allay as much as possible their physical pain and then the psychological pain that comes from the uncertainty about their future (and their family’s future) that is inherent with any serious illness.

Allaying a patient’s uncertainty takes a physician’s time; there is just no way around it. But it fundamentally remains your choice in every encounter how much you will succumb to the ever-present pressures to minimize your time with the patient. Furthermore, though you may enjoy the artifice of duty hour limits while in training, once in practice you should never forget that in becoming a physician, you chose to always place your patients’ interests before yours, so always try to give your patients whatever time of yours they need. As a rule to live by, “do unto others as you would have them do unto you” will not be going out of style anytime soon.

Final Words



Odds are you will be competent upon finishing your training, but competence is merely necessary, not sufficient, for happiness. If you got into medicine for the reason most of us did, every day you spend serving your patients and colleagues the best you can will go a long way toward furthering your own happiness. Good luck!


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
View the full PDF of this issue

References

  1. Wood W. Fellows’ perspectives: looking back: lessons learned in fellowship. HemOnc Today. May 25, 2010. Available at HemOnc Today. Accessed August 15, 2010.
  2. Wood W. In practice: getting started as an attending. HemOnc Today. July 25, 2010. Available at HemOnc Today. Accessed August 15, 2010.
  3. American Cancer Society. Cancer Facts & Figures 2010. Atlanta: American Cancer Society; 2010.


CommunicationEach year the healthcare industry weathers a heavy financial burden: the cost of medical malpractice claims. In the article “10 Ways to Reduce Medical Malpractice Exposure—Doctors, Lawyers, and Lawsuits,” which was published in the March 2002 issue of Physician Executive, Dr V. Franklin Colon reported that the annual dollar costs were well into the billions. The solution to the problem, however, is not to pay out exorbitant premiums to ensure adequate malpractice insurance coverage. It is much simpler than that.

“I think oftentimes the simplest things are the most effective,” said Gerald Chambers, a medical malpractice defense attorney at the law firm of Turner Padget Graham & Laney P.A., based in Columbia, South Carolina. “Communication is one of the major factors in avoiding litigation and assisting in the defense of a lawsuit, as well.”

And it takes only a few minutes.

Building Rapport



Peter Hoff man is an attorney and chair of the Professional Liability Group at Eckert Seamans, a law firm in Philadelphia, Pennsylvania. He said that people go into medicine be cause they want to help others. They work hard in college and medical school, and then at some point between their second year in medical school and when they become an attending physician the situation changes. For many physicians, several factors—such as the sheer amount of work and responsibility— can cause them to treat patients as cases, not as people.

“Th e people and families that they’re dealing with…are under a tremendous amount of stress [and] uncertainty, and they know their life is changing—and certainly not changing for the better,” Hoff man explained. “I think that the most important thing for [oncology fellows] to realize is that they’re dealing with people, not 3 x 5 index cards. And they owe to their patients and to themselves, the time that it takes— maybe time that they don’t think they have—to develop a relationship and rapport with these people and with their families.”

Chambers echoed those thoughts. He said that numerous lawsuits are brought by patients or their family members simply because they got angry with the physicians. Th ey feel that the physicians have not spent enough time talking with the patients and helping them to understand their cases.

“Sometimes it’s just that the patient is upset with their doctor because they feel like they’re not being given the time and the attention that they deserve,” Chambers said. “Often this is avoided by simply spending a couple of extra minutes with them.”

He also pointed out that discussions between physicians are equally important, especially in an oncology practice, where various consultations with the patient are necessary and sophisticated lab tests need to be ordered. It is also critical to communicate with the lab to ensure that the results of an ordered test do not slip through the cracks.

“And make sure the results are being communicated between the various physicians who may be taking care of a patient,” Chambers added. “Because often it’s not just 1 doctor who’s taking care of a patient, it’s a team of doctors. And you need to make sure that everyone understands what the game plan is and who’s responsible for what.”

"Gerald Chambers said that numerous lawsuits are brought by patients or their family members simply because the got angry with the physicians."

Detailed Documentation

Along with communication, documentation is critical for helping to avoid malpractice claims. Even effective, thorough communication should be documented. Dr Barry Lang was an orthopedic surgeon for 23 years and has worked for the past 15 years at Law Doctors, a medical malpractice agency based in Boston, Massachusetts. He claimed that he was able to effectively link communication and documentation during his years as a practicing physician.

“I had a Dictaphone in every examining room, and the purpose was several-fold,” Lang explained. “Number 1, when you speak with a patient—when you take their history and describe what their treatment program is going to be—it helps to have the patient hear it a second time. And since you have to make notes of the encounter anyway, you might as well give the patient the opportunity to hear it a second time.”

Lang continued, “So after I had completed taking the information from the patient after the examination, instead of waiting until the end of the day to try to recall what may have gone on with 20 or more patients—or just scribbling a few notes where I might leave something important out, and then leaving the patient with just 1 conversation between the two of us—I would pick up the Dictaphone and I would dictate a complete note of what just transpired.”

Lang said the Dictaphone not only saved him time and effort, it gave the patient the opportunity to hear the exchange a second time and opened the door to an additional opportunity for discussion.

“Th en you ask the patient, ‘Did I forget anything and do you completely understand?’” said Lang. “If there are any questions at that time, you can go over them. So not only does that help the doctor, it also helps the patient. In addition, it may help avoid litigation—or if there is litigation, you have a set of notes that outline everything you did for your own defense.”

Chambers agreed. He says it is critical for oncology fellows to ensure that patients understand, to the best of their ability, the recommendations and treatment options they are being presented with. And in the field of oncology, it may be difficult for a layperson to understand the concepts and terminology that physicians often take for granted.

"Just because the document states that the form covers everything, including death, does not completely protect the doctor."
“It’s a lot easier to put an X-ray up on a screen and say, ‘Okay, here’s where you broke your arm’ than to put up an MRI and say, ‘Th ere’s where your cancer is,’” Chambers said. “I think with oncology more so than other fields, you just have to take more time to explain to the patient what their situation is and what the treatment options might be. You don’t want to over-document, which can become problematic as well, but you need to communicate, and you need to document your communication, as well.”

Informed Consent



Lang noted that a very important part of communication is informed consent. Too often the informed consent form is just a printed sheet from the hospital that is very generalized. “And I would say that in my practice, about 9 out of 10 times, nothing is filled in by the doctor,” he claimed. “Th ere’s just a signature on the bottom of the page by the patient and the doctor.” Lang explained that informed consent does not relieve the doctor of negligent care. Just because the document states that the form covers everything, including death, does not completely protect the doctor. Instead, the physician needs to write in certain common complications that he or she has spoken about with the patient.“A doctor isn’t responsible for writing down every possible complication of every procedure,” Lang said. “His writing would have to be encyclopedic. He doesn’t have to include extremely rare complications. Th e law protects him with that.” Lang continued, “But if the doctor knows that there are certain complications that can occur with a surgical procedure… he should write that down so the patient understands, and so the patient can’t later say the physician didn’t discuss that.”

Lang also stressed that there is a time and place to obtain a patient’s informed consent. He said that the form should be signed during an office visit before the patient is admitted to the hospital. Th at indicates that the doctor has spent time talking to the patient and that the patient did not sign a bunch of papers without reading them while stressed and/or medicated.

“You’re talking about the expenditure of a few minutes to save 4 years of litigation,” Lang said. “It’s well worth the investment. A lot of doctors are rushed, they’re overworked, and these things slip through the cracks, and then they get into trouble. And it’s really so easy to take those couple of extra minutes just to avoid the litigation.”

A Matter of Trust



Hoff man explained that the bond between patients and physicians is very important. He urged physicians to look their patients in the eye and talk to them as if they matter—as though they were speaking with their own aunt or uncle. Hoff man said, “Put them at ease and develop a trust.”

And when things go wrong? Hoff - man said, “[With something] as simple as an IV injection that’s not done the right way, or [with] an IV that’s hard to establish and the patient is in pain, the physician has to say, ‘I understand this happened and I apologize for that. Th is is what we’re going to do to try to make it better.’ That’s a skill that’s not taught.”

Hoffman pointed out that cancer is often referred to as The Big C, but that “C” also stands for “communication.” He said, “You only have so much time with the patient, but you want to make them feel that they’re the only thing on your mind at that time.”

If You Suspect Litigation



Despite all your precautions, malpractice claims are going to occur. Chambers said that if there is even the slightest hint of litigation on the horizon, you should contact your malpractice insurance company.

“Typically, most [malpractice] carriers will go ahead and investigate the claim and even retain an attorney to investigate it,” Chambers said. “For instance, if you get a request for a medical record saying something to the effect [of] ‘We are requesting the medical record of this patient to determine whether or not the treatment you provided was appropriate’… you need to immediately put your carrier on notice, and more likely than not they will get an attorney involved in investigating that claim early on.”

Chambers pointed out that in most states the statute of limitations is somewhere around 2 to 3 years, and it is typical that a plaintiff ’s attorneys will wait until the very end of that time to file a lawsuit.

“All of a sudden you’re trying to remember back to what happened 2 years ago, and people may have moved on,” he said. “There may have been a key nurse involved who is no longer there, or a partner [has] moved on. It’s just not as fresh in your memory. So it’s always best to start investigating those [malpractice] claims at the earliest opportunity.”Ultimately, there are no guaranteed, surefire ways to make you immune from malpractice charges. But if you show your patients that you are not arrogant, you care about them, and you will take the time to allay their fears, you have made a crucial first step toward potentially preventing a costly lawsuit.


Ed Rabinowitz is a veteran healthcare journalist based in Upper Mt. Bethel Township, PA.

This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
View the full PDF of this issue


Delivering bad newsHow do you tell a 45-year-old mother of 2 that not only has her breast cancer returned but it is now incurable? Or how do you explain to a 22-year-old student that despite intensive chemotherapy and a 6-week hospitalization, he still has acute leukemia and is not eligible for a bone marrow transplant? Even for an experienced oncologist, walking into a room and initiating a conversation that will change the life of someone who sought your help can be a daunting challenge.

Early in your oncology training, learning the biology and treatment of a dozen malignancies was a task that seemed overwhelming. For many oncologists, knowing how to compassionately deliver bad news—something that is often learned through trial and error—is less important than absorbing and understanding an avalanche of cancer-related information. But just as you need to know how to discuss the efficacy and side effects of a chemotherapeutic agent whose name at first you could barely pronounce, you must learn to disclose the truth with sensitivity for patients’ concerns. This is a vital skill that all oncologists must hone.

The Importance of Compassionate Communication



Difficult conversations between oncologists and patients about prognosis, disease progression, and death are a crucial part of the treatment process. Whereas physicians may not recall all the difficult conversations they have had, despite how painful they seemed at the time, patients and their families will remember them word for word. They will remember whether you approached this juncture with truth and compassion, or whether it was awkward, rushed, and filled with medical terms they could not understand. They will remember if they left this life-changing visit with a sense of clarity and understanding or with fear and hopelessness.

Good communication can help clarify patients’ understanding of their disease, ease adjustment, and lessen physical and emotional pain. It can also leave them more satisfied with their care.

Learning Communication Skills



Many people believe that effective communication skills are not something that can be taught or learned and that some physicians are just better or more natural at it. Though it may be true that some may have an innate facility for conversation, you can develop the necessary tools to communicate clearly, effectively, and compassionately.

Fellowship is an excellent time to begin developing your skills. Just as you study the algorithms of the National Comprehensive Cancer Network to treat lung cancer, you can learn a framework for how to approach a difficult conversation that will make the task less daunting while offering deeper value to your patients.

The literature has proposed a number of models for effective communication, but the most widely accepted is “SPIKES,” a 6-step protocol developed by Dr Walter Baile and colleagues at The University of Texas MD Anderson Cancer Center.1 The individual letters represent the following: (1) setting up the interview, (2) addressing the patient’s perception, (3) obtaining the patient’s invitation, (4) giving knowledge and information to the patient, (5) addressing the patient’s emotion with empathic responses, and (6) strategy and summary.

According to Baile and his team, the goal of SPIKES is to allow you to fulfill the following 4 important objectives of the interview in which you deliver bad news1:
  1. Gather information from the patient.
  2. Provide intelligible information in accordance with the patient’s needs and desires.
  3. Support the patient by employing skills to reduce the emotional impact and isolation experienced by the recipient of bad news.
  4. With the patient’s input and cooperation, develop a strategy in the form of a treatment plan.

The SPIKES Protocol



Meeting these 4 goals can be accomplished by completing the steps of the SPIKES protocol. Although all 6 steps are not always needed, when they are it is important that you follow them in order:

"You will ultimately develop your own style of delivering bad news to patients."
Step 1: Setting up the interview. You should be sensitive to the patient’s surroundings as she receives life-changing news. Be sure that you are in a private room and that she is accompanied by a family member, if desired. One of the most challenging aspects of having difficult conversations is the time involved. But even if you feel rushed, you should sit down and maintain eye contact with the patient to help her relax and show her that she is your priority. You should tell her in advance of any time constraints or expected interruptions.

Step 2: Addressing the patient’s perception. Before launching into a detailed conversation, ask open-ended questions to get an accurate picture of how the patient perceives her medical situation. Th is not only gives you a glimpse into whether she is experiencing denial, wishful thinking, or unrealistic expectations, but it allows you to tailor your discussion based on what she already knows.

Step 3: Obtaining the patient’s invitation. To you as an oncologist, it may seem obvious that the patient is in your office and therefore is prepared to hear full information about her diagnosis, prognosis, and treatment. But some patients do not want all this information. Asking a patient, “Would it be okay to go over the details of your test results?” or “Shall we spend more time discussing the treatment plan?” will let you know how she wants to receive the information.

Step 4: Giving knowledge and information to the patient. Th is is the part of the conversation we tend to focus on and likely have the most experience with. When giving medical facts, start at the level of comprehension and vocabulary of the patient. If necessary, use words such as “spread” instead of “metastasized” and “sample of tissue” instead of “biopsy.” Do not forget to repeatedly check in with the patient to ensure that she understands what you are saying.

Step 5: Addressing the patient’s emotion with empathic responses. Responding to strong emotions is one of the most difficult challenges in breaking bad news. Patients’ emotions may vary from silence to disbelief, crying, anger, or denial. Physicians often feel uncomfortable addressing these strong emotions and may compensate by providing more information about the disease or treatment. An empathic response is one in which you not only recognize the emotion that the patient is experiencing (such as anger, sadness, or denial) but directly name it back to her. For example, after hearing that her metastatic colon cancer has progressed, the patient is surprised and angry. An empathic comment would be, “I can tell that this news is not the news you expected and that it makes you very angry. I also wish that the news were better.” A comment like this lets the patient know that you understand how she feels and validates that such thoughts are normal and expected.Step 6: Strategy and summary. Before discussing the treatment plan, it is important to determine whether the patient is ready. If she is still experiencing strong emotion, it is unlikely that she will be able to move on to discuss a treatment plan or prognosis. Isolation, fear, and uncertainty are common feelings that patients may have, and letting them know that you will be with them on this journey is reassuring. Once you determine that the patient is ready to discuss the treatment plan, you must understand her treatment goals, such as symptom control. You can then frame hope in terms of what is possible to accomplish.

Final Thoughts



You will ultimately develop your own style of delivering bad news to patients, and this model is just 1 tool that can be used as a beginning framework for enhancing your communication abilities. The patient benefits, plus you are rewarded by learning skills that transform the dreaded task of delivering bad news into a skill that can be mastered with practice. Also, you will probably find that your self-confidence increases over time. Armed with this knowledge, you will soon find that the words will flow easier, your connections to your patients will become stronger and more meaningful, and you will become better able to understand their disappointments, fears, and hopes for the future.


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
View the full PDF of this issue

Sheetal M. Kircher, MD, is a second-year oncology fellow at Northwestern University’s Feinberg School of Medicine in Chicago, Illinois.

Reference

1. Baile WF, Buckman R, Lenzi R, Glober G, Beale EA, Kudelka AP. SPIKES—A six-step protocol for delivering bad news: application to the patient with cancer. The Oncologist. 2000;5:302- 311.


Though it may seem that the job interview itself is the most daunting aspect of your job search, in reality it is what looms at the end that makes even the most confident fellow anxious: the dreaded salary-negotiation process. But you can conquer your fear. Whether you are negotiating an $80K or $580K salary, the strategies for success are the same.

“It’s about finding the right job and making sure they want to hire you before you start negotiating salary,” said Lee E. Miller, author of Get More Money on Your Next Job… in Any Economy and co-author of A Woman’s Guide to Successful Negotiating: How to Convince, Collaborate, & Create Your Way to Agreement. And the entire process starts with being properly prepared.

What Are You Worth?

Eric Dickerson, managing director at Kaye/Bassman International in Dallas, Texas, is a top recruiter for the medical field. He said that well before going on a job interview, it is essential that you clearly understand your value in different regions of the country. That is important for fellows, because they often want to live and work in a certain geographical area. Recruiters can tell you the median compensation for a medical oncologist, but unless they do some research they cannot tell you what it will pay in the South, West, North, or East. And even within those regions there are variances. Certain markets have salary caps due to reimbursement constraints that have developed over the last 5 to 10 years. Other areas will pay more based on the demands of the marketplace and according to the needs of a particular hospital or physician practice.

“Doing the research is not just looking at a national salary survey,” Dickerson explained. “It’s truly understanding the geography of where you are or where you want to be.”

So, where can you find that data? Miller said that there is a lot of general information available on the Internet. But for a specialized area like oncology, it is best to talk with people in the field, including members of trade associations. This is not unlike first researching the selling prices of comparable neighborhood homes while house hunting.

“You want to learn what other people in similar positions are earning,” Miller said.

At this stage, you may wonder whether you should work with a recruiter. Dickerson cautioned, however, that not all physician recruiters are well versed in the oncology field, so you should determine their particular strengths and weaknesses. If you tackle the job search process on your own, you will certainly save money. Recruiters earn their commissions by taking a percentage of your future salary, making your actual take-home amount smaller. But if you choose to use a recruiter, be sure you understand the level of physicians they have worked with as well as their knowledge of the oncology market.

Dickerson added, “It never hurts physicians to interview various [recruitment] firms to decide with whom they want to work.”

Lee E. Miller said, ‘If you want to buy a Mercedes, you don’t go out and buy a Hyundai just because it’s cheaper.’ ”

Broaching the Subject

Experts agree that salary is the very last thing that should be discussed in the job interview process. According to Miller, it is all about timing.“Think of it in terms of when you buy a car,” he suggested. “What’s the first thing a car salesman does? He gets you to drive the car. Because once you drive the car and you fall in love with [it], all of a sudden it’s not the price that matters.” Miller said the buyer will then try to figure out how to afford the vehicle, because he just has to have it.

“The same is true with a candidate,” claimed Miller. “Once they fall in love with you and you’re the one they want, then it’s ‘How do we make this happen?’” They won’t “buy” the lower-priced oncologist if he or she is less qualified than you are. Using a vehicle analogy, Miller said, “If you want to buy a Mercedes, you don’t go out and buy a Hyundai just because it’s cheaper.”

Raising the salary issue too early during the interview process can also harm your chances of landing the position you desire. For example, if you float a figure and it is too high, you have just priced yourself out of the position. If you come in too low, the interviewer may think you do not consider yourself qualified enough. Or, they may eagerly hire you because they realize they have found a bargain.

“The basic rules in life are, you don’t get what you deserve— you get what you negotiate,” Miller said.

Dickerson echoed those thoughts. “Negotiation 101 says that when your initial offer is accepted immediately, that indicates they know it’s a good deal and you could have gotten a whole lot more,” he explained. “You’re shooting yourself in the foot.”

Rather than discuss dollars, Dickerson suggested you demonstrate your value to the hospital or medical practice. For example, he encouraged fellows to talk about the job and about the facilities. Who are your peers? What does the practice group look like? Tell the interviewer you would like to speak with others at the hospital or practice. Salary is important, but there are a lot of other deeper, long-lasting factors beyond the money.

“By taking that approach, what you’re doing is really demonstrating a focus on the value you could bring,” Dickerson said. “Therefore, when it gets to the point at the end of the game that it’s time to talk about money, you have taken the time to demonstrate that value. And therefore your perceived value would deservedly be closer to the best possible market price you could have, versus raising the [salary] question at the very beginning.”

women do not negotiate

Women (Unfortunately)
Don’t Negotiate

The differences between men and women in the business and medical worlds have been debated for ages. One difference that appears undeniable, however, is that women tend to shy away from the negotiation process. According to Lee E. Miller, women tend to negotiate less often than men and accept the initial salary offer.

“Very rarely is the first offer the best offer,” Miller explained. “There’s usually something to negotiate. And when women do negotiate, they tend to ask for too little.”

Miller’s point is echoed in a wide range of studies, many of which are published in Women Don’t Ask: Negotiation and the Gender Divide by Linda Babcock and Sara Laschever. In their book, the authors note the following:

  • In surveys, 2.5 times more women than men said they feel “a great deal of apprehension” about negotiating.
  • Men initiate negotiations about 4 times as often as women.
  • Asked to pick metaphors for the process of negotiating, men selected “winning a wrestling match” while women said “going to the dentist.”
  • Twenty percent of adult women (22 million) say they never negotiate at all, even though they often recognize negotiation as appropriate and even necessary.

In addition, failure to negotiate can have a long-lasting impact. By not negotiating a first salary, an individual stands to lose more than $500,000 by age 60. According to studies, men are 4 times as likely as women to negotiate their first salary.

Proven Negotiating System

Jim Camp is the president and CEO of Camp Negotiation Systems, and an accomplished negotiator who has developed a negotiation system that is taught in MBA programs worldwide. He is also the author of NO: The Only Negotiating System You Need for Work and Home.Camp said that the first step in the negotiation process is to understand the concept of mission and purpose. In other words, be clear about what you are trying to deliver. For an oncology fellow, that means understanding what you will deliver not only to the patient, but also to the hospital or healthcare organization. Too often that is not clearly thought out.

“How can you help someone else see what you’re bringing, what you’re delivering, if you can’t see it yourself?” asked Camp.

The second step is to recognize the problems inherent in your particular negotiation. For example, although an oncologist and a urologist are both specialists, an oncologist brings a different value to an organization. But if the healthcare organization is trying to establish pay equity across the spectrum of physicians, that is a problem that must be dealt with. Negotiate it out of the negotiations by creating the value that separates you from others in your field or profession.

You will also need to contain your emotions. Camp claimed that decisions “are made 100% emotionally [and] not intellectually, with facts.” He continued, “We all have to deal with what we call baggage: the emotions we bring to the game. The key is to lower that emotion until it’s almost nonexistent and create a vision so that decisions can be made comfortably.”

Those emotions could be tied to someone other than the fellow who is engaged in the salary negotiation process. Dickerson pointed out that personal factors, especially family and the desire to live within a particular geographic location, can significantly reduce an individual’s leverage when it comes to salary negotiation. “There’s a wide variety of comfort levels that people have with that,” said Dickerson. “It’s important to evaluate where that falls among your priorities.”

The next step, said Camp, is to know exactly what you want. Then have a vision of what you want to happen next, after the negotiation. That vision can be viewed in small steps, not big ones. You may just want the person you are negotiating with to take all of the information you have provided, digest it, and then schedule a follow-up meeting. Whatever it is, make sure you carefully think through what you want because, Camp noted, you just might get it.

Perks and Competition

It is often said that competition brings out the best in people. And according to Miller, there is nothing better for a job-seeking fellow than a hospital or practice competing for you. For example, suppose 2 hospitals have expressed an interest in having you join their staff . Hospital A has offered a higher salary, but hospital B is where you would truly rather work. Miller suggested the following approach.

“Tell hospital B that they’re your first choice [and] that you would really love to work there because it’s a great fit,” he said. “But, you have an offer from hospital A. Is there anything hospital B can do to sweeten the offer? Just put it on the table and leave it open.”

And remember, Miller added, it is not always about the money. The reality is that sometimes the compensation at one facility is high because the job is terrible. Sometimes the facility offering the lower salary, combined with perks such as health benefits and vacation leave, might just be the better package.


Ed Rabinowitz is a veteran financial journalist based in Upper Mt. Bethel Township, Pennsylvania.

This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
View the full PDF of this issue


man on cell phoneIt was midnight and I had just been jarred out of a sound sleep by the startlingly repetitive beeping of my pager. I fumbled for it on my nightstand and glanced at the display. It was the hospital’s emergency department. “Damn,” I thought.

Half asleep, I wandered downstairs. I tried not to trip on the stairs as I prepared my foggy brain for the medical conversation I was about to have. I successfully navigated the steps and sat down at my desk. My home “office” is actually in my kids’ playroom, though it doubles as my workspace. (Ah, the oncology fellow’s life of luxury….)

I picked up the phone and dialed. “Hello?” said the emergency department physician on the other end. “Yes, this is Dr Mendler, the oncology fellow who is returning your page,” I replied. (I was relieved that I was waking up enough to put a full sentence together.)

The physician said, “Dr Mendler, I was hoping to run a case by you that we have here in the ED. The patient is a 35-year-old man who had a bone marrow transplant about 2 months ago and is now presenting with a lowgrade fever. He’s had some sinus congestion but no other localized signs of infection. Do you think it’s okay if we send him home with close follow-up, or should we admit him?”

At this point I was fully awake. I had been on the inpatient transplant service 2 months ago and had spent 1 day each week in one of the transplant clinics. I knew many of the transplant patients very well.

“Who’s the patient?” I asked.

The physician responded, “His name is Jonathan, a guy with a history of acute lymphoblastic….Wait a minute, his labs just came back. His white blood cell count is 100 and his platelets are 15. His counts were normal 5 days ago.”

I was hit by a wave of nausea. I could not believe that Jonathan was potentially relapsing. It happened too fast. Please, God, don’t let this be a relapse, I prayed.

A Lone Wolverine Among Buckeyes

My mind wandered back to everything I knew about Jonathan. He was a young man whom I had fi rst met a few months previously, toward the latter stages of his myeloablative, allogeneic stem cell transplant for acute lymphoblastic leukemia. In the transplantation ward he would often bang away on his laptop, preparing lesson plans for when he would return to his job as a high school English teacher.

Jonathan also had moxie. He took an unabashed, unapologetic stance as a Michigan Wolverines fan among a sea of Ohio State Buckeyes fans on the ward. (For those of you who have never spent time in Columbus, Ohio, there is no mercy for Michigan fans, even for those in the midst of a bone marrow transplant.) His wife was often there with him, and they spoke frequently of their 1-year-old daughter and how much he missed her during the weeks of his transplant. I remembered his exuberance on his day of discharge, when he was going back home to see her, having survived another stage of his battle against leukemia. I also recalled the day in the transplant clinic, a few weeks after his discharge, when he brought the attending physician 2 model race cars, each of which was personalized with the name of the attending’s 2 children. I remembered thinking, “What a hell of a nice guy. Not only is he appreciative of everything we’ve done for him, but he’s taken the time to get to know the names of his doctors’ kids and give them gifts.”And now, after all that Jonathan’s been through, could he really be relapsing? After speaking with the ED physician, I paged the hospital’s attending transplant physician, who is a mentor, and filled him in on everything. He said to me, “You know, Jason, we’ll give him salvage therapy, but he’s almost certainly going to die from this. It just sucks.” I paused for a moment to digest this. After receiving his life-altering diagnosis, Jonathan had had to deal with months of intensive chemotherapy treatments, brutal side effects, bone marrow biopsies, remissions, and uncertainties. But through it all, he had retained hope for the future.

Now it was all being blown to hell by one blood draw in the emergency department. The transplant attending physician and I philosophized for a few moments about the nastiness of a disease that relapses after total body irradiation, myeloablative doses of chemotherapy, and an allograft. There would be no silver lining in this cloud.

Pushing On

I hung up the phone and all was quiet. I climbed back upstairs and lay in my bed. I wanted someone to tell me that everything would be okay and that this had all been a bad dream. That voice never came. I ached for Jonathan, for his wife, and especially for his daughter, who would never really get to know her dad. “How will his family go on?” I thought. “How will I go on?”

How will I go on? I pondered this question as the clock struck 4 AM. I was drained, not simply because of tonight’s news but from a year of experiencing a multitude of young, vibrant people fighting losing battles against cancer. I wondered how I would provide optimism to my patients the next day with the hurt of Jonathan’s relapse still drenching my soul. I wondered how I could spend a career doing this. How could I continue to bear witness to the worst of what cancer does to people and still push on? Was I resilient enough? Was I courageous enough? Was I selfless enough?

My body and mind finally succumbed, and I fell asleep. My alarm woke me a couple of hours later, and I groggily got up after a few thumps on the snooze button. My insides felt like a sour brew of exhaustion and despair. I desperately needed a dose of perspective. I flipped through the pages of a book of quotations that I keep beside my bed and came across one from Mahatma Gandhi:

I have found that life persists in the midst of destruction, and, therefore, there must be a higher law than that of destruction.

I thought about this for a moment and felt a twinge of hope. Despite all the cancer-induced destruction I see every day, there must be a way to see the persistence of life. I was not sure how I would find it, but it seemed well worth a try. I resolved to look for this life force in each patient I saw that day. I realized that these signs would appear differently in each person, and would be hard to find in some, but I felt confident that it was there in everyone. A sense of well-being came over me and I began to mop up the hurt. I felt hope take hold more fully in my body. “I can do this. My patients need me to do this. I need me to do this,” I thought. I straightened my tie, grabbed my coffee, clipped on my pager, and walked out the door, on a mission to find life.


Jason H. Mendler, MD, PhD, is a clinical fellow in the Division of Hematology & Oncology at Th e Ohio State University in Columbus.

This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
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Image of stethoscope over hundred dollar billsThe healthcare system in the United States has become increasingly unsustainable. We hear frequent reports in the media and within our hospitals about the inability to improve health outcomes despite spiraling healthcare costs. The financial burden of cancer care is monumental. In 2008, overall costs were estimated at $228 billion, which included $93 billion in direct medical expenditures, $18.8 billion in lost productivity, and $116.1 billion in indirect costs.1

One example of this economic burden is seen in an analysis of patients with metastatic breast cancer. In this analysis, direct costs averaged $35,164 per year. New targeted-therapy drugs costs range from $20,000 to $50,000 per year per patient, and these costs continue to increase. Another example is seen in colorectal cancer therapy, which increased an incredible 340-fold between 1994 and 2004.2 The drugs we prescribe as oncologists account for 40% of all Medicare prescription costs. This is in contrast to only 4% of federal dollars that are directed toward cancer prevention.3 This article will discuss the impact that the Patient Protection and Affordable Care Act (PPACA) will have on our patients with cancer, on our hospital systems, and on us, the physicians.

Historically, Americans have low rates of adherence to recommended screenings for breast, cervical, and colorectal cancers. ”

Impact of Health Reform on a Patient With Cancer



When you combine the costs of tests, imaging, physician services, chemotherapy, surgery, and radiation therapy, the price tag on cancer treatment may range anywhere from $40,000 to more than $100,000 per patient. There are provisions within the PPACA that may offer modest advantages for our patients, including greater scrutiny when raising insurance premiums. Because of the increased requirements for employers to provide insurance coverage, individual states will form health insurance exchanges or cooperatives that offer low-cost options for workers as well as create competition in the marketplace. It is unclear how this will be federally regulated; many of these exchanges may operate differently because they will be created at the state level. Federally, the government will provide subsidies to low-income individuals so they can obtain insurance. With these changes, it has been estimated that 32 million additional individuals may be covered by 2019.4

One of the biggest concerns of patients is whether PPACA will cover preexisting conditions. Under the current plan, children with preexisting conditions such as cancer are protected from being excluded from insurance and will also be covered until the age of 26 under a parent’s insurance plan. For those patients who fall into the category of non–Medicare-eligible retirees older than age 55, there will be access to subsidized high-risk pools and insurers will not be allowed to set annual or lifetime limits on coverage. These changes will likely have a significant impact on patients with cancer who may fall into the age range that is not yet eligible for Medicare benefits.stethoscope over American flag A major challenge for our patients is finding coverage for their skyrocketing prescription drug costs. This will become especially important in cancer treatment as we increasingly develop targeted agents, many of which are in oral form. Currently, there is a large gap in Medicare Part D coverage. Many patients find themselves in the “donut hole,” causing them to struggle financially because their coverage is lacking. As the PPACA reforms take effect, there will be a $250 subsidy for those affected by the donut hole. By 2020, however, it is projected that 75% of oral medications will be covered by Medicare—a significant improvement over today’s Medicare coverage.

Historically, Americans have low rates of adherence to recommended screenings for breast, cervical, and colorectal cancers. Recent Centers for Disease Control data reveal that 38% of Americans older than age 50 have not had their recommended colonoscopy and sigmoidoscopy screening, and 24% of women aged 40 to 50 years and 21% of women over age 50 have not had recommended mammogram screening in the last 2 years.5 Preventive, quality-focused, cost-effective care will be the major PPACA initiatives, with preventive services coverage being federally mandated. Medicare will cover 100% of actual charges and fees for preventive care, such as cancer-screening exams. Incentives to Medicare beneficiaries may increase compliance with screening recommendations; this might ultimately save thousands of lives while cutting healthcare costs.

The expanded healthcare access will affect those covered under Medicare, private insurance, and PPACA. Unfortunately, of the 32 million people with newfound coverage, up to 50% will be covered under Medicaid and may not benefit from the expanded coverage. It is unclear if those with Medicaid will face the same challenges they currently do. In addition, it is possible that hospitals and private practice will continue to suffer financially by caring for Medicaid patients.

Impact of Health Reform on Private Practice and Hospital Systems



PPACA will have both positive and negative impacts on hospital finances. Under the expanded care, up to 95% of the US population will be insured. On the positive side, this will dramatically decrease the number of completely uninsured people, reducing hospitals’ bad debt. Currently, approximately 15.3% of the population is uninsured and 35% is underinsured. For the most part, hospitals are burdened with uncompensated medical care costs that one 2001 report estimated to be $35 billion.6

These financial benefits, however, will be offset by a $14 billion reduction in Medicaid’s disproportionate share hospital (DSH) payments, which will begin in 2014.4 DSH payments provide financial assistance to hospitals that serve a large number of low-income patients, such as the uninsured and those with Medicaid. Medicaid DSH payments are the largest source of federal funding for uncompensated hospital care. For the hospitals that depend on DSH, this will add additional burden to an already stressed system; this may ultimately result in hospital consolidations, additional hospital services bring cut, and hospital closures. Medicare will provide expanded coverage by making cuts using the following strategies: not paying for hospital-acquired conditions, which will save $1.4 billion over 10 years; not paying for excessive readmissions, saving $7.1 billion over 10 years; and additional Medicare/Medicaid efforts to reduce fraud, saving $2.9 billion over 10 years.In order to raise the quality of care delivered and provide incentives to hospital systems that are able to cut costs, accountable care organizations (ACOs) are an integral aspect of provisions set to go into effect next year. According to the Centers for Medicare & Medicaid Services (CMS), an ACO is defined as “an organization of healthcare providers that agrees to be accountable for the quality, cost, and overall care of Medicare beneficiaries who are enrolled in the traditional fee-for-service program who are assigned to it [sic].”7 The pillars of ACO are care coordination, care effectiveness, population health management, safety, and efficiency.8 In this system, if an ACO is able to meet performance standards and achieve a specified level of savings for an “episode of care,” then the ACO would share in some of the cost savings. The expected effect of ACO implementation on cancer care remains unknown at this time.

Impact of Health Reform on Physicianspills on american flag



Medical oncologists have felt significant financial pressures even prior to the passing of PPACA. The American Society of Clinical Oncology estimates that 80% of patients in this country receive their care in a community setting. Under this model, patients typically visit their physician in a private-practice office where they receive their infusional chemotherapy. Under this system, the private practice has purchased the drug and will bill the payer for both drug and administration. PPACA is expected to drastically alter this model by changing reimbursement for chemotherapy, supportive drugs, and professional services, and by attempting to move all practices toward ACOs.

Prior to 2005, the CMS reimbursed practices at 95% of average wholesale price for chemotherapy and associated drugs, and this rate was quite profitable for oncologists. With the Medicare Modernization Act of 2005, the oncologists’ profits plummeted after drug reimbursement became based on average sales price (ASP) rather than average wholesale price (AWP). (Editor’s note: Before we went to press, the Senate introduced S. 733, a bill designed to correct this reimbursement issue.) ASP provides approximately 49% less in value than AWP. These changes have already increased the number of referrals to hospital infusion centers and have created partnerships between hospitals and private groups in order to shift financial risk to larger hospital systems. In addition to decreased margins in delivering pharmaceuticals, reimbursements for professional services will also decrease. The combination of these financial threats poses a major risk to small private practice groups because they will likely struggle to meet ACO regulations.

Medical oncologists have felt significant financial pressures even prior to the passing of PPACA. ”

Preparing for Change

In the future, the stresses on the healthcare system will magnify. By 2030, the US population will expand to 365 million people, with 72 million adults over the age of 65. As the baby boomer population ages, the incidence of cancer is predicted to increase more than 45% from 2010 to 2030. There were 1.6 million patients with cancer in 2010; this number will swell to 2.3 million in 2030.9 This increase will occur as the oncologist workforce continues to shrink. In preparation, it is essential that our disjointed system of care be restructured to be more efficient, nonduplicative, cost-effective, evidence-based, and safe. As these cancer care delivery models evolve, it will be essential that physicians take an active role in policy changes in order to protect their livelihood as well as continue to provide high-quality patient care.


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
View the full PDF of this issue

Sheetal Kircher, MD, is a second-year fellow at Northwestern University Feinberg School of Medicine in Chicago, Illinois.

References

  1. American Cancer Society. Economic Impact of Cancer Web site. http://www.cancer.org/cancer/cancerbasics/economic-impact-of-cancer. Accessed on March 13, 2011.
  2. Schrag D. The price tag on progress—chemotherapy for colorectal cancer. N Engl J Med. 2004;351:317-319.
  3. Meropol NJ, Schulman KA. Cost of cancer care: issues and implications. J Clin Oncol. 2007;25:180-186.
  4. American Hospital Association. Special Bulletin. Summary of major provisions in final house reform package. March 22, 2010. http://www.nmhs.net/documents/HCreformfinalsummary032010_000.pdf. Accessed March 20, 2011.
  5. Behavior risk factor surveillance system survey data. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2007.
  6. Whitman G. Hazards of the individual health care mandate. Cato Policy Rept. 2007;29:9-12.
  7. Medicare “Accountable Care Organizations” Shared Saving Program—New section 1899 of Title XVIII. https://www.aace.com/sites/default/files/CMSPremlimQA.pdf. Accessed March 20, 2011.
  8. McClellan M, McKethan AN, Lewis JL, et al. A national strategy to put accountable care into practice. Health Aff (Millwood). 2010;29:982-990.
  9. Smith BD, Smith GL, Hurria A, et al. Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol. 2009;27:2758-2765.


writing an articleAs an oncology fellow you have chosen what is arguably the most research-driven field in all of medicine. Indeed, the lives of your patients depend, in large part, upon the expeditious flow of novel and increasingly safe and more effective therapies from the lab to clinical practice. This seemingly lofty goal is now more attainable than ever, but requires that knowledge be shared and information exchanged in reputable peer-reviewed journals.

Patients are clearly the primary stakeholders in this endeavor, but the list of those who rely on a solid track record of publications as a means to a critical end is a lengthy one. To varying extents, the ability to publish impacts everything from research funding to clinicians’ reputations to the good standing or very existence of programs and entire institutions—and the competition is stiff.

While researchers and clinicians are not necessarily expected to be world-class writers, a well-written article that effectively communicates the topic at hand and adheres to the journal’s standards, style, and guidelines is, indeed, more likely to be published than one that doesn’t live up to these standards.

But can an article really be rejected based solely on an author’s inability to produce a well-written manuscript? “Absolutely,” said Kelly Brooks, managing editor of Journal of Oncology Practice. “The content might be appropriate for our journal, but all manuscripts are peer-reviewed. If the editors think the writing quality isn’t worthy of inclusion in the Journal, they may certainly reject it for that reason,” she cautioned.

Luckily for you, few, if any, would-be authors ever bother to read an article about the ins and outs of getting published, and instead move blindly through this unfamiliar and often confusing territory. For this reason, any effort you make to inform yourself about this process will give you a proverbial leg up.

Behind the Scenes



Understanding the process that leads to a paper’s acceptance or rejection is the first step toward attaining the above-mentioned advantage. Much like going to a job interview, preparing an article for submission to a peer-reviewed journal would be somewhat of a fool’s errand if you did not first get a sense of what the decision-makers are looking for.

While the process varies somewhat from journal to journal, newly submitted manuscripts generally get their first perusal at the hands of the editor-in-chief, who is usually a renowned expert clinician who evaluates the submissions less for the quality of their writing than for their timeliness, relevance, and potential interest to readers.

Once accepted by the editor-in-chief, the paper must pass muster with the editorial review board, a group of clinicians and academicians—all experts in their fields—who are charged with the task of evaluating the submission for content, scientific accuracy, appropriateness for their journal, and relevance to the journal’s readers. Based on these criteria, review board members can accept or reject a manuscript outright, but can also return the paper to the author(s) with a request for clarification, revisions, or even a complete rewrite. At that point, acceptance for publication becomes contingent upon the author’s ability to make the requested revisions to the satisfaction of the board.

“We have, indeed, rejected papers after asking for revisions,” said Brooks, “because the author(s) ultimately couldn’t produce a well-written paper.”It is only after these requested revisions have been made and approved that the paper moves on to the journal’s editorial staff, whose job is to ensure that the article is as clear, concise, and error-free as possible. Ideally, the editing process serves as a series of checks and balances, with an initial edit performed for content and scientific accuracy (by the managing or senior clinical editor), followed by a second edit for features such as flow, organization, and proper style (by the copy editor) and, finally, a proofreader’s line-by-line inspection for typos and errors in spelling and grammar. In this way, the paper is seen by multiple individuals, each of whom contributes a fresh perspective and pair of eyes, hopefully catching errors and inconsistencies not seen by the previous editor.

While most editors prefer this system of checks and balances, it is not unusual for a single person to perform all these steps, depending on the size of the journal and its staff. Even the best editor will acknowledge that errors are more likely when a single person performs all of the needed editing steps, underscoring the need for authors to submit papers that are as “clean” as possible. In fact, the more changes a paper requires, the greater the risk not only of introducing errors but also of changing the author’s intended meaning, even if subtly. An author who submits a paper in need of a “heavy edit” also runs another risk; namely, that the author’s “voice” will be lost, and the article will ultimately reflect the writing style of the editor rather than that of the author.

At some point during the editing process the author(s) might again be asked for clarification or additional information, this time by the editors. Once the editing and revisions are complete, some (but not all) journals will send the author a PDF of the typeset proof, providing one last chance to make sure the article reads the way the author intends.

Despite the possible bumps in the road, this process can and should go smoothly. To that end, the following tips are intended to give you the aforementioned leg up in getting your paper published, and in making the process as painless as possible, from submission, to acceptance, to publication. (See “Tricks of the Trade: Getting Ready to Publish.”)

Know Your Readers



Medical writing is not a one-size-fits-all proposition. On the contrary, writing for journals requires that the same content be presented differently, depending on the needs and knowledge of your readers. Knowing your readers should, in fact, be considered the first commandment of any type of writing, and requires not only that you identify your readers, but also that you determine their levels of comprehension as well as what they do and don’t need to know.Let’s assume, for example, that your area of expertise is gynecologic oncology and your article deals with a specific surgical technique. An article written for a journal whose readers are largely nononcologists will be read more with academic interest than with the intent to learn the ins and outs of the technique. In other words, the readers will need sufficient background information to bring them up to speed on a topic that’s not within their area of expertise, but will not want or require the amount of detail needed by someone who intends to employ the technique you’re describing. If you intend to submit your article to a general oncology journal, keep in mind that some of your readers will be those from your subspecialty but the majority will not. In this case, less background information is required but the description of the technique might focus more on potential candidates, benefits, and outcomes, all of which would be of interest to oncologists who might refer their patients for such treatment. Finally, if the article will appear in a journal read primarily by those in your subspecialty, any background information should be summarized and the technique in question might be described in more of a step-by-step fashion for readers who might, themselves, ultimately consider performing such a procedure. The trick is to strike a delicate balance between providing your readers with the information they want and need and not insulting them with lengthy explanations of information considered to be common knowledge.

Along these same lines, Journal of Oncology Practice copy editor Wayson Jones provided some words of advice from “down in the trenches,” noting that jargon and phrases coined within your discipline should be avoided, especially when writing for clinicians outside your area of expertise.

“A good copy editor who’s confronted with such language will do his or her best to ‘translate’ it into more commonly understood verbiage, and doing so introduces the possibility of changing the author’s intended meaning,” he said.

Tricks of the Trade:
Getting Ready to Publish

The following tips will help to give you a leg up when you consider submitting an article for publication.

  • Purchase a copy of the latest version (10th edition) of the AMA Manual of Style or access it online (www.amamanualofstyle.com).
  • To identify the readers of a particular journal, check the masthead and contact a staff member from the sales and marketing team. These are the people in the best position to give you an accurate breakdown of the journal’s readership.
  • Never submit an article without first reading a number of articles from your target journal. If you don’t have a copy handy, check the journal’s Web site for current and past issues.
  • Give your first and subsequent drafts to a colleague whose knowledge and experience are similar to those of your intended readers. Ask for and accept constructive criticism.
  • When preparing original research for publication, clarify your target journal’s policy about news stories appearing in medical trade publications. While, in theory, publication of a summary of your findings in such a trade magazine shouldn’t affect your chances of being published in a peer-reviewed journal, different editors have very different views on this topic. As with most things in life, it’s better to be safe than sorry.

Heed the Guidelines

Once you have effectively tailored your article’s content to the needs of your readers, the task becomes one of “styling” the article to conform to the journal’s standards. The vast majority of medical journals apply the standards put forth in the AMA Manual of Style, an indispensable resource for anyone and everyone who writes or edits for medical publications. While it is generally a very safe bet to use the AMA Manual of Style as a guide, the information in your target journal’s guidelines for authors/manuscript submission should supersede that in the AMA Manual of Style when inconsistencies exist.

Even so, if you were to ask a room full of copyeditors about their biggest pet peeve, you’d probably hear something along the lines of, “Everything they need is right there in the author guidelines. Isn’t anyone reading them?” Copy editors come by their frustration honestly. Despite the fact that peer-reviewed journals offer relatively specific guidelines for manuscript submission and style (in print, online, or both), a surprising number of authors either don’t bother to read them or only scan them and basically choose to ignore the information they provide. And that information is invaluable. It includes the formats in which to submit text, tables, and figures; preferred spacing and font style/size; styling of references and footnotes; information required for author biographies; and statements of potential conflict.

A good copy editor will usually have a relatively sound working knowledge of the topics covered in his or her journal, but an author should never assume that the knowledge of any member of the editorial staff approaches the level of a physician’s expertise. Jones provides some words of caution along these lines, citing failure to properly structure tables and figures as an example of an oversight that can lead to big problems.

He said, “Some authors try to cram too much information into a table, or ignore the guidelines and send a table that’s formatted improperly or not at all, leading to misaligned rows and columns that force editors to guess.”

This, warns Jones, leaves the copy editor with the task of attempting to line up headings and subheadings with corresponding data, inviting potential errors. Similar problems can arise from figures not designed according to the journal’s standards, forcing the copy editor to try, for example, to make sense of unintelligible symbols superimposed on clinical art. The same issues can arise from improperly expressed statistics, medication dosages, and units of measure.

Admittedly, all author guidelines are not created equal; some are more specific than others and some are in need of updating. Even so, these instructions are your best resource for properly preparing a manuscript for submission. And because the guidelines are written by those who will be editing your article, it only makes sense to adhere to them as closely as possible.

If you read the guidelines but still have questions, 2 excellent options remain. The first of these options is to contact the editor named in the guidelines or in the journal’s “call for papers.” That editor would, no doubt, much rather take a phone call or respond to an e-mail than have to chase down an author in mid-edit to clarify matters of style. Your second option is to use the journal itself as a guide; in it you can find 1 or 2 articles similar to yours (eg, original research, case studies) and use those articles as models. Doing so also will give you a sense of the preferred tone of the journal’s articles (ie, formal vs more conversational).

Revise and Respond

The last bit of advice relates to the need to respond to any and all requests for clarification, and to do so in a timely fashion. A good editor will insert queries that leave no doubt about the information being requested, and will also tell authors exactly how to respond to those queries and by what date. Journals live and breathe by deadlines, and failure to respond to all queries or to do so by the specified date will likely jeopardize your article’s slot in the upcoming issue. To avoid such a situation, it’s also important to ensure that you or the author designated the primary contact for the journal is easily accessible during the review and editing process.

Revise and Respond



Whether you are the first or last author on your article, the time and effort invested in the process will determine whether your insights and knowledge will ultimately be shared with their intended recipients. The task is at once rewarding and challenging. It requires patience, care, and attention to detail—qualities already well known to oncologists.


Laura Bruck is a Cleveland, Ohio–based freelance medical writer and editor who has served as a copy editor, senior clinical editor, and managing editor for a variety of peer-reviewed journals and medical trade publications since 1987.

This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
View the full PDF of this issue


No smoking signIn this country, an estimated 46 million people—20.6% of all adults—smoke cigarettes. Cigarette smoking also happens to be the leading cause of preventable death in the United States, accounting for approximately 443,000 deaths, or 1 of every 5 deaths each year. Approximately 40% of these deaths are from cancer, of which lung cancer is the most prevalent.

In addition to the disastrous impact that tobacco use has on our collective health as a nation, it wreaks havoc on our economy. Cigarette smoking is estimated to be responsible for $193 billion in annual health-related economic losses in the United States—that’s $96 billion in direct medical costs and approximately $97 billion in lost productivity. Cigarette smoking results in 5.1 million years of potential life lost in the United States annually.

It is estimated that 70% of smokers want to quit completely and that 45% of smokers have tried to quit. Yet we realize from our interactions with patients that this is often a losing battle. Patients, even those with lung cancer, at some point in time will return to smoking. Compared with the billions of dollars that cigarette companies pour into marketing their products, the healthcare system is ill-equipped to respond. Smokers who want to quit often have limited resources available to them. As fellows and residents, we often know how important it is to counsel, yet have limited time with each patient to do so.

There are many smoking cessation interventions available, group sessions being one of them. As effective as they are, they are often an option only for those who can pay for them. As fellows and residents, we not only have a responsibility to help fight this major public health hazard, but we are also in an excellent position to do so. Most training programs are affiliated with community health centers. Approximately 20 million Americans are served by such centers, with 40% of these affiliated with residency programs. The majority of patients that visit such centers are poor—the very people who smoke the most and who therefore need the most help. In the following sections, we provide an overview of how fellows/ residents can set up and successfully run a smoking cessation clinic.

Starting Out



Planning is of paramount importance. You will need to speak with the health center director and ensure that resources are available to run such a clinic, which is held in a group meeting format in 2-hour-long sessions once a week for 4 weeks. The following are needed:

  • A large conference room that can hold 10 to 15 people and that is available for a 2-hour slot on a specified day every week for 4 consecutive weeks
  • 2 patient exam rooms
  • A nurse and a medical assistant (MA) who are available each week for that 2-hour time period
  • An attending physician who can be available for 30 minutes per session
  • A whiteboard and pens and paper for the patients


Patient Enrollment



Once you have selected a day and a 2-hour time slot, begin by advertising the clinic. Print out flyers, hang them up in the clinic, and give them out to patients. Have a system in place where the MAs ask each patient coming through the clinic about his or her smoking status. If the patients smoke, at checkout have the staff off er to enroll them in your free smoking cessation clinic. Many will take you up on the off er. Once you have 10 to 15 patients enrolled, you are ready to start your very own smoking cessation clinic!Next, we will describe how you should conduct each of the 4 sessions. Note that the group sessions will last for approximately 1 hour, with the remaining 1 hour used for individual patient counseling in exam rooms. This counseling allows the clinic to bill for the sessions.

Session 1: Committing to Quit



Start off by congratulating the patients for joining. Introduce them to the notion of smoking cessation through behavior modification and group therapy along with pharmacotherapy, if necessary. Stress the importance of follow-up through subsequent sessions. Hand out printed smoking cessation material, if available.

Next, talk about the harmful effects of smoking. Involve the group and ask them how much they know about the dangers associated with smoking. Discuss the heightened risk of cancer and chronic obstructive pulmonary disease (COPD). A useful exercise is to give out straws and ask the patients to pinch their noses and only breathe through the straws in their mouths; explain that if they do not stop smoking, this is how it will feel when they have emphysema.

Discuss in detail the benefits of quitting smoking. Specifically mention the health benefits, such as having more energy and a reduced risk of cancer and heart and lung diseases. Emphasize the psychological benefits, such as increased self-esteem and self-respect and a sense of accomplishment in quitting. Next, talk about the financial benefits, such as reduced insurance premiums, decreased future healthcare costs, and an almost $2000 savings per year from not buying cigarettes.

Wrap up by preparing patients for session 2. Prior to the next session, ask patients to think about what triggers their smoking. They should consider the reasons why they smoke as well as their desire to quit. Have them reflect on their past attempts to quit and why they failed and to start thinking about a quit date. Answer any questions that they may have. At the end of this and each subsequent session will be individualized patient sessions. (These are described at the end of the article.)

Session 2: Exploring the Smoking Habit



Straws This session will help patients understand the psychological aspects of smoking. It is designed to explore in detail the patients’ reasons for smoking and why they want to quit, and to reflect on past experiences with quit attempts.

Start off by asking patients to discuss the reasons they smoke. Write them down on the whiteboard. Ask them if they think smoking is a psychological need or truly a physical addiction to nicotine. Ask them when they have their first cigarette in the morning. Then ask each patient why he or she likes or dislikes smoking. This exercise will start a discussion among the participants and help them realize the reasons they smoke so that they can plan to gradually eliminate those reasons.

Discuss the circumstances in which they smoke each cigarette. Are they happy, sad, angry, frustrated, nervous, or something else? Make a list on the whiteboard of all the triggers for the different patients. They will soon realize that everyone has fairly similar triggers.

Next, talk about the true desire of the patient to quit. Discuss why it is so important to do so. Make sure they understand that they may have to undergo many months—if not years—of self-reflection and attempts at quitting before finally being successful.

Now, discuss in more detail the patients’ past quit attempts. Discuss the methods used. Ask them how long their quit periods lasted and whether the attempts were successful. Talk about the reasons why the patients feel that specific past interventions did not work. Toward the end of this session, you will discuss some strategies to cope with urges to smoke. Ask them to remember the “4 Ds” when they feel the need to smoke: delay, deep breath, drink water, and do something else. Ask each patient to come up with 3 situations that made him or her really want to smoke again. Write those on the whiteboard. Then ask them what they could do instead.

Session 3: Arming Patients With the Tools to Quit



Hopefully, by now the patients will have a clear idea of what makes them smoke and what strategies they can use to quit. This session is about dealing with recovery symptoms (ie, nicotine withdrawal) and the correct use and side effects of different smoking cessation products. At the end of this session the product of choice should be prescribed, if appropriate for the patient.

It is important to teach patients how to deal with withdrawal. Explain that after quitting smoking, the body experiences both physical and psychological “recovery symptoms.” These symptoms decrease after the first few days and usually pass within 2 to 4 weeks. Specific interventions that can help are taking fluids for a dry mouth, sipping warm water for a cough, and having low-calorie snacks to combat hunger pangs. Other symptoms that are expected are insomnia, fatigue, headache, irritability, and constipation.

Next, you will review products that can be used for smoking cessation. These include nicotine replacement (eg, patch, gum, lozenge, inhaler), bupropion, and varenicline (Chantix). Based on patient preference, any product or combination can be chosen. If nicotine replacement is chosen, it is best to prescribe the patch plus a short-acting nicotine product (eg, gum, lozenge) to deal with the cravings.

You will need to describe in detail how to correctly use each product, their advantages and disadvantages, and their side effects. This sort of material is easily found on Web sites such as Uptodate.com.

Session 4: Preventing Relapse



At this point, you hope that the patients have quit smoking and are perhaps also on a smoking cessation aid. This is the last session of the series and will mainly focus on relapse prevention and answering any questions that the patients might have about the program and the previous sessions.

First off , discuss relapse-prevention techniques. Relapse prevention requires that patients develop a program that suits them and that they will follow if they begin to slip back to smoking. Talk about avoiding situations that serve as triggers to smoke. Exercising and taking up new hobbies often help. At the end, provide a short recap of all the sessions. If patients are using any of the smoking cessation aids, ensure that they are using them correctly. Answer any questions. Also be sure that you book follow-up visits with the patient’s primary care provider specifically for smoking cessation consultation.

Individual Patient Sessions



These sessions are required for billing purposes. The patients would already have had their vital signs taken by an MA when they registered for the course. The staff will bring them to the exam rooms and each meeting with the fellow or resident should not take more than 3 minutes. Briefly go over the specific reasons that the patient should quit. If the patient has a disease, such as coronary heart disease, the physician should tailor the smoking cessation plan accordingly. Briefly document your discussion and then precept with an attending physician. If needed, other patient complaints or concerns should be addressed on a separate visit. This meeting is only for smoking cessation.This program serves as a basic outline and can be tailored to your own specific needs and patient population. If you would like more details about running a smoking cessation clinic, please contact Dr Khan at cyruskhan@gmail.com.


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
View the full PDF of this issue

Cyrus Khan, MD, is a second-year hematology/oncology fellow at the Western Pennsylvania and Allegheny General Hospital in Pittsburgh. Realizing that the lack of smoking cessation services was a major drawback to the efforts of patients who wanted to quit smoking, he helped start his community health center’s very first smoking cessation program.

Alice Ulhoa-Cintra, MD, is a second-year hematology/oncology fellow at the Western Pennsylvania and Allegheny General Hospital in Pittsburgh. Her primary interests encompass all aspects of solid tumor oncology, including cancer-preventive strategies with the potential for a significant public health impact, such as smoking cessation initiatives.


Doctor stands outside hospitalAfter fellowship training, you—the oncology or hematology fellow—need to make some important decisions. Do you sign on with an academic institution, join a hospital or existing practice, or start your own oncology or hematology practice? If you decide to do the latter, there are many options to consider. And as with almost every business, it is all about location—but confidence in your abilities is important too.

“There are little markets all over the country,” said Dirk Davidson, MD, who heads up Tennessee Plateau Oncology in Crossville. “And probably the main reason nobody is in them is because [the physicians] … don’t think they can start and manage such an operation.”

But with the right game plan, you can open your own lucrative practice in an area previously thought to be unprofitable.

Location, Location, Location



Alan Hill is a certified public accountant and a principal and director of medical services at Rea & Associates, an Ohio-based public accounting firm. Hill said that when considering the location of a new oncology practice, you must determine whether there is a need in the area being served. In other words, if you start your practice in a place that contains other oncologists, it will be more difficult to acquire your own patients.

“Talking with [local] hospitals is a good way to go,” advised Hill. “Hospitals know where there is a need in their area, and you might be able to approach them for assistance in starting up your practice, because that’s where you are going to be referring your patients. They might be able to tell you about the population in that area. Location—knowing what your market ecosystem looks like—is definitely an issue.”

Population is another key consideration. Last November, John Jones, MD, opened the doors to his Simplicity Urgent Care facility in Arlington, Virginia. He and his partner, John Maguire, MD, were looking for an area with a population density of 40,000 to 50,000 people within a 2-mile radius of their practice. They researched population demographics, including the number of young families in the area, and the average local income. They also checked out their competition.

“It’s important to know who’s located near you, as far as other oncologists or any other practice,” Jones said. “A lot of that is simply going through a physician directory and finding out where they are. We did not want [any other physicians] within a 3-mile radius of us.”

As proprietors of an urgent care facility, Jones and Maguire wanted to be on a well-traveled road. It was imperative that they were easily accessible via public transportation. In a departure from the norm, Jones and Maguire looked at retail space, which is likely the opposite of what an oncology practice ought to consider.

“An oncology practice would probably go into a medical office building,” said Jones. “And while medical office buildings don’t [always] have the prime real estate location, such as being on a major road, they’re also less expensive. An oncology practice doesn’t need to be on a major highway because it’s more referral-based and establishes relationships with a lot of local doctors.”

Financing the Deal



Unless you have a rich uncle who will lend you the funds necessary to get your oncology practice up and running, you will likely need to secure a loan through a local bank. But in today’s tight economy, are banks lending? Hill confirmed that they are, but the loan terms are more restrictive than they used to be.Hill said he is starting to see more banks targeting loans to the healthcare field. “Within the bank you’ll want to seek out the healthcare department—those who do the financing in that area,” he said. “Because it is a little different; it’s not a machine shop. There isn’t inventory attached. There’s machinery, but not like a large widget manufacturer employing 100 people. So…you need to make sure you align yourself with a banker who works in healthcare.”

Nevertheless, Jones said, be prepared to make a presentation that includes a spreadsheet with predicted expenses and a cash flow forecast. It can be challenging for an oncologist coming straight out of a fellowship who is starting a medical practice for the first time because there is much you don’t know. For example, how much will you earn per patient? How many patients will you see? How much do you plan to spend per square foot on build-out (ie, the process of finishing a raw space)? What is the average salary of a receptionist? How many receptionists will you need?

“There are a lot of variables in the equation,” Jones said. “And the bank is going to want to see all of these numbers so they know that you’ve thought through the entire process…before you go to them.” He pointed out that it might be helpful to hire an accountant or attorney who understands this process. Jones said, “We used an urgent care consultant who helped set up other urgent care practices and she was very helpful.”

Staffing the Practice



Davidson is also the co-founder of Crossville, Tennessee–based Oncology Partners, which helps oncology practices maximize their efficiency. He cautioned that an oncology practice just starting up should consider doing so with minimal employees: perhaps just a receptionist and a nurse, in addition to the physician.

“That’s always an issue: how many people do you really need?” said Davidson. “A lot of people think they need to project an image of strength and size, so they automatically hire more people than they need. If you think you are going to administer chemotherapy soon, then hire a good chemotherapy nurse who can also draw blood and run an IV. But remember that as you grow, you can always add people appropriately.”

Hill advised that when it comes to running the practice, physicians need to determine how hands-on they want to be in managing the day-to-day tasks as opposed to hiring someone else to do it for them.

“I’m a big fan of getting somebody who can manage your office for you.” he said. “Look for someone with credentials, such as MGMA [Medical Group Management Association]. They stay on top of office issues and what’s going on in the practice of medical office management. That way you can spend more time seeing patients and less time on office matters.”

Jones agreed with that advice. He and Maguire brought in a business manager a couple of months before the center opened its doors, and Jones believes that it was one of their best decisions. Jones said, “She had run a practice before, she knew what questions to ask, and we…let her manage most of that.” It is a strategy he suggested that oncology fellows employ. Jones said that when oncology fellows leave their fellowship, “they’re going to be moonlighting or working for other groups. They’re going to be working in order to maintain an income, so setting up a new practice is something they will be doing in their off time.”Jones acknowledged that there are “a million” pitfalls to avoid when starting a practice. He said one lesson that he and his partner were surprised to learn is that things end up costing more than they expected. When they initially spoke with their banker, they asked for a set loan amount. But the banker said, “Let me give you 20% extra, because no matter how you cut this project, it’s going to cost more than you think it will.” Jones said, “And you know what? He was right.”

Covering the Bases



Hill outlined the importance of relationship building. Before starting the practice, he said you should make some phone calls to an accountant, an attorney who practices healthcare law, a banker who handles healthcare finance, and a malpractice carrier. You will also want to consider whether you should open a practice on your own or with a partner. Davidson said that’s a decision a physician has to feel comfortable with. “If you go into a partnership and you’re at odds with your partner, that’s chaos,” he said. “When you go [into your own practice] you want career satisfaction. Do you feel like you’re in charge or that you can practice medicine the way you feel is right? Those are important considerations.”

Jones said that he has known his partner for 10 years and they have worked together in a hospital. For him, it has been crucial to have someone with whom he can bounce ideas around.

“Picking the right partner is critical,” Jones said. “And you also have to figure out how many partners you want. The more partners you have, it becomes more of a committee decision rather than you and another guy just getting it done.”

Ultimately, deciding to start your own practice requires careful consideration of all of the variables involved. (See “Should You Start Your Own Practice?”) Doing the legwork to research and evaluate locations, the competition, financing, staffing, potential partnerships, and other key factors will help you launch a successful medical practice.

Should You Start Your Own Practice?

If you are contemplating starting an oncology or hematology practice upon completion of your fellowship but you're not certain if it's the right move for you, consider this decision-making tool from Starting a Medical Practice, Second Edition, published by the American Medical Association. Simply circle the answers that are most true for you, then see which column contains the highest score.

 
 
 
Sole Proprietor
Partnership or Group
Practice—Part Owner
Employed
 
1.   Do you prefer to make your own decisions?
2.   Are you comfortable with making difficult decisions?
3.   Are you organized and detail oriented?
4.   Do you perform well under productivity incentives to see X number of patients?
5.   Do you perform well when having your clinical utilization monitored?
6.   Do you enjoy marketing and networking?
7.   Are you willing to compromise on your objectives or settle on an issue?
8.   Are you a competent record keeper?
9.   Do you enjoy managing and leadership?
10. Are you good at containing expenses?
11. Do you have the mindset of a business owner who can focus on profits, in       addition to patient care?
 
Yes
Yes
Yes
No
No
Yes
No
Yes
Yes
Yes
Yes
 
 
Somewhat
Somewhat
Somewhat
Somewhat
Somewhat
Somewhat
Somewhat
Somewhat
Somewhat
Somewhat
Somewhat
 
 
No
No
No
Yes
Yes
No
Yes
No
No
No
No
 
 
Total:
 
 
 

Ed Rabinowitz is a veteran healthcare journalist based in Upper Mount Bethel Township, Pennsylvania.

This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
View the full PDF of this issue


Oncology Fellows October IssueOncology Fellows features articles written by practicing physicians, clinical instructors, researchers, and current fellows who share their knowledge, advice, and insights on a range of issues.

This issue contains articles on:

When Cancer Hits Close to Home

Public Speaking Tips for Fellows

How to Perform the Perfect Bone Marrow Biopsy

Loan Repayment Programs for Oncology/ Hematology Fellows


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
View the full PDF of this issue


Oncology Fellows December/January IssueOncology Fellows features articles written by practicing physicians, clinical instructors, researchers, and current fellows who share their knowledge, advice, and insights on a range of issues.

This issue contains articles on:

Day in the Life of a Fellowship Program Director

Interviewing 101: Tips for Landing your First Post-Fellowship Position

Physician Notes in the Age of Electronic Medical Records

Reducing Errors During Patient-Care Handoffs


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.
View the full PDF of this issue


The International Journal of Targeted Therapies in Cancer is focused on the use of targeted therapies and personalized medicine—one of the most rapidly growing and clinically challenging areas of oncology today.

This issue contains articles on:

  • What Turns a Good Cell Bad?
  • Breast Cancer: Beyond Herceptin
  • Melanoma: Are You Ready for PI3K/Akt Inhibitors?
  • A Better Understanding of the SCK/KIT Pathway
  • Lung Cancer: When Targeted Therapies Don’t Work
  • Basal Cell Carcinoma: Hedgehog Speeds Along
  • Myeloproliferative Neoplasms: The Many Possibilities of JAK Inhibition


OncologyLive Targeted Therapy News March IssueOncologyLive Targeted Therapy News covers the most important developments in cancer care today, personalized medicine and targeted therapies. The publication is strongly committed to providing oncology healthcare professionals the information and resources they need to deliver the best possible treatment to their patients

This issue contains articles on:

  • The Hope and Challenges of Personalized Medicine
  • Changing Paradigms for NSCLC in Personalized Therapy Era
  • Biomarker Identifies Patients With Advanced Lung Cancer Who Will Gain Most From Add-On Cetuximab
  • Prostate Cancer Armamentarium Expanding
  • And more on Head and Neck Cancers, Prostate Cancer, Hematologic Malignancies, Lung Cancer, Renal Cell Carcinoma, and Breast Cancer


Reovirus

Reovirus
The first stage of enrollment has been completed in a phase III clinical trial that will examine the use of a human reovirus, in combination with chemotherapy, in patients with head and neck cancer. Oncolytics Biotech Inc. announced April 2 that it has enrolled 80 patients in the trial of Reolysin, a variant of the respiratory enteric orphan virus. The patients, who have platinum-refractory head and neck cancers, will receive Reolysin in combination with paclitaxel and carboplatin. “This is an important milestone for this study,” Brad Thompson, PhD, president and CEO of Oncolytics in Calgary, Canada, said in a press release. “A data analysis that will involve examining evolving progression-free survival will now be performed on this patient group to determine the probability of success in the second stage of the study.”

The randomized, double-blind trial will assess the intravenous administration of Reolysin with the two chemotherapy drugs versus chemotherapy alone in patients with metastatic or recurrent squamous cell carcinoma of the head and neck, or squamous cell cancer of the nasopharynx, who have progressed on or after prior platinum-based chemotherapy. It is being conducted in 80 centers in 12 countries in North America and Europe. The primary endpoint is overall survival.

Reolysin works by infecting patients with the reovirus, to which most people have been exposed by adulthood, and which typically causes few or no symptoms, the company said. Normal cells are able to fight the infection, but cancer cells with Ras gene mutations cannot, and the unchecked multiplication of the virus kills them by causing them to rupture. Then, the virus moves on to destroy nearby tumor cells. (NCT01166542)

Strategies Targeting the Hallmarks
of Cancer

Strategies Targeting the Hallmarks of Cancer Click to enlarge.

This figure illustrates some of the many approaches employed in developing therapeutics targeted to the known and emerging hallmarks of cancer.

EGFR indicates epidermal growth factor receptor; CTLA4, cytotoxic T lymphocyte-associated antigen 4; mAb, monoclonal antibody; HGF, hepatocyte growth factor; VEGF, vascular endothelial growth factor; PARP, poly-(ADP ribose) polymerase.

Source: Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674. Reprinted with permission.

At the turn of the millennium, Douglas Hanahan and Robert Weinberg presented their seminal article on the “hallmarks of cancer,” six alterations in cellular physiology that are essential to the transformation of normal cells into cancerous ones.1 Just over a decade has passed since then, and though the hallmarks remain central to tumor biology and research, it is now generally accepted that the original six hallmarks may not be sufficient for malignant transformation, and that additional hallmark capabilities may be involved.2

Impaired Metabolism: Cancer’s Sweet Tooth

Research has shown that cancer cells undergo a metabolic switch, a fundamental change in the metabolism of all four major classes of macromolecules (carbohydrates, proteins, lipids, and nucleic acids).3

The Warburg effect4 is the best characterized metabolic change, in which cancer cells switch their means of energy production from oxidative phosphorylation to glycolysis, even in the presence of normal levels of oxygen (thus termed aerobic glycolysis). To compensate for the reduced ATP production efficiency with aerobic glycolysis, cancer cells increase uptake of glucose, a phenomenon that has proved useful for tumor detection and monitoring, serving as the basis for [18F]fluorodeoxyglucose positron emission tomography (FDGPET). The Warburg effect has since been demonstrated in numerous tumor types, and genes for glycolysis are overexpressed in the majority of cancers examined, leading to the suggestion that altered metabolism should be considered an additional hallmark of cancer.3,5

A variety of therapeutic strategies targeting different points in the glycolytic pathway are being evaluated.3 During the initial stages of tumor growth, the low oxygen environment promotes expression of hypoxiainducible factor (HIF) 1, a major transcription factor that subsequently activates numerous glycolytic enzymes, including pyruvate dehydrogenase kinases (PDKs), lactate dehydrogenase (LDH)6, and glucose-6-phosphate dehydrogenase (G6PD).A variety of inhibitors targeting these proteins have been developed. The G6PD inhibitor, 6-amino-nicotinamide, has demonstrated antitumor effects in leukemia, glioblastoma, and lung cancer cell lines.3 Salts of dichloroacetate (DCA), which inhibit PDK, are in phase II trials for squamous cell carcinoma of the head and neck.7 EZN-2968 from Enzon Pharmaceuticals (an antisense oligonucleotide inhibitor of HIF1) is in phase I trials for advanced solid tumors.8 LDH inhibitors are among the most promising agents, though they remain in the early stages of development.6 The serine/threonine kinase AKT is also an important driver of the glycolytic phenotype, stimulating ATP generation through multiple mechanisms; the AKT inhibitor MK-2206 (Merck & Co.) is currently undergoing phase II trials in non-small cell lung cancer (NSCLC) and hematological cancers, among others.9

Oxidative phosphorylation

A metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate (ATP).

Aerobic glycolysis

In normal cells, in the absence of oxygen, energy production switches from oxidative phosphorylation to anaerobic glycolysis, whereby glucose is converted into pyruvate in order to generate ATP. Cancer cells use glycolysis to generate energy even in the presence of oxygen.
AMP-activated protein kinase (AMPK) couples energy status to growth signals, and as such, a considerable amount of research has focused on determining whether agonists of AMPK could be used to recouple these signals in cancer cells and shut down cell growth. Examples of AMPK agonists that are under evaluation include the commonly used antidiabetic drugs metformin and phenformin.3

Not all tumors use aerobic glycolysis; approximately 30% of tumors are FDGPET– negative. Some tumors use glutamine instead. Drugs targeting glutamine include phenylacetate, which completed phase II trials for brain tumors,10 and the green tea polyphenol EGCG, which may target glutamine metabolism and is in phase I trials for small cell lung carcinoma.11,12 However, previous studies with these agents have reported mediocre results and, as such, efforts are ongoing to develop more specific and potent inhibitors of glutamine.

Some researchers take the theory of altered cancer cell metabolism one step further and believe that all other hallmarks of cancer can be linked to altered metabolism, and that, in fact, cancer should be viewed as a metabolic disease.12 This is an important hypothesis because, if true, it could change the way that we treat cancer. Current treatment paradigms are typically based on the premise that cancer is a genetic disease, and that genomic instability (see below) and the accumulation of genetic mutations are the initiating factors in the development of cancer; usually, treatment strategies involve targeting proteins that are overexpressed, or whose expression is lost as a result of a mutation.

Potential metabolic therapies include dietary restriction, which naturally lowers glucose levels and has been shown to significantly reduce growth and progression of numerous tumor types (including mammary, brain, pancreas, colon, lung, and prostate). Dietary restriction has the potential to be a broadspectrum, nontoxic therapy that targets multiple signaling pathways at once; however, the strategy of long-term 20% to 40% calorie restriction that has been studied for many years is associated with chronic weight loss (cachexia). Therefore, current American Cancer Society recommendations suggest that cancer patients receiving chemotherapy should increase calorie and protein intake.However, more recent studies have shown that fasting for up to five days, followed by a normal diet, may protect patients against the toxic effects of chemotherapy (by differentially protecting normal cells from chemotherapeutic drugs) without causing cachexia. Numerous clinical trials are examining the impact of dietary restrictions on the risk of various cancers.12,13 Thus, dietary restriction could represent a promising adjuvant to chemo- or radiation therapy.

Genomic instability

An increased tendency of alterations, in the form of mutations and chromosomal rearrangements, to the genome of cancer cells.

Genomic Instability: How Do Tumors Accumulate So Many Mutations?

In the “chicken-and-egg” question of what is the initiating step in cancer, the majority of researchers still view cancer as a genetic disease, the result of a succession of alterations in the genome of normal cells that drives the acquisition of the hallmarks of cancer. However, the ability of genomic “guardians,” such as the tumor suppressor protein p53, to detect and repair DNA damage, ensures that rates of spontaneous mutation are usually very low. Genomic instability explains the increased susceptibility of the cancer genome to mutation and is a key characteristic of all cancer cells. Thus, it has been proposed that genomic instability is another hallmark of cancer. Others feel it should be treated as an “enabling characteristic” of all other hallmarks of cancer.

We still have a very limited understanding of the molecular mechanisms underlying genomic instability. Different tumors (even different examples of the same tumor type) have different patterns of DNA mutation, which is a key limiting factor to currently available therapeutic strategies that target oncogenic signaling pathways. Identifying the initiating step in genomic instability and targeting that could prove to be an important therapeutic strategy in the future.14,15

Epigenetics

Biochemical changes to the DNA that don’t involve an alteration in the nucleotide sequence (as mutations do), but still affect gene expression or cellular phenotype. Epigenetic mechanisms include the addition of methyl groups to the DNA or the packaging of the DNA with histone proteins.

Epigenome

The overall epigenetic state of the DNA within an individual cell.

Epigenetic Changes: Flipping the Genetic Switch

Epigenetic factors, such as DNA methylation and histone modification, ensure the timely expression or silencing of genes. They are particularly important in differentiated cells, silencing the expression of developmental genes and allowing the expression of only tissue-specific and housekeeping genes. Alterations in the patterns of epigenetic modification may lead to inappropriate reactivation of developmental genes, driving cancer.

Studies over the last decade have shown the importance of epigenetic mechanisms in regulating the expression of genes critical to cellular transformation pathways. Combined with the observation that cancer cells have a distinct epigenome compared with normal cells, this has led to the suggestion that epigenetic modulation should be considered another hallmark of cancer.16Unlike genetic alterations, epigenetic changes are potentially reversible, and it might be possible to “reset” the cancer epigenome with pharmacologic or genetic therapeutic strategies. A number of agents are under evaluation in this respect. Demethylating drugs, which inhibit methylation, include 5-azacitidine (Vidaza, Celgene) and 5-azadeoxycitidine/decitabine (Dacogen, Eisai, Inc). Both citidine analogs are FDA-approved for the treatment of myelodysplastic syndrome, which transforms into acute myeloid leukemia (AML) in one-third of patients. Both are also currently undergoing phase III trials for AML.16-18

Another mechanism of epigenetic control is through microRNAs (miRNAs), small noncoding RNAs that regulate gene expression. Studies have shown that miRNA expression is deregulated in cancer. miRNA-based anticancer therapies are being developed via two different strategies: (1) use of oligonucleotides or virus-based constructs to block the expression of an oncogenic miRNA or substitute for the loss of expression of a tumor-suppressing miRNA; and (2) use of small-molecule drugs to modulate miRNA expression by targeting their transcription or processing. An example of the former is anti-miR-122 (miravirsen, SPC3649, Santaris Pharma), which has completed phase I and II clinical trials for the treatment of the hepatitis C virus and the prevention of associated liver cancer. Small-molecule inhibitors are in the early stages of development, focusing on miR-21, which is frequently upregulated in cancer.19

Table. Key Therapeutics Targeting the "New" Hallmarks

Therapeutic Agent Hallmark Targeted Manufacturer Stage of Development/Clinical Trials
Dichloroacetate Metabolism Sanford Health Phase II trial for squamous cell carcinoma of the head and neck in combination with cisplatin and definitive radiation (Clinicaltrials.gov identifier: NCT01386632).
HIF-1–inhibitors
(EZN-2968)
Metabolism Enzon Pharmaceuticals Phase I trial in adults with advanced solid tumors with liver metastases (Clinicaltrials.gov identifier: NCT01120288).
AKT inhibitors
(eg, MK-2206)
AKT inhibitors primarily target the original hallmarks of cancer associated with dysregulated growth of cells; however, they may also target the altered metabolism of cancer cells of the head and neck in combination with cisplatin and definitive radiation (Clinicaltrials.gov identifier: NCT01349933). Merck & Co., Inc. Phase II trials in the treatment of recurrent platinum-resistant ovarian, fallopian tube, or peritoneal cancer (Clinicaltrials.gov identifier: NCT01283035), relapsed refractory acute myelogenous leukemia (Clinicaltrials.gov identifier: NCT01253447), relapsed or refractory diffuse large B cell lymphoma (Clinicaltrials.gov identifier: NCT01466868), advanced colorectal carcinoma (Clinicaltrials.gov identifier: NCT01333475), relapsed lymphoma (Clinicaltrials. gov identifier: NCT01258998), relapsed chronic lymphocytic leukemia or small lymphocytic leukemia in combination with bendamustine hydrochloride and rituximab (Clinicaltrials.gov identifier: NCT01369849), stage I, II, and III breast cancer (Clinicaltrials.gov identifier: NCT01319539), advanced gastric or gastroesophageal junction cancer (Clinicaltrials.gov identifier: NCT01260701), advanced breast cancer tumors with PIK3CA mutations and/or PTEN loss (Clinicaltrials.gov identifier: NCT01277757), and other phase I and II trials.
Metformin Metabolism   Phase III trials in early-stage breast cancer (Clinicaltrials.gov identifier: NCT01101438), and a number of phase II trials in patients with breast cancer, (Clinicaltrials.gov identifier: NCT01266486), in combination with chemotherapy in patients with pancreatic cancer (Clinicaltrials.gov identifier: NCT01210911), in combination with paclitaxel in patients with metastatic or recurrent head and neck cancer (Clinicaltrials.gov identifier: NCT01333852), among others.
Demethylating drugs (5-azacitidine and 5-azadeoxycitidine) Epigenetic alterations Celgene

Eisai, Inc.
Both 5-azacitidine (Vidaza) and 5-azadeoxycitidine (Dacogen/decitabine) are FDA-approved for the treatment of myelodysplastic syndrome. Also undergoing phase III clinical testing for acute myeloid leukemia (Clinicaltrials.gov identifiers: NCT00260832 and NCT01074047) and a number of phase I/II trials, for example in combination with capecitabine and oxaliplatin for the treatment of metastatic colorectal cancer (Clinicaltrials.gov identifier: NCT01193517) and in minimal residual disease chronic myeloid leukemia (Clinicaltrials.gov identifier: NCT01460498).
miRNA-based therapy (anti-miR-122/ miravirsen) Epigenetic alterations Santaris Pharma Completed phase II trials for the treatment of hepatitis C virus and the prevention of associated liver cancer (Clinicaltrials.gov identifier: NCT01200420).
Sipuleucel-T (Provenge) Immune system evasion Dendreon Corporation FDA-approved for the treatment of advanced, hormone-refractory prostate cancer. Also currently undergoing a number of phase II trials in prostate cancer patients in combination with a variety of other agents.
Ipilimumab (Yervoy) Immune system evasion Bristol-Myers Squibb FDA-approved for the treatment of metastatic melanoma. Currently undergoing phase II trials in the neoadjuvant setting in combination with leuprolide acetate in prostate cancer patients (Clinicaltrials.gov identifier: NCT01194271) and a phase I trial in Japanese subjects with non-small cell lung cancer in combination with paclitaxel and carboplatin (Clinicaltrials.gov identifier: NCT01165216).
Daclizumab (Zenapax) Immune system evasion Roche Currently undergoing phase II trials in combination with chemotherapy and stem cell transplant for Hodgkin lymphoma (Clinicaltrials.gov identifier: NCT01468311).
Basiliximab (Simulect) Immune system evasion Novartis Currently undergoing phase II trials for the prevention of graft-versus-host disease after nonmyeloablative allotransplantation for the treatment of blood cancer (Clinicaltrials.gov identifier: NCT00975975).

The Immune System and Inflammation

There has been much debate over the role of the immune system in cancer; it appears to play a dual role in fighting off and in promoting cancer growth. In the early 2000s, researchers developed the “immunoediting” hypothesis, which suggests that an immune response is initially raised against cancer cells (the “elimination” stage). Subsequently, the surviving cancer cells accumulate mutations that enable them to evade the immune response, a so-called “equilibrium” stage.Eventually, the tumor cells that have acquired the ability to evade the immune system establish themselves as a growing tumor (the “escape” stage).20 As a result, immune evasion is now considered to be an additional hallmark of cancer, while inflammation is thought to be an “enabling characteristic,” supplying molecules that support growth, survival, and angiogenesis, among other cancer hallmarks, into the tumor microenvironment.2,21

A variety of forms of immunotherapy are being explored as possible treatments for cancer. These include vaccines, designed to elicit an immune response to specific tumor antigens, monoclonal antibodies targeting tumor antigens, and small-molecule inhibitors against molecular or cellular mediators of cancer-induced immunosuppression.20 Vaccines offer the advantages of being easy and relatively inexpensive to produce, easy to administer in a clinical setting, and specific to particular tumor types.

At a Glance…

Cancer cells undergo fundamental changes in their metabolism, with the best characterized being the “Warburg effect.” Since the metabolism of cancer cells is different from normal cells in the body, targeting molecular components of that altered metabolism may offer potential therapeutic strategies. Targeting metabolism as a whole through dietary restriction is also being investigated.
Cancer cells develop a succession of alterations to their genome that results in the acquisition of other hallmarks of cancer, a phenomenon termed genomic instability. It is now believed that genomic instability constitutes a hallmark of its own, or indeed may be the initiating “enabling characteristic” that drives the formation of cancer.
The reversible modifications that the DNA undergoes, known as epigenetic changes, are different in cancer cells, which may be important in regulating the expression of genes critical to the formation of cancer. It may be possible to “reset” the epigenome of a cancer cell using a variety of pharmacologic or genetic therapies.
The immune system appears to play a dual role in cancer, both fighting it off in the early stages and subsequently promoting cancer growth later on in the development of cancer. A number of forms of immunotherapy are being developed as possible cancer treatments, including vaccines, monoclonal antibodies, and small-molecule inhibitors.
Vaccines against a number of different tumor antigens are being developed as anticancer treatments.22 The results of many vaccination trials have been disappointing, possibly because they have been conducted in metastatic patients. It is now believed they will be more active in patients with minimal residual tumor burden, such as after preoperative chemotherapy. Sipuleucel-T (Provenge, Dendreon Corporation) is the first FDA-approved cancer vaccine, a dendritic cell vaccine approved for treatment of advanced, hormone-refractory prostate cancer.20,22,23Ipilimumab (Yervoy, Bristol-Myers Squibb) is a monoclonal antibody against cytotoxic T lymphocyte antigen-4 (CTLA-4) that is FDA-approved for the treatment of metastatic melanoma, and is currently undergoing phase II trials in the neoadjuvant setting in prostate cancer and phase I trials in combination with chemotherapy in non-small cell lung cancer patients, among other trials.20

Finally, T regulatory (Treg) cells have been identified as one of the most powerful suppressors of the antitumor immune response. Studies have shown a clear relationship between the ratio of Treg cells to T effector (Teff; killing) cells and patient prognosis; the fewer Treg cells, the better. Although research is still in its infancy, evidence suggests that inhibition of Treg cells may provide an extremely useful therapeutic strategy, particularly in combination with immunotherapies that activate Teff cells.

Treg cell-targeting strategies thus far have focused on monoclonal antibodies or ligand-directed toxins targeted against receptors on the surface of the cells. They include two drugs that target the cell surface molecule CD25: daclizumab (Zenapax, Roche), undergoing clinical trials in patients with Hodgkin lymphoma, and basiliximab, (Simulect, Novartis), in phase I/II clinical trials in patients with Hodgkin and non-Hodgkin lymphoma, cutaneous melanoma, peripheral T cell lymphoma, and breast cancer.24,25


Jane de Lartigue, PhD, is a freelance medical writer and editor based in the United Kingdom.

References

  1. Hanahan DW, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70.
  2. Hanahan, DW, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674.
  3. Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nature Rev Cancer. 2011;11(2):85-95.
  4. Warburg O. On respiratory impairment in cancer cells. Science. 1956;124;269-270.
  5. Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell. 2008;134(5):703-707.
  6. Granchi C, Bertini S, Macchia M, Minutolo F. Inhibitors of lactate dehydrogenase isoforms and their therapeutic potentials. Curr Med Chem. 2010;17:672-697.
  7. ClinicalTrials.gov. Study of DCA (Dichloroacetate) in combination with cisplatin and definitive radiation in head and neck carcinoma, http://clinicaltrials.gov/ct2/show/NCT01386632?term=dichloroacetate&rank=3. Accessed April 18, 2012.
  8. ClinicalTrials.gov. A pilot study of EZN-2968, an antisense oligonucleotide inhibitor of HIF- 1alpha, in adults with advanced solid tumors with liver metastases, http://clinicaltrials.gov/ct2/show/NCT01120288?term=ezn-2968&rank=1. Accessed April 18, 2012.
  9. ClinicalTrials.gov. Assessment of efficacy and safety of perifosine, bortezomib and dexamethasone in multiple myeloma patients, http://clinicaltrials.gov/ct2/show/NCT01002248?term=perifosine+phase+III&rank=1. Accessed April 18, 2012.
  10. ClinicalTrials.gov. Phenylacetate in treating children with recurrent or progressive brain tumors. http://clinicaltrials.gov/ct2/show/NCT00003241?term=phenylacetate+phase+II&rank=1. Accessed April 18, 2012.
  11. ClinicalTrials.gov. Oral green tea extract for small cell lung cancer, http://clinicaltrials.gov/ct2/show/NCT01317953?term=EGCG&rank=19. Accessed April 18, 2012.
  12. Seyfried TN, Shelton LM. Cancer as a metabolic disease. Nutrition & Metabolism. 2010;7:7-22.
  13. Lee C, Longo VD. Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients. Oncogene. 2011;30:3305-3316.
  14. Negrini S, Gorgoulis VG, Halazonetis TD. Genomic instability—an evolving hallmark of cancer. Nature Rev Mol Cell Biol. 2010;11:220-228.
  15. Martin SA, Hewish M, Lord CJ, Ashworth A. Genomic instability and the selection of treatments for cancer. J Pathol. 2009;220:281-289.
  16. Berdasco M, Esteller M. Aberrant epigenetic landscape in cancer: how cellular identity goes awry. Dev Cell. 2010;19(5):698-711.
  17. ClinicalTrials.gov. Intravenous (IV) decitabine and oral bexarotene for acutemyelogenous leukemia (AML). http://clinicaltrials.gov/ct2/show/NCT01001143?term=5-azadeoxycytidine&rank=3. Accessed April 18, 2012.
  18. ClinicalTrials.gov. Trial evaluating induction therapy with idarubicin and etoposide plus sequential or concurrent azacitidine and maintenance therapy with azacitidine. http://clinicaltrials.gov/ct2/show/NCT01180322?term=5-azacytidine&rank=4. Accessed April 18, 2012.
  19. Garzon R, Marucci G, Croce CM. Targeting microRNAs in cancer: rationale, strategies and challenges. Nature Rev Drug Disc. 2010;9:775-789.
  20. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565-1570.
  21. Colotta FA, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009;307):1073-1081.
  22. Curigliano G. Immunity and autoimmunity: revising the concepts of response to breast cancer. The Breast. 2011;20(suppl 3):S71-S74.
  23. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.
  24. Byrne WL, Mills KHG, Lederer JA, O’Sullivan, GC. Targeting regulatory T Cells in cancer. Cancer Res. 2011;71:6915-6920.
  25. Cavallo F, De Giovanni C, Nanni P, Forni G, Lollini P. 2011: the immune hallmarks of cancer. Cancer Immunol Immunother. 2011;60(3):319-326.


The International Journal of Targeted Therapies in Cancer is focused on the use of targeted therapies and personalized medicine—one of the most rapidly growing and clinically challenging areas of oncology today.

This issue contains articles on:

  • Cancer Research Moves Beyond the Original “Hallmarks of Cancer”
  • ALK Rearrangements as a Therapeutic Target in Advanced Non-Small Cell Lung Cancer
  • Immunotherapy in Advanced Melanoma
  • BRAF Inhibitors in Melanoma
  • MET Inhibitors in Cancer Therapy
  • MetMAb and ARQ 197 in Non-Small Cell Lung Cancer


OncologyLive Targeted Therapy News covers the most important developments in cancer care today, personalized medicine and targeted therapies. The publication is strongly committed to providing oncology healthcare professionals the information and resources they need to deliver the best possible treatment to their patients

This issue features articles on:

  • ASCO: A Focus on Personalized Medicine
  • The Rising Cost of Cancer Care in the Era of Individualized Therapy
  • A New Look at Survival Data for Sipuleucel-T
  • Targeted Therapies in Breast Cancer: Increasingly Promising— and Complicated




Antoni Ribas, MD Corresponding Author:

Antoni Ribas, MD

Department of Medicine, Division of Hematology-Oncology; Jonsson Comprehensive Cancer Center at the University of California, Los Angeles (UCLA), Los Angeles, CA;
aribas@mednet.ucla.edu

Abstract



The histology of melanoma is dependent upon driver oncogenic mutations in a major signaling pathway, with up to 70% of advanced melanomas having mutually exclusive activating mutations in the mitogen-activated protein kinase (MAPK) pathway. Mutations closely follow different clinical-pathological presentations of melanoma. The BRAFV600E mutation makes up over 90% of the mutations in BRAF, which are present in approximately 50% of all melanomas. The BRAF inhibitor vemurafenib induces high antitumor activity in patients with BRAF-mutant metastatic melanoma and improvement in survival, leading to its approval by the FDA. Similar results have been eported with another BRAF inhibitor, dabrafenib. Resistance to BRAF inhibitors does not follow the common pathways of resistance to other ATP-competitive targeted kinase inhibitors. Instead, so far, mechanisms of resistance can be divided into two major groups: reactivation of the MAPK pathway and MAPK-independent pathways. An understanding of acquired resistance to BRAF inhibitors is already resulting in new combination therapies to prevent or treat some of the resistance mechanisms, and additional novel combinations are under study.

Biology of MAPK and BRAF Mutations in Melanoma

Melanoma has become one of the best examples of a cancer histology dependent upon driver oncogenic mutations in a major signaling pathway. This is because up to 70% of advanced melanomas have mutually exclusive activating mutations in the mitogen-activated protein kinase (MAPK) pathway, resulting in constitutive signaling leading to oncogenic cell proliferation and escape from apoptosis.1 These mutations are not randomly distributed since they closely follow different presentations of melanoma:
  1. Mutations in c-Kit: Mutations in the c-Kit receptor tyrosine kinase (RTK) are located in similar exons as in gastrointestinal stromal tumors (GISTs) and are more prevalent in mucosal melanomas and acral lentiginous melanomas.2 These are two subtypes of melanoma that are not related to the carcinogenic effects of ultraviolet light or history of sunburns. Overall, c-Kit mutations are present in less than 2% of melanomas.
  2. Mutations in NRAS: RAS mutations in melanoma are preferentially in NRAS, as opposed to other cancers where mutations are more frequent in KRAS or HRAS. They cluster in the RAS hotspot mutation sites, in particular at Q61, and were the first oncogenic driver mutation described in melanomas.3 These mutations tend to appear in melanomas located on intermittently sun-exposed or chronically sunexposed skin. Emergent data suggest that they are more frequent in melanomas in older individuals. Overall, NRAS mutations are present in approximately 20% of melanomas.
  3. Mutations in BRAF: The BRAFV600E mutation, which leads to the substitution of valine by glutamic acid at position 600 (V600E) in the BRAF kinase, is the most common point mutation in melanoma, present in approximately 50% of cases.4,5 The BRAFV600E mutation makes up over 90% of the mutations in BRAF, with other amino acid substitutions at this position (V600K, V600D, or V600R) being much less frequent.5 Increasing evidence suggests that the frequency of the BRAFV600E mutation is inversely correlated with age, with a higher incidence in patients between ages 20 to 40 years than patients older than age 60 years.

    With increasing age, the second most common BRAF mutation, BRAFV600K, is more frequently seen.6 Uncommon mutations at other positions of the BRAF gene often lead to decreased kinase activity, which may still be oncogenic through the transactivation of CRAF. This happens because BRAF usually forms dimers with CRAF, and it has been shown that certain mutations in BRAF or drugs that block BRAF can paradoxically increase the function of CRAF, resulting in increased MAPK signaling.1,5,7
  4. Mutations in GNAQ and GNA11: Melanomas arising from the choroidal layer of the eye are clinically distinct from the rest of melanomas in terms of their risk factors (which are mostly unknown), clinical appearance, and natural history. Not surprisingly, these melanomas are driven by different oncogenic mutations in GNAQ and GNA11, which are part of the signaling complex of G-coupled receptors.8,9 These mutations seem to signal through protein kinase C (PKC) and farther downstream through the MAPK pathway, resulting in constitutive oncogenic signaling.
BRAF protein

Structure of the BRAF protein.

BRAF Inhibitors in Clinical Use

Two specific BRAF inhibitors with high antitumor activity in patients with BRAF-mutant metastatic melanoma are in clinical use: the FDA-approved vemurafenib10-12 and the experimental agent dabrafenib (formerly GSK2118436).13 They both induce high frequency of tumor responses, specifically in BRAFV600-mutant metastatic melanoma mediated by the inhibition of oncogenic MAPK signaling.14The most common side effects of the selective BRAF inhibitors are grade 1 and 2 arthralgia and a variety of skin proliferative conditions, in particular a variety of keratotic hyperproliferative lesions. The main grade 3 toxicity with the use of single-agent BRAF inhibitors is the development of secondary cutaneous squamous cell carcinomas, mostly of keratoacanthoma subtype.10-12,15 These nonmelanoma skin cancers frequently appear within the first few weeks of therapy in patients with pre-existing chronic skin sun damage. They are usually treated with local excision and do not require changing the doses or discontinuing therapy with the BRAF inhibitor.

The mechanistic basis of their development is the paradoxical MAPK activation with BRAF inhibitors, where the blockade of BRAF within a dimer with CRAF results in increased MAPK signaling through the paradoxical transactivation of CRAF.12,16 Differential toxicities between the two leading BRAF inhibitors are the higher incidence of photosensitivity with vemurafenib and the higher incidence of fevers with dabrafenib.17 The mechanistic bases of these two side effects are yet to be determined.

Mechanisms of Acquired Resistance to BRAF Inhibitors

Resistance to BRAF inhibitors does not follow the common pathways of resistance to other kinase inhibitors, in that no mutations in the actual target kinase have been described that would make the drug binding ineffective. Notably, no mutations have been described in patient-derived samples that would correspond to the T315I, resulting in resistance to imatinib in chronic myelogenous leukemia,18 or the T790M mutation, resulting in resistance to gefitinib in non-small cell lung cancer.19 Instead, a variety of mechanistically different resistance pathways have been described in subsets of acquired resistant tumor biopsies. These can be divided into two major groups when focusing on mechanisms reported to date in patient-derived samples:

  1. Reactivation of the MAPK pathway: Although secondary acquired mutations in BRAF have not yet been identified, several alterations leading to reactivation of oncogenic signaling through the MAPK pathway result in acquired resistance to BRAF inhibitors. Of note, the resistant lesions universally maintain the BRAFV600 mutation. However, there can be other changes in BRAF itself, including amplifications of the mutant BRAFV600 gene20 and truncations in the BRAF protein through alternate splicing, resulting in increased kinase activity due to increased dimerization.21Secondary mutations upstream or downstream of BRAF would also be predicted to result in resistance, and secondary mutations in NRAS and MEK (MAPK/ERK kinase) have been described in patientderived samples.22,23 However, some patients with a concurrent mutation in BRAFV600 and MEKP124 at baseline can still have responses to clinical BRAF inhibitors.24 Finally, overexpression of the MAPK protein Cot without mutations has been suggested to also lead to acquired resistance.25 Most of these resistance mechanisms could be blocked by downstream inhibition at the level of MEK or ERK (extracellular signal-regulated kinase).
  2. MAPK-independent pathways: In some cases of acquired resistance, the BRAF inhibitor continues to demonstrate ability to block oncogenic BRAFV600 signaling,22 and the cell adapts to gain oncogenic signaling from another pathway. This is induced by the overexpression or overactivation of RTKs such as the platelet-derived growth factor receptor beta (PDGFR-β) 22,26 or the insulin-like growth factor 1 receptor (IGF-1R).27 These RTKs provide a MAPK-redundant oncogenic signaling through the PI3K-Akt pathway. In preclinical models, this signaling can be inhibited by drugs that block PI3K, Akt, or TORC,26,28-30 but clinical trials are not yet started.

Addressing Acquired Resistance With Combination Therapies

Even in cases with reactivation of the MAPK pathway leading to acquired resistance to BRAF inhibitors, sequential administration of a MEK inhibitor does not result in secondary tumor responses,31 which recapitulates data from preclinical models.29 This is probably because there is a continued need to block oncogenic BRAFV600 signaling in a direct way. Also, in agreement with data from preclinical models,32 there is early clinical evidence of secondary responses when adding a MEK inhibitor to continued therapy with a BRAF inhibitor in patients progressing on single-agent BRAF inhibitors.33

The upfront use of combined therapy with a BRAF inhibitor and a MEK inhibitor may provide even greater benefit by preventing the development of MAPK-driven acquired resistance mechanisms (as opposed to treating resistance). The testing of the combination of BRAF and MEK inhibitors as the first oncogene-targeted therapy for BRAF-mutant melanoma has been done with the combination of dabrafenib and the MEK inhibitor trametinib (formerly GSK1120212), with early evidence of improved benefit.33,34 When compared to single-agent BRAF inhibitors, combined therapy with a MEK inhibitor may induce higher antitumor activity through a more profound oncogenic MAPK inhibition, while leading to more durable responses by preventing the MAPK-dependent acquired resistance mechanisms.

An additional benefit of this combination is that MEK inhibitors can block paradoxical MAPK activation that results in the development of cutaneous squamous cell carcinomas.12,16 This phenomenon may also be implicated in inflammatory-like toxicities from BRAF inhibitors, such as rash and joint pain. Therefore, the combination of BRAF and MEK inhibitors is a rare example of two agents that when combined have increased antitumor activity with decreased toxicities.Studies combining a BRAF inhibitor with a PI3K or Akt inhibitor to treat or prevent MAPK-independent resistance are likely to start in the clinic given the wealth of supportive preliminary evidence from the laboratory. 26,28-30 In addition, several clinical trials are under way combining MEK inhibitors with PI3K or Akt inhibitors, which also test the potential benefit of blocking both signaling pathways in melanoma. These studies will need to be balanced with the risk of increased toxicities when simultaneously blocking the MAPK and the PI3K/Akt pathways.

Clinical Pearls

  • The major grade 3 toxicity with single-agent BRAF inhibitors is the development of secondary cutaneous squamous cell carcinomas, which generally appear within the first few weeks of therapy in patients with pre-existing chronic sun skin damage.
  • There is early clinical evidence of secondary responses when adding a MEK inhibitor to continued therapy with a BRAF inhibitor in patients progressing on single-agent BRAF inhibitors.
  • Studies combining a BRAF inhibitor with a PI3K or Akt inhibitor to treat or prevent MAPK-independent resistance are likely to start in the clinic, given the wealth of supportive preliminary evidence from the laboratory.

Combining Targeted Therapies and Immunotherapies

Most evidence suggests that the high initial rates of tumor responses with BRAF-targeted oncogene pathway inhibitors do not last as long as the rather infrequent but highly durable tumor responses with immunotherapy agents such as interleukin-2 (IL-2) or the anti-CTLA4 antibody ipilimumab.35 The promise of combining these two modes of therapy is to maintain the high frequency of tumor responses achieved with BRAF inhibitors and make them more durable with immunotherapies.36,37

Preclinical studies demonstrated that BRAF inhibitors are not detrimental to human or murine lymphocyte function,38,39 which provides further rationale for the clinical testing of these two strategies. BRAF inhibitors may actually increase the antitumor function of lymphocytes because they may also induce paradoxical activation of the MAPK pathway in activated lymphocytes, as seen in other cells that have strong RAS-GTP activation. 7,40,41 Finally, BRAF inhibitors may increase the direct presentation or cross-presentation of tumor antigens to the immune system.38

Conclusions

The treatment of patients with metastatic melanoma has been improved by applying basic biology knowledge in oncogenic signaling and immune regulation to the clinic. This understanding of the means to improve patient care at a molecular level predicts that the advances will continue in the near future. Understanding acquired resistance to BRAF inhibitors is already resulting in new combination therapies that prevent or treat some of the resistance mechanisms. Additional treatment avenues based on the increasing understanding of molecular mechanisms driving this cancer are likely to reach the clinic in the near future.


References

  1. Gray-Schopfer V, Wellbrock C, Marais R. Melanoma biology and new targeted therapy. Nature. 2007;445:851-857.
  2. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135-2147.
  3. Padua RA , Barrass N, Currie GA. A novel transforming gene in a human malignant melanoma cell line. Nature. 1984;311:671-673.
  4. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949-954.
  5. Wan PT, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of BRAF. Cell. 2004;116:855-867.
  6. Long GV, Menzies AM , Nagrial AM , et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29:1239-1246.
  7. Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140:209-221.
  8. Van Raamsdonk CD , Bezrookove V, Green G, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009;457:599-602.
  9. Van Raamsdonk CD , Griewank KG, Crosby MB , et al. Mutations in GNA 11 in uveal melanoma. N Engl J Med. 2010;363:2191-2199.
  10. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809-819.
  11. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366:707-714.
  12. Su F, Viros A, Milagre C, et al. RA S mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012;366:207-215.
  13. Wilmott JS, Long GV, Howle JR, et al. Selective BRAF Inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin Cancer Res. 2012;18:1192-1194.
  14. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010;467:596-599.
  15. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516.
  16. Oberholzer PA, Kee D, Dziunycz P, et al. RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RA F inhibitors. J Clin Oncol. 2012;30:316-321.
  17. Arkenau HT , Kefford R, Long GV. Targeting BRAF for patients with melanoma. Br J Cancer. 2011;104:392-398.
  18. Gorre ME , Mohammed M, Ellwood K, et al. Clinical resistance to STI -571 cancer therapy caused by BCR -ABL gene mutation or amplification. Science. 2001;293:876-880.
  19. Pao W, Miller VA , Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Medicine. 2005;2:e7..
  20. Shi H, Moriceau G, Kong X, et al. Melanoma whole-exome sequencing identifies (V600E)BRAF amplification-mediated acquired BRAF inhibitor resistance. Nature Communications.2012;3:724.
  21. Poulikakos PI, Persaud Y, Janakiraman M, et al. RA F inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. 2011;480:387-390.
  22. Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to BRAF(V600E) inhibition by RTK or NRAS upregulation. Nature. 2010;468:973-977.
  23. Wagle N, Emery C, Berger MF, et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol. 2011;29(22):3085-3096.
  24. Shi H, Moriceau G, Kong X, et al. Sensitivity of BRAF/MEK1 double-mutant melanomas to BRAF inhibitors. Cancer Discovery [in press]; 2012.
  25. Johannessen CM , Boehm JS, Kim SY, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468:968-972.
  26. Shi H, Kong X, Ribas A, et al. Combinatorial treatments that overcome PDGFR{beta}- driven resistance of melanoma cells to V600EB-RAF inhibition. Cancer Res. 2011;71:5067- 5074.
  27. Villanueva J, Vultur A, Lee JT, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell. 2010;:683-695.
  28. Jiang CC , Lai F, Thorne RF, et al. MEK-independent survival of BRAFV600E melanoma cells selected for resistance to apoptosis induced by the RAF inhibitor PLX4720. Clin Cancer Res. 2010;17:721-730.
  29. Atefi M, von Euw E, Attar N, et al. Reversing melanoma cross-resistance to BRAF and MEK inhibitors by co-targeting the AKT/mTOR pathway. PLoS ONE. 6:e28973, 2011.
  30. Paraiso KH, Xiang Y, Rebecca VW , et al. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res. 2011;71:2750- 2760.
  31. Kim KB, Lewis KD, Pavlick AC, et al. A Phase II study of the ME K1/ME K2 inhibitor GSK1120212 in metastatic BRA F-V600E or K mutant cutaneous melanoma patients previously treated with or without a BRAF inhibitor. Pigment Cell Melanoma Res. 2011;24:1021. Abstract.
  32. Paraiso KH, Fedorenko IV , Cantini LP, et al. Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy. Br J Cancer. 2010;102:1724-1730.
  33. Flaherty K, Infante JR, Falchook GS, et al. Phase I/II study of BRA Fi GSK2118436 + ME Ki GSK1120212 in patients with BRAF mutant metastatic melanoma who progressed on a prior BRAFi. Pigment Cell Melanoma Res. 2011.
  34. Infante JR, Falchook GS, Lawrence DP, et al. Phase I/II study to assess safety, pharmacokinetics, and efficacy of the oral MEK 1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral BRAF inhibitor GSK2118436 (GSK436). J Clin Oncol .2001;29:Abstract CRA 8503.
  35. Ribas A, Hersey P, Middleton MR , et al. New challenges in endpoints for drug development in advanced melanoma. Clin Cancer Res. 2012;18:336-341.
  36. Begley J, Ribas A. Targeted therapies to improve tumor immunotherapy. Clin Cancer Res. 2008;14:4385-4391.
  37. Ribas A, Flaherty KT. BRAF targeted therapy changes the treatment paradigm in melanoma. Nature Rev Clin Oncol. 2011;8:426-433.
  38. Boni A, Cogdill AP, Dang P, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 2010;70:5213-5219.
  39. Comin-Anduix B, Chodon T, Sazegar H, et al. The oncogenic BRAF kinase inhibitor PLX4032/RG7204 does not affect the viability or function of human lymphocytes across a wide range of concentrations. Clin Cancer Res. 2010;16:6040-6048.
  40. Halaban R, Zhang W, Bacchiocchi A, et al. PLX4032, a selective BRAF(V600E) kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF melanoma cells. Pigment Cell Melanoma Res. 2012;23:190-200.
  41. Poulikakos PI, Zhang C, Bollag G, et al. RA F inhibitors transactivate RA F dimers and ERK signalling in cells with wild-type BRAF. Nature. 2011;480:387-390.


Patricia LoRusso

Patricia LoRusso, DO

The year 2011 marked a milestone of sorts for new drug approvals by the FDA. Thirty-five new medicines were approved—the second highest number of approvals in the last decade. Seven were oncology drugs, including the first one approved for Hodgkin lymphoma in 30 years. With the influx of these new drugs, awareness and education for oncologists are paramount, and this year’s annual meeting of the American Society of Clinical Oncology (ASCO) will include educational seminars on these latest clinical advances. Leading researchers involved in the development of the oncology drugs will provide practical advice on individual new therapies.

This new feature is part of a set of pre-meeting seminars that start one day before the official meeting kick-off. Notably, six of the seven drugs discussed are targeted treatments. Two of these treatments, axitinib and vismodegib, were approved by the FDA in 2012. Drugs to be discussed include:

  • Vemurafenib (Zelboraf, Genentech), an oral, small-molecule BRAF inhibitor for patients with metastatic melanoma whose tumors harbor a BRAFV600E mutation.
  • Crizotinib (Xalkori, Pfizer), an oral, small-molecule, dual inhibitor of the c-MET and ALK receptor tyrosine kinases for advanced non-small cell lung cancer (NSCLC) that expresses the EML4-ALK fusion gene.
  • Brentuximab vedotin (Adcetris, Seattle Genetics), for intravenous infusion, an anti-CD30 antibody for the treatment of CD30-positive relapsed Hodgkin lymphoma and relapsed systemic anaplastic large cell lymphoma.
  • Abiraterone acetate (Zytiga, Janssen), an oral inhibitor of the cytochrome P450 17A1 protein (CYP17A1) for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in men who have received prior chemotherapy.
  • Axitinib (Inlyta, Pfizer), an oral small-molecule inhibitor of multiple tyrosine kinases including cKIT, VEGFR 1-3, and PDGFR, for treatment of relapsed advanced renal cell carcinoma (RCC).
  • Vismodegib (Erivedge, Genentech), an oral inhibitor of the Hedgehog pathway for the treatment of advanced basal cell carcinoma (BCC). Uninhibited signaling of the Hedgehog pathway is the molecular driver of BCC.


Targeted Therapy Presentations to Watch for at ASCO

Metastatic melanoma: Results of the phase III METRIC clinical trial of trametinib, a MEK inhibitor tested in a global, randomized trial of patients with metastatic melanoma, the results of the phase III BREAK-3 trial of dabrafenib, a BRAF kinase inhibitor; also, an update on a phase I/II trial of dabrafenib combined with trametinib in treatment-naïve patients.

RCC: Results of the global, randomized, phase III TIVO-1 clinical trial testing the efficacy of tivozanib, a receptor tyrosine kinase inhibitor, against sorafenib, the current standard of care, as a first-line treatment for advanced RCC.

Liver cancer, RCC, prostate cancer, and thyroid cancer: Four oral presentations of studies with cabozantinib (XL184) are expected during ASCO. Cabozantinib is a small-molecule inhibitor of the tyrosine kinases c-Met and VEGFR2. The four presentations will be:

  • Clinical data of a phase II randomized, discontinuation trial in hepatocellular carcinoma
  • Efficacy of cabozantinib in patients with metastatic, refractory RCC
  • Phase II nonrandomized, expansion cohort results in chemotherapy-pretreated mCRPC
  • Full results of the pivotal phase III EXAM trial in medullary thyroid cancer patients

Non-small cell lung cancer: Results of the pivotal phase III LUX-Lung 3 trial of afatinib in treatment-naïve patients with metastatic NSCLC with EGFR mutations. The trial compares the efficacy of afatinib, an irreversible ErbB family inhibitor, to pemetrexed/cisplatin. Mutations in EGFR, also known as ErbB1, are found in approximately 12% of Caucasians and as many as 40% of Asian patients with NSCLC.

Acute myeloid leukemia and acute lymphoblastic leukemia: Six-month follow-up data from the pivotal PACE trial of ponatinib, a pan-BCR-ABL inhibitor, in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who are resistant or intolerant to the currently approved BCR-ABL inhibitors dasatinib and nilotinib, or who have the T315I mutation. Positive preliminary data were presented at the American Society of Hematology (ASH) meeting in December 2011.

Immunotherapy for melanoma, RCC, and lung cancer: Several abstracts will be presented on phase I and phase II clinical trials of MDX-1106/ BMS-936558, an anti-PD1 immunotherapy that is seen as the next generation of immunotherapy after ipilimumab. Anti-PD1 is being developed by Bristol-Myers Squibb. Results are expected from the large expansion cohort data of the phase I/II solid tumor trial and potentially from the phase II RCC trial.

Another pre-meeting session will focus specifically on targeted therapy approaches. Patricia LoRusso, DO, of the Karmanos Cancer Institute, Detroit, Michigan, in the session “Where Did We Come From, Where Do We Go From Here?” will give a bird’s-eye view of targeted therapies, discussing past and present development and how to approach the next phase based on what targeted therapies have taught us thus far. Because many of the new targeted therapies are oral medications that patients take at home, the ways in which patients are educated about their treatments and monitored have fundamentally evolved. The management of side effects of targeted therapies will be discussed in a session by an oncology nurse, Peg Esper, MSN, MSA, RN, ANP-BC, AOCN, from the University of Michigan School of Nursing, Ann Arbor.“Targeted therapies for such tumors as metastatic melanoma, prostate cancer, and renal cell cancer will most likely be presented at the meeting,” said LoRusso. “There is also a lot of activity ongoing with other novel targets, such as agents targeting the PI3 kinase pathway and various isoforms of the PIK3CA mutation. Hopefully some of this data will be mature enough and presented as well.”

According to LoRusso, the face of melanoma has changed completely because of targeted and biologic treatments: “There has been a huge impact.” Phase III results of the effectiveness of vemurafenib for melanoma were presented at last year’s ASCO plenary session. This compound has had a major impact on the BRAF-mutated subset of melanoma. Results of new targeted treatments and their combinations will likely be a highlight of this year’s meeting as well.

LoRusso sees combination therapies as the future of targeted therapies. “In metastatic disease, where we are going for one major target because there is one major driver mutation—such as with basal cell cancers, ALK-mutated lung cancer, or BRAF-mutated melanoma, for example—the majority of these patients will eventually go on to progress despite continued therapy,” said LoRusso. “Based on this evidence, combination targeted therapies is the way to go forward.”

Many monotherapies have not resulted in robust responses, or at least not in long-term responses, according to LoRusso. “We are in the process of being challenged to re-think how we give these targeted therapies, especially if combination data demonstrate better efficacy over monotherapy.” LoRusso also pointed out that because of the high potential cost of combining therapies, combinations will have to show robust efficacy in order to be widely utilized.

Science is what is driving the combination therapies. Hypothesis-driven clinical trials based on robust laboratory research results is now much more prevalent, said LoRusso. The challenge will be to not only further develop new therapies, but to find better ways to measure progress and genomic evolution of a tumor through the course of disease and treatment.

ASCO: Targeted Therapy Educational Sessions

Treating patients with targeted therapies requires a new approach to diagnosis (using molecular biomarkers), monitoring of patients, management of new types of adverse events, and cost decisions due to high prices of these medications. We have witnessed a range of successes in the advancement of targeted therapy research and clinical trials, and approvals for different types of cancers. For example, lung cancer, breast cancer, and melanoma are now at the forefront of personalized medicine and targeted therapy options. The following ASCO 2012 educational meeting sessions will highlight the latest research developments in targeted treatments and new ways clinicians need to be thinking about this type of approach to cancer care.

Several sessions specifically highlight personalized medicine for different tumor types:
– “The Cost of Lung Cancer Care: Screening, Personalized Medicine, and Palliative Care” (Friday, June 1)

– “Personalized Medicine in Lung Cancer in 2012” (Saturday, June 2)

– “New Options, New Questions: How to Select and Sequence Therapies for Metastatic Melanoma” (Saturday, June 2)

– “‘Personalized’ Oncology for Colorectal Cancer: Ready for Prime Time or Stop the Train” (Tuesday, June 5)

– “Mechanisms of Resistance to Targeted Anticancer Agents” (Saturday, June 2)

– “Biologic Principles of Targeted Combination Therapy” (Sunday, June 3)

  • Many TKIs are approved for a range of cancers, including imatinib and dasatinib for CML, gefitinib for breast and lung cancers, erlotinib for lung and pancreatic cancers, and sunitinib for RCC. “Laboratory and Clinical Insights into Resistance to Tyrosine Kinase Inhibitors” (Sunday, June 3) will address a key issue in the use of TKIs.
  • A novel view on targeted therapies will be discussed on Monday, June 4, in the session “Targeting Critical Molecular Aberrations Early in the Course of Solid Tumors: Is It About Time?” Targeted therapies are now predominantly utilized in the advanced cancer and metastatic setting, but this session will discuss moving these agents into the adjuvant setting, and potentially even to earlier-stage settings.
  • A “Meet the Professor” session on Monday, June 4, “Bringing Personalized Cancer Therapy into Routine Use,” will focus on the practical aspect of personalized care for clinicians.
Serial biopsies are at times necessary and ultimately can benefit a patient by providing accurate information that influences further treatment. However, these biopsies can be invasive and come with many adverse effects. “We realize that the information biopsies provide is important for treatment decisions and assessment of disease. They are important but associated with toxicities,” LoRusso said. New technologies such as assaying for circulating tumor cells or circulating DNA are in development as potential ways to access the cancer information less invasively—a topic to be discussed at the ASCO 2012 meeting.Identifying patients who will benefit most from a medication is also important, both for patient outcomes and to minimize cost of care, two major ongoing issues in oncology. “We need to focus on what is best for the patient,” said LoRusso.

Provocative NCI Questions To Be Addressed

A key theme at this year’s ASCO meeting will be sessions that aim to address some of the provocative questions that were assembled by the National Cancer Institute (NCI) in 2011. The goal of the questions is to identify and address the most complex cancer care and research problems. The ASCO sessions will be a forum for the oncology community to discuss the problems and think of innovative, “outside-the-box” ways to use laboratory, clinical, and population studies to begin to offer answers. Many educational sessions at ASCO will highlight these questions.

One of the proposed questions, “Why do many cancer cells die when suddenly deprived of a protein encoded by an oncogene?” highlights the ability of targeted therapies to inhibit a specific driver mutation within a tumor. The question also brings to light our relatively meager understanding of why inhibition of oncogenic drivers leads to cancer cell death for some tumor types but not others. Many broad and tumor type-specific sessions will address this question. Some of these sessions include “Biologic Principles of Targeted Combination Therapy,” “Developing a Targeted Therapy: Issues in the Age of Personalized Therapy,” and “New Options, New Questions: How to Select and Sequence Therapies for Metastatic Melanoma.”

Dr. Thomas J. Smith

Thomas J. Smith, MD

Emerging targeted therapies are extending survival in many cancers, but the cost of these new treatments is often high. For example, sipuleucel-T (Provenge, Dendreon) for metastatic castration-resistant prostate cancer costs $93,000 for the full course of three infusions. Ipilimumab (Yervoy, Bristol-Myers Squibb), the first treatment for metastatic melanoma to improve overall survival in more than 10 years, costs $120,000 for four infusions over a span of just three months. Everolimus (Afinitor, Novartis), for renal cell carcinoma and pancreatic cancer, costs $10,000 a month.

Many of these medications are indicated at the final stage of cancer; on average, they extend lifespan by a few months at most. As a result, as new therapies become available in clinical practice, questions about costs versus benefits are increasingly emerging. Among the often difficult questions being asked: Are the survival gains worth the burden on the healthcare system and individual patients? How do we pay for new drugs, diagnostics, and technologies— and who should pay?

Like it or not, economics are driving treatment choices for patients in the real world. Even when a drug is covered by insurance, many patients are not able to afford even the copay. Thus, despite advances in innovation and care, cost is hindering use of new therapies.

To gain perspective on these issues, Targeted Therapy News spoke with Thomas J. Smith, MD, director of Palliative Medicine at The Sidney Kimmel Comprehensive Cancer Center and professor of Oncology at Johns Hopkins Medical School in Baltimore, Maryland. Smith discussed the rising cost of cancer therapies, the burden of cost, and the cost-benefit analysis of end-of-life care, and will also speak about these issues at the 2012 annual meeting of the American Society of Clinical Oncology (ASCO) in a session titled, “Costs of Cancer Care: Affordability, Access, and Policy.”

TTN: How can oncologists stay informed about the best decisions on care alongside their patients in the context of new high-cost targeted therapies?

Smith:
It is complicated. I think the first question we have to ask ourselves as oncologists is, “Does it work?” Is there a clear-cut improvement in overall survival or disease-free survival, or quality of life that makes it better than other treatments? If the answer to this first question is yes, then the next question is, “How much does it cost and to whom?” And these are really difficult questions because sometimes the cost can be extraordinary to society as a whole but very little to the patient. The patient may only have an annual $1000 copay for a $120,000 new melanoma treatment, for example. In other cases, they may need to pay up to 40% of the cost of treatment. Oncologists need to discuss costs directly with their patients. I have learned to ask my patients, “What is your insurance coverage?” and “How much is this going to cost you?” before having the patient receive a $120,000 bill they cannot pay.

For example, aromatase inhibitors for breast cancer cost $450 a month even though there are three of them on the market and all of them are essentially interchangeable. This gets to an issue of compliance. Some patients simply cannot afford the 20% copay. The cost of the end-of-life care is very high for cancer patients. How do oncologists reconcile these costs with providing the best treatment for their patients, while also recognizing whether the quality of life may be more important for a patient with advanced-stage cancer?

Many of us were trained to treat the disease and as long as there is something that can be done, to keep treating as long as it does not make the patient deathly ill. This has worked for our patients for the most part. Sometimes, I think the deathly ill part gets neglected a little bit because we tend to ask less about our patients’ quality of life than we should.

What role does palliative care play?

Palliative care was always designed to improve patients’ symptoms and coping, to lessen depression, and to lessen caregiver burden. It is only an interesting sidebar that it results in cost savings. The cost savings are substantial. It could be anywhere from 20% to 50% of the cost in the last month or six months of life that can be reduced. This type of care allows patients to get out of the hospital, where most people don’t want to be.

How does this affect our current healthcare spending as a whole?

There are really imperative reasons to have this cost discussion. First, our cancer care system is simply not sustainable. Even though it is only 5% of the national budget, in the insured population it is 15% to 20%, a substantial amount. The cost per person per year in the US is $8100. It is $4500 in Canada for exactly the same amount of health benefit. The cost of insurance for a family of four has gone from $6000 in the year 2000 to over $15,000 in the year 2012. Insurance premiums went up 8% to 9% last year, and that is simply not sustainable either. There were close to a million, if not more, medical bankruptcies last year alone. So we need to do something. The question is, “What can we do that will cause as little harm as possible?”

What are some of the ways that oncologists can curb costs while providing good care for patients at the end of life?

There are a couple of strategies for oncologists that make good sense. One is to get people into a care system that keeps them out of the hospital near the end of life. The best way to do this is hospice. ASCO and many of us who are practicing oncologists are now recommending that when patients have about three to six months left to live, they should visit a hospice for information. This does a few things. It makes it real for the patient and the family that this is where things are headed and it is time to plan. It introduces the hospice team as the best way to take care of people at the end of life—which all professional societies agree on, every single one. It introduces the hospice care team as part of the regular oncology care plan. Integrating the hospice early is now part of best practices for most oncologists. It makes the transition easier, so that when a patient has tried a third-line chemotherapy in lung cancer or colorectal cancer without success, the oncologist can say, “Now is the time for you to switch to the hospice care,” with the nurses and social workers that the patient has already met.

ASCO released palliative care guidance in March of this year. How do you see this being implemented?Palliative care should be a part of the care of anyone with a serious illness. The uptake should not be slow. All of us who are practicing oncologists work with hospice providers. I like to use the analogy of we know the radiation therapist and our surgeons very well. We know their phone numbers and their fax numbers probably by heart. For the hospice providers, it tends to be a love-hate relationship. It shouldn’t be that way. It should be part of the normal process of care. I think oncologists like me should be calling the hospice providers and saying, “We actually work a lot together. Let’s figure out what we can both do to improve the care our patients get.” Hospice providers like to see patients when they have at least a month to live rather than a day left to live. It is a terrible process of care when we simply avoid having this conversation until the patient is bed-bound, in renal failure, and has an infection and two days left to live. In this situation, hospice is just scurrying around and doesn’t even have a chance to speak to the patient, and is left to pick up the pieces for bereavement and grief counseling. Patients in hospice care and with palliative care tend to live longer rather than shorter.

ASCO and many of us who are practicing oncologists are now recommending that when patients have about three to six months left to live, they should visit a hospice for information.
Oncologists should speak to the hospice providers to understand how they can do better. We should ask them how our statistics compare to the national average in terms of referral time. As oncologists, we need to be having realistic conversations about how many treatment types a patient can go through before we run out of options. Saying that there is a limit to treatments and there will be a time when treatment will only do more harm than good is necessary. This conversation needs to happen early and be reinforced throughout treatment.

Who are the other players that need to be involved in these cost decisions on a policy level?

This is a big point. I don’t think that cost control should fall to the individual oncologist. I think one of the worst things would be that no one at the insurance or government or societal level wants to make these decisions, so it is all a burden on the individual oncologist. I don’t think individual oncologists should be the only ones having difficult conversations with patients because no one else wants to do it. But, as oncologists, we need to be prepared to ask our patients about cost.

What is the current level of change and awareness on a government and policy level?

Change is already happening. Insurance companies are making decisions about what they cover and don’t cover. Medicare makes decisions by basically not making decisions on whether Medicare will pay for an FDAapproved indication. But we do need to be having more adult conversations about what we can and cannot pay for. This extends beyond cancer to ventricular assist devices, $100,000 pulmonary hypertension treatment, and the expensive rheumatologic drugs. We cannot continue to spend the way we have been spending.

The US highly values new scientific innovation. The FDA last year approved 35 new, innovative drugs. Most of these approvals were the first global approvals. How do we reconcile the need and benefit of new innovations in spite of cost?I think it is fascinating that the average cost of a new therapy has gone up by hundreds of percentage points while the improvement in overall survival or disease-free survival has stayed at about 1%. I would like to see data showing that [the cost increases are] due to the increased cost of clinical trials, but it seems hard to imagine. I think companies are doing what we would like them to be doing from a business perspective. They are valuing their drugs at what they think the market will bear. It is great for the company, but it is impossible to sustain.

There may be instances where targeted therapies or testing will actually save money. A good example is the Oncotype DX 21 [21 gene assay] in breast cancer, which we use routinely. The data are quite convincing that this allows us to spare chemotherapy in many situations and simply treat patients with a hormonal agent. To me, there is not an obvious correlation between a high price and the fact that a therapy is targeted. Many of these drugs are in the metastatic setting at the end of life. We as a society need to step up and say, “How much of this can we actually afford?”

As an individual oncologist, I can’t fix the cost of targeted therapies. What I can fix as a regular oncologist is the high cost of end-of-life care, much of which is not desired by the patient. I can fix this part by having an open and honest conversation with patients and their families about the reality of the situation. Keeping patients out of the hospital in the last one or two months of life would save billions of dollars for insurance companies and Medicare, and it is what many patients want. This cost savings will allow us to better afford many of these innovative and exciting therapies, all of which I want to keep using.

Are we going in the right direction and having this discussion?

I think that it is fascinating to see what is being proposed on the federal level. A lot of the plans being proposed will actually turn over the benefit determination to insurance companies. It will not be Medicare making the decision, but it will contract with an insurance company that will determine what is covered. Somehow, that is thought to be better at this point. Medicare is already divided into regions. Coverage is determined by someone, whether a bureaucrat or at a large company. I think things will get worse before they get better.

Dr. Axel Grothey

Axel Grothey, MD

Results from two phase III trials in metastatic colorectal cancer (mCRC) and unresectable gastrointestinal stromal tumors (GIST) that have progressed despite prior treatment indicate that the multi-tyrosine kinase inhibitor regorafenib may offer some benefit.

The phase III international CORRECT trial showed that regorafenib may be a new treatment option that achieves disease control in mCRC that has progressed on multiple lines of standard therapy including 5-fluorouracil (FU), oxaliplatin, irinotecan, bevacizumab, and cetuximab. The trial achieved a statistically significant improvement in overall survival (OS). The trial was unblinded in October 2011 after an interim analysis of patients in the placebo arm were offered regorafenib therapy. The full results of the trial were presented at the American Society of Clinical Oncology (ASCO) 2012 Gastrointestinal Cancers Symposium in January 2012. The trial has since been expanded to a phase IIIb open-label protocol for mCRC patients who have progressed following standard of care. Follow-up results will be presented at the upcoming ASCO Annual Meeting in June 2012.

A total of 760 patients with mCRC who had progressed despite therapy were randomized 2:1 to receive either regorafenib or placebo. Both study arms also received best supportive care. Patients received regorafenib 160 mg (n=505) or placebo (n=255) once daily for three weeks, followed by one week with no treatment.

Median OS was 6.4 months for regorafenib and 5.0 months for the placebo arm, an improvement of 29%. The estimated hazard ratio for OS was 0.773 (one-sided P = .0051). Median progression- free survival was 1.9 months and 1.7 months for the regorafenib and placebo arms, respectively. The most frequent grade 3 or higher adverse events included hand-foot skin reaction in 17%, fatigue in 15%, and diarrhea in 8% of patients. Some patients had their dosages reduced to manage side effects.

“This is the first small-molecule kinase inhibitor with proof of efficacy in colorectal cancer and is a potential new standard of care in this patient population,” said lead author Axel Grothey, MD, Mayo Clinic, Rochester, Minnesota. “The main emphasis of these findings is that this drug delays disease progression, achieving a much higher disease control rate than placebo,” Grothey added. The disease control rate was 44% for regorafenib and 15% for placebo (P < .000001).

Regorafenib is a multikinase inhibitor that shows antiangiogenic activity against vascular endothelial growth factor receptor 2 (VEGFR2) and TIE2. The inhibitor blocks various kinases involved in tumor cell proliferation, new blood vessel formation, and the interaction between tumor cells and the microenvironment.

Study findings showed no difference in response in patients treated with two versus three or four lines of prior therapy, according to Grothey. Previous smallmolecule multikinase inhibitors were investigated in conjunction with chemotherapy but showed no benefit in mCRC.

Grothey believes that regorafenib worked because it was used as a single agent. He speculated that because tumors evolve due to therapy exposure, a “promiscuous” multitargeted therapy may be needed in a last-line setting. The drug is under investigation in combination with FOLFIRI chemotherapy as a second-line treatment for mCRC in a phase II trial.“A lot of pharmaceutical companies shy away from this very sick patient population, but this is a population in need, and we can do drug development here,” Grothey said. He added that the CORRECT trial shows that placebo-controlled trials are feasible in a population with unmet needs, particularly refractory colorectal cancer.

Regorafenib also holds promise for patients with GIST. In April 2012 it was announced that the phase III GRID trial met its primary endpoint of a statistically significant improvment in progression- free survival in patients with metastatic and/or unresectable GIST whose disease had progressed despite prior therapy. Full trial results will be presented at the upcoming ASCO annual meeting in June 2012.

Finally, regorafenib is being investigated in phase II trials for treatment-naïve patients with metastatic renal cell carcinoma and liver cancer.


Key Research
Grothey A, Sobrero AF, Siena S, et al. Results of a phase III randomized, double-blind, placebocontrolled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after standard therapies. Presented at the ASCO Gastrointestinal Cancers Symposium; January 19-21, 2012; San Francisco, CA. J Clin Oncol. 2012;(suppl 4; abstr LBA385).


Dr. Sonali M. Smith

Sonali M. Smith, MD

One of the major developments in cancer treatment in recent years has been the potential of drugs that target the oncogenic phosphatidylinositol- 3-kinase (PI3K)/Akt pathway and the mammalian target of rapamycin (mTOR), a downstream effector of the pathway. The intracellular pathway is central to cell proliferation, growth, and angiogenesis, so it’s no surprise that it’s implicated in a number of different tumor types, including breast, non-small cell lung, and renal cell cancer. Mutations and changes in expression have been found in every major node of the pathway. Typical mutations include mutation or amplification of PI3K, overexpression of the oncogene AKT, or inactivation of the tumor suppressor phosphatase and tensin homolog (PTEN). Research has shown that alteration of normal PI3K pathway signaling translates to a poor patient prognosis and resistance to available treatments. This makes the role of the PI3K pathway in tumor evolution particularly important to understand.

This multifunctional pathway has been recognized as a particularly attractive target for patients with lymphoma. “The PI3K pathway appears continuously deregulated among lymphoma malignancies,” said Sonali M. Smith, MD, director of the Lymphoma Program at the University of Chicago Medical Center, Illinois. Molecular ties linked to abnormal PI3K pathway signaling have been demonstrated in mantle cell lymphoma (MCL), a mature B-cell non-Hodgkin lymphoma, as well as in Hodgkin lymphoma. Specifically, mTOR, a serine/threonine kinase that is a key downstream target of the PI3K pathway, as well as an important regulator of normal development, has been associated with lymphomagenesis.

“[mTOR] appears to be an excellent target in MCL,” Smith said. “Overexpression of the protein cyclin D1 is the hallmark of mantle cell lymphoma. This protein is controlled in part by mTOR. So this is a very nice rationale for testing mTOR inhibitors in this cancer.” Smith added that the entire PI3K/Akt/ mTOR pathway, not just mTOR, is valid as a target in MCL.

Temsirolimus (Torisel, Pfizer), an mTOR inhibitor, has been studied in patients with MCL in phase II trials. The response rate in these trials was about 40% and lasted six months, according to Smith. This led to combination trials, including temsirolimus combined with rituximab (Rituxan, Genentech) and everolimus (Afinitor, Novartis) combined with the CHOP chemotherapy regimen.

In a phase III trial testing the efficacy of temsirolimus compared to choice of therapy in 162 heavily pretreated patients with relapsed or refractory MCL, temsirolimus significantly improved progression- free survival (hazard ratio [HR] = 0.44; P = .0009) compared with the investigator’s choice. Objective response was 22% among patients receiving temsirolimus and 2% in the control group. The study established an effective clinical dose for temsirolimus monotherapy—the trial tested two different once-weekly dosages—and the results led to approval of the agent in Europe for relapsed or refractory MCL in 2009.

“The challenge with the classic mTOR inhibitors is that there is a lot of resistance,” said Smith, who was one of the investigators in the phase III study. It is not yet clear why only certain patients respond and why the responses are not durable. Smith believes that second-generation mTOR inhibitors, although still in early-stage trials, may be more promising for MCL.Another approach that exploits the PI3K/mTOR pathway is targeting PI3 kinase, the major switch that signals to mTOR. The compound GS-1101 (Gilead) specifically inhibits the delta isoform of PI3K and is in clinical trials for MCL and other types of lymphoma. The compound has “a lot of activity” in MCL, according to Smith.

MCL is one of the most difficult-to -treat subtypes of non-Hodgkin lymphoma. Between 2% and 7% of all patients with non-Hodgkin lymphoma have MCL. The disease is often diagnosed at stage IV and is most common in men age 60 years and over. Because this older patient population is more likely to have comorbidities, they are not candidates for more intensive treatments, even though cytotoxic chemotherapy regimens—including rituximab and the chemotherapy regimen CHOP— appear to be effective in achieving a response, and even complete remission in many cases. Additionally, many patients relapse after receiving front-line treatments.


Key Research
Hess G, Smith SM, Berkenblit A, Coiffier B. Temsirolimus in mantle cell lymphoma and other non-Hodgkin lymphoma subtypes. Semin Oncol. 2009; 36(suppl 3):S37-S45.


Dr. Brian Rini

Photo by © ASCO/Todd Buchanan 2012

Brian Rini, MD
Axitinib (Inlyta, Pfizer) is the seventh drug approved for the treatment of advanced renal cell carcinoma (RCC) since 2005. The small-molecule tyrosine kinase inhibitor (TKI) that inhibits vascular endothelial growth factor receptors (VEGFR-1, 2, 3), platelet-derived growth factor receptor (PDGFR), and c- KIT was approved by the FDA in January of this year as a second-line treatment. Axitinib joins three other multi-tyrosine kinase inhibitors, two mTOR inhibitors, and an antiangiogenic therapy as available treatments for metastatic RCC.

“We went from almost no therapies to many promising therapies. Now, patients with metastatic disease are living more than twice as long as they did before—two years on average. It’s harder to measure quality of life and how much better they feel, but they feel better being alive than not, and that’s the ultimate test,” said Brian Rini, MD, associate professor of Medicine at Case Western Reserve University and a practicing oncologist at the Cleveland Clinic Taussig Cancer Institute in Cleveland, Ohio. Rini was the principal investigator of the pivotal phase III AXIS trial that led to the approval of axitinib in RCC.

Rini presented AXIS trial secondary results at the American Society of Clinical Oncology (ASCO) 2012 Genitourinary Cancers Symposium. The original trial results were presented at the annual 2011 ASCO conference. The 723 patients on the trial who had failed an initial systemic therapy (either sunitinib, bevacizumab plus interferon- alpha, temsirolimus, or cytokines) for treatment of their metastatic clear-cell RCC were randomized to either 5 mg of axitinib or 400 mg of sorafenib (Nexavar, Bayer)—both administered twice a day (BID). The majority of patients (54%) had received sunitinib as their initial therapy. Treatment was discontinued in 14 of 359 patients receiving axitinib and in 29 of 355 patients receiving sorafenib.

PFS was roughly equivalent in the titrated and nontitrated groups of axitinib-treated patients, and both groups had superior PFS versus sorafenib in this second-line setting. ”
–Brian I. Rini, MD
Patients in the axitinib arm began with a 5-mg dose; those who tolerated this dose could be titrated up to a 10-mg dose, depending on tolerability. The outcome and frequency of adverse events were similar in both patients whose axitinib dose was titrated and those who received a constant dose: Both subgroups showed superior responses compared with sorafenib. Progression- free survival (PFS), the primary outcome, favored the axitinib arm, which had a median PFS of 6.7 months compared with 4.7 months for the sorafenib arm (hazard ratio [HR] = 0.665; P < .0001). Prior treatment did not affect outcomes; both patients previously treated with sunitinib and cytokine therapy had a robust response to axitinib. The objective response rates were 19.4% for patients taking axitinib compared with 9.4% for those on sunitinib (P = .0001).The AXIS trial was the first trial for kidney cancer to compare two kidney cancer drugs. “I started working with this drug eight years ago, so it’s been a long road,” Rini said. “Thousands, if not tens of thousands, of people must come together to make trials like this happen, not to mention the patients,” he said. “This is the fun part, when we get to the end and get results like this. It’s gratifying for all the hard work people have put in along the way.” Rini was also involved in the phase III trial of bevacizumab combined with standardof- care interferon-alfa that resulted in approval of the combination by the FDA in 2009 for metastatic RCC.

Because earlier-stage trials showed intrapatient variability on the ability to achieve therapeutic levels with the standard 5-mg BID dose, a dose-titration strategy was applied to normalize plasma levels of axitinib exposure. In the phase III study, criteria for dose titration included no toxicity greater than grade 2 for two weeks or more, a blood pressure of <150/90 mmHg, and no antihypertensive medication. Investigators had the discretion to titrate axitinib to 7 mg, and then to 10 mg, depending on patient reaction to the drug. A total of 25% of patients experienced dosage reductions or progression, and one-third did not need any dosage changes. Thirty-seven percent received escalating doses of axitinib—17% to 7 mg and 20% to 10 mg.

The phase IIII secondary analysis presented by Rini showed a roughly equivalent PFS in the titrated group compared with the nontitrated group of axitinib-treated patients. Both subgroups had a superior PFS compared with patients treated with sorafenib. Adverse events were consistent among the titrated and nontitrated patients.

“One would expect this,” Rini said. “Both groups had similar blood levels of the drug,” No difference in PFS was observed in the axitinib-treated groups who had a prior response to sunitinib, but PFS improved in sorafenib-treated patients with a prior response to sunitinib. “This is a small subset of patients,” he said. A further subanalysis of patients from the AXIS trial who had initially received cytokine therapy was presented at the 2012 ASCO meeting in June.

Axitinib is currently being tested in the front-line metastatic RCC setting. The fully-accrued trial is testing axitinib given at a 5-mg dose twice daily compared with sorafenib at 400 mg twice daily, the same dose as in the second-line study. After four weeks, axitinib-treated patients are segregated to either a dose-titration or a steady 5-mg dose subgroup. Results of the trial are expected in 2013. Data from the phase II first-line trial of axitinib was presented at the 2012 ASCO annual meeting by Rini.

RCC researchers are getting more comfortable with axitinib titration, according to Daniel C. Cho, MD, of the Beth Israel Deaconess Medical Center in Boston, Massachusetts. Cho believes that this titration approach should also be applied to other therapies. He noted that sorafenib is too toxic at higher doses, but that the newer TKIs may be more amenable to dose titration.

Despite the progress in new treatments, the field has a long way to go, Rini said. New therapies have extended patients’ lives, but resistance is a major issue. The researcher is determined to continue to develop unique approaches and new drugs for RCC. Thankfully, new potential treatments are in the pipeline, with some already in phase III trials.

A phase III IMPACT global trial is testing a therapeutic vaccine, IMA901, in combination with sunitinib compared to sunitinib alone in treatment-naïve metastatic RCC patients. IMA901 is a combination of multiple tumor-associated peptides. The vaccine is being developed by immatics biotechnologies GmbH.The primary endpoint of the trial is overall survival. Phase II data had shown both promising immune response and survival in patients with advanced RCC. Another trial, at the Cleveland Clinic, is a sunitinib-dosing study. The phase II pilot study started last year to test whether giving sunitinib for six months, and then giving the patients a break from the drug for two months, may be more efficacious than continuous drug therapy. The rationale is that the two-month break may provide a better quality of life for patients. The long-term on-off schedule may be more sustainable compared to ongoing therapy that results in intolerable side effects that result in discontinuation of treatment.


Key Research
Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378:1931-1939.


Patrick Hwu, MD

Patrick Hwu, MD

Two new treatments for metastatic melanoma were approved in 2011—the first in more than a decade. Ipilimumab (Yervoy, Bristol-Myers Squibb), an immunotherapy, showed overall survival improvement, leading the FDA to approve the therapy for both treatment-naïve and previously treated patients in March of that year. Five months later, vemurafenib (Zelboraf, Genentech), a targeted BRAF inhibitor, was approved for use in metastatic melanoma tumors that have the BRAFV600E mutation—about 40% of all patients with meatstatic melanoma. Even before the formal approval of the BRAF inhibitor, the two companies that manufacture ipilimumab and vemurafenib, Bristol-Myers Squibb and Genentech, respectively, entered into a collaboration to formally test the safety and efficacy of the combination therapy in patients with the BRAF mutation. The phase I/II, 50-person, dose-escalation trial formally started in November 2011. At the 2012 American Association of Cancer Research annual meeting held at the end of March, melanoma researchers from the MD Anderson Cancer Center in Houston, Texas, presented formal evidence supporting the combination trial.1 Patrick Hwu, MD, head of MD Anderson’s Department of Melanoma Medical Oncology, presented data showing that adding a BRAF inhibitor to immunotherapy can reverse the immunosuppressive tumor microenvironment induced by the BRAF mutation.

Additionally, the researchers found that a BRAF inhibitor increased the immune response to a tumor in a mouse tumor model. The study provided evidence that the BRAF inhibitor targeted therapy does not prohibit the immune function of patients with metastatic melanoma. This is an important result, as evidence exists that kinase-targeted treatments can have detrimental off-target effects on the cells of the immune system. Vemurafenib may not because of its specificity and minimal off-target effects, according to Gregory Lizée, PhD, of the same department, who was also a part of the study. Both human data and mouse models led to the conclusion that the combination of a BRAF inhibitor with immunotherapy may act in a synergistic way.

Another recent study addresses mechanisms of resistance to BRAF inhibitor treatment in patients with metastatic melanoma.2 Roger Lo, MD, PhD, and colleagues at the Johnsson Comprehensive Cancer Center at the University of California in Los Angeles have discovered how tumor cells are able to stop responding to treatment with vemurafenib. The team sequenced the protein-coding parts of the genome of tumors from patients treated with the drug. “Patient biopsy-oriented translational research is absolutely key to overcoming targeted drug resistance,” Lo stressed.

The research team found the tumors to have higher copy numbers of the BRAF gene, meaning the tumor is producing extra BRAF protein, rendering inhibition by the drug ineffective. About 20% of patients (a total of 20 were sampled) who developed resistance had this amplification of the BRAF gene. Using cell lines, the researchers also found that the combination of a BRAF and MEK inhibitor could overcome the amplification-driven resistance. This combination treatment is currently in a phase I/II clinical trial for advanced melanoma.“[In an earlier study], we initially found no evidence of secondary mutations in the BRAF gene,” said Lo.3 “This shifted the pharmaceutical community away from further drug development for alternative BRAF inhibitors that might circumvent mutated BRAFV600 harboring secondary mutations. The surprise is we have recently come full circle to find that alterations in BRAF—beyond the mutation that activates this oncogene—are important.” These BRAF mutations include truncations in the gene4 and the newly described BRAF amplification.

Researchers have discovered resistance mechanisms that account for somewhere between 60% and 70% of resistance cases; the other relapsed patients develop resistance by as yet unknown means. The next steps for Lo and his team will be to study each individual patient and find out what happens during relapse at the molecular level. This research will facilitate next-generation clinical trials and new therapies that can be combined for a more robust response. It could also result in ways to avoid needing to overcome resistance. “The goal is to understand all possible mechanisms and deduce the common denominator molecules that can be targeted, together with mutant BRAF, in combinatorial approaches,” Lo said. Already, the combination of a BRAF inhibitor with a MEK inhibitor is expected to be a “powerful two-hit,” increasing efficacy and reducing side effects, Lo said.


References

1. Hong DS, Vence L, Falchook G, et al. BRAF(V600) inhibitor GSK2118436 targeted inhibition of mutant BRAF in cancer patients does not impair overall immune competency. Clin Cancer Res. 2012;18:2326-2335.
2. Shi H, Moriceau G, Kong X, et al. Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun. 2012;3:724.
3. Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;16;468(7326):973-977.
4. Poulikakos PI, Persaud Y, Janakiraman M, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. 2011;480(7377):387-390.


Alex A. Adjei, MD, PhD Corresponding Author:

Alex A. Adjei, MD, PhD

Department of Medicine,
Roswell Park Cancer Institute,
Buffalo, NY;

alex.adjei@roswellpark.org

Abstract



The MET signaling pathway is abnormal in a wide variety of cancers and stimulates cell growth, invasion, and metastasis, as well as promoting resistance to apoptosis. Because of its ubiquitous role in cancer cells, the MET axis has been seen as an attractive target for cancer therapy. Over the last four years, more than 10 anticancer agents targeting different aspects of MET signaling via different mechanisms have been introduced into the clinic. The majority of MET inhibitors are still in late phase I and phase II trials, but at least three compounds, tivantinib, onartuzumab, and cabozantinib, are in phase III trials in lung cancer and medullary thyroid cancer. Ongoing research is aimed at identifying predictive biomarkers that can help identify patients most likely to respond to these compounds. The terminology for this pathway can be confusing. The gene is c-MET, the protein product of the gene is MET.

The MET Signaling Pathway



c-MET was cloned in 1984 and described as a new transforming gene distinct from the then-known RAS family of oncogenes.1 Shortly after c-MET’s initial discovery, its unique high-affinity ligand known as HGF (hepatocyte growth factor, also called scatter factor [SF]), was purified2 and cloned.3 It should be noted that MET is the only known receptor for HGF. The regulatory pathway of MET and HGF governs various cell processes by modulating important signaling cascades in cancer and in normal cells. For example, MET plays a central role in tissue and organ development of embryos, including development of the placenta, liver, and muscle, and the nervous system.4,5 The role of MET in adults is largely restricted to participation in organ regeneration, notably in wound healing, as well as in the pathogenesis of liver, kidney, and heart diseases.6-9

Activation of the MET receptor, usually upon binding of HGF, results in the classic sequence described for receptor tyrosine kinases, including receptor dimerization, phosphorylation of intracellular residues, and initiation of a signal transduction cascade through direct interactions with adaptor proteins, especially GRB2-associated-binding protein 1(GAB1)10, leading to various cellular effects. In addition, the MET pathway interacts with several other cell surface receptors and intracellular pathways, including the HER family (HER1/2/3)11, IGF-1 receptor12, integrins13, and Fas death receptor.14

The Role of the MET Pathway in Cancer

In experimental cancer models, increased signaling through the MET pathway results in acquisition or reinforcement of all elements of the malignant phenotype. These include tumor cell proliferation, motility, invasiveness, migration, and survival. In addition, endothelial cell proliferation and motility occur, resulting in tumor angiogenesis.15 It should also be noted that MET is expressed not only in tumor cells and endothelial cells, but also in osteoblasts (bone-forming cells) and osteoclasts (bone-removing cells). HGF binds to MET on all of these cell types, giving the MET pathway an important role in multiple autocrine and paracrine loops. Activation of MET in tumor cells appears to be important in the establishment of metastatic bone lesions. At the same time, activation of the MET pathway in osteoblasts and osteoclasts may lead to pathological features of bone metastases, including abnormal bone growth (ie, blastic lesions) or destruction (ie, lytic lesions). Thus, targeting the MET pathway may be a viable strategy in preventing the establishment and progression of metastatic bone lesions.

The MET pathway is abnormally regulated in a wide range of human cancers, including the most common epithelial cancers such as breast, colorectal, lung, pancreatic, hepatic, and ovarian cancers.16 Aberrant MET signaling results from several molecular mechanisms, including germline or somatic c-MET gene mutation, c-MET chromosomal rearrangement, c-MET amplification, c-MET transcriptional upregulation, or ligand-dependent autocrine or paracrine changes. These mechanisms are described briefly following.

Figure 1. MET Signaling Pathway and Inhibitory Targets With Agents That Act on These Targets

MET Signaling Pathway and Inhibitory Targets With Agents That Act on These Targets

Hover mouse over to enlarge
MET activation sets into motion a cascade of signaling events. Recruitment of SH2-domain-containing molecules activate a number of pathways, including the RAS–RAF–MEK–ERK and the PI3-Kinase-AKT axis, leading to cell proliferation, invasion, angiogenesis, and metastasis. Inhibitory approaches target various molecules involved in MET activation and signaling.

Receptor and Ligand Overexpression

Transcriptional upregulation of c-MET resulting in MET overexpression is the predominant mechanism of c-MET activation encountered in cancer and is present in different types of cancer, including sarcoma, hematologic malignancies, glioblastoma, medulloblastoma, mesothelioma, melanoma, and in the majority of, if not all, carcinomas.16 In this setting, MET activation depends on ligand binding, following an autocrine, or, probably more frequently, paracrine secretion of HGF.The molecular mechanisms resulting in MET overexpression remain poorly described. In a minority of cases, gene amplification (described below), may be the basis of high MET expression. In several clinical studies, aberrant MET signaling—in particular, overexpression of MET and/or HGF—has been correlated with poor clinical outcome, exemplified by rapid dissemination of disease and short survival. Overexpression of MET and HGF are also thought to result in resistance of tumor cells to chemotherapy and radiotherapy.16

Gene Amplification

Gene amplification refers to the production of multiple copies of a particular gene, which typically amplifies the function attributed to the gene. To evaluate gene copy number, fluorescence in situ hybridization (FISH) and real-time polymerase chain reaction (PCR) are most frequently used, with Southern blot, chromogenic in situ hybridization (CISH), comparative genomic hybridization (CGH), and single nucleotide polymorphism (SNP) array technologies as alternative tools. When high gene copy number is documented by one of these techniques, a specific reference DNA sequence known not to be amplified in tumor cells must be used in addition, as a denominator, to differentiate amplification from polysomy.

Amplification of oncogenes has been described in many cancers. HER2 amplification in breast cancer, for example, represents the main criterion for selecting patients for trastuzumab therapy. Other examples are EGFR amplification in non-small cell lung cancer (NSCLC) and glioblastoma. Gene amplification is one of the mechanisms resulting in gene copy number increase, which is restricted to a specific section of DNA. Polysomy, in which a specific chromosome is represented more than twice (also known as aneuploidy), is another genetic alteration resulting in multiple copies per cell of the same gene. Polysomy is therefore a biologically different phenomenon from gene amplification.

Gene Mutations

Rarely, the c-MET gene can be affected by somatic or germline point mutations. Sporadic c-MET mutations occurring in the kinase domain have been described to date in ovarian17, head and neck18, childhood liver19, thyroid cancers20, diffuse large B-cell lymphoma21, and gliomas.17-21 In addition, mutations occurring in the juxta-membrane domain of the MET receptor have been demonstrated in gastric, papillary renal cell, mesothelioma22, NSCLC23, small cell lung cancer (SCLC)24, diffuse large B-cell lymphoma21, and melanoma.25 In general, these mutations are rare, typically occurring in 5% or less of these tumors. One exception is in hereditary papillary renal cell carcinoma (RCC), which seems to depend on aberrant MET activity. In this disease, a nonrandom duplication of the allele bearing the mutated MET gene has been described related to trisomy of chromosome 7 in almost all cases.26 Experimental data confirm that these are classic activating mutations.27

Table 1. Selected Examples of Specific MET Inhibitors

Drug Name Drug Target Stage of Clinical Development
rilotumumab HGF
IgG2 Mab
Phase II: multiple tumors
ficlatuzumab HGF
IgG1 Mab
Phase II: NSCLC
TAK-701 HGF
IgG1 Mab
Phase I: solid tumors
onartuzumab MET
IgG1 Mab
Phase III: NSCLC
Phase II: several tumors
tivantinib MET TKI Phase III: NSCLC
Phase II: several solid tumors
EMD1214063
EMD1204831
MET TKI Phase I: solid tumors
 
INCB28060 MET TKI Phase I: solid tumors

NSCLC indicates non-small cell lung carcinoma.

MET Inhibitors in the Clinic

Several MET pathway inhibitors are currently being studied in the clinic. These agents focus on the serial steps that lead to activation of MET (Figure 1 and Table 1):

  1. HGF specific binding to MET can be prevented by competitors that prevent HGF ligand from interacting with the MET receptor, blocking downstream activation of the pathway. Several anti-HGF humanized antibodies are being studied (rilotumumab, ficlatuzumab).
  2. MET receptor activation can be prevented by receptor blockage by specific monoclonal antibodies that bind to and degrade the receptor (eg, onartuzumab).
  3. MET receptor activation can also be targeted by selective MET kinase inhibitors such as tivantinib (ARQ197) and PF04217903, which have specific selectivity for MET receptor tyrosine kinase, or nonselective MET kinase inhibitors such as crizotinib (PF02341066), cabozantinib (XL184), and foretinib, which have broad activity against MET and other receptor tyrosine kinases that have also been shown to be important in cancer.

Anti-HGF Monoclonal Antibodies

A number of monoclonal antibodies that bind HGF are currently in clinical trials. These include ficlatuzumab, rilotumumab, and TAK701.

Ficlatuzumab (previously called AV299) is a humanized anti-HGF IgG1 monoclonal antibody that has completed phase I trials as a single agent and in combination with gefitinib. Toxicities are fatigue, peripheral edema, diarrhea, headache, and hematologic toxicity. Phase II trials are ongoing in NSCLC.28

TAK701 is a humanized IgG1 monoclonal antibody that has just completed phase I testing. Toxicities included fatigue, pleural effusion, and abdominal pain. The future development plans of this compound are unclear.28

Rilotumumab (previously called AMG102) is a fully humanized IgG2 monoclonal antibody29 that has undergone phase I and II clinical trials. It is currently under evaluation as monotherapy in phase IB-II trials in ovarian and renal cancer, as well as in combination with antiangiogenic targeted agents in glioma, erlotinib in NSCLC, panitumumab in colorectal cancer, and platinum-based chemotherapy in SCLC, mesothelioma, and gastric cancer, as well as with mitoxantrone in prostate cancer.

Anti-MET Receptor Antibodies

Onartuzumab (previously called OA-5D5 or OAM4558g and later, METMAb): Earlier efforts to develop MET-directed antibodies failed due to the tendency of bivalent antibodies to cause receptor dimerization, and therefore activate the MET receptor. This agonistic activity has been prevented by producing a monovalent human IgG1 antibody with murine variable domains. The resulting monoclonal antibody, onartuzumab, has been studied in a number of clinical trials. A randomized phase II trial comparing onartuzumab/erlotinib to erlotinib treatment in second- or third-line NSCLC has been reported.30 In the intent-to-treat population of approximately 120 patients, there was no evidence of efficacy in adding onartuzumab to erlotinib. Using a prototype immunohistochemistry (IHC) assay to divide patients in the study into two groups according to a prespecified diagnostic cutoff, there were significant improvements in progression-free and overall survival in the patients with high MET expression by IHC. This “MET high” group was defined as 50% or greater of cells on the diagnostic slide with a staining intensity of 2+ or 3+ (Figure 2). Fifty-four percent of patients were in this “MET high” group. A puzzling finding was the fact that the “low MET” patients did worse when they received onartuzumab in combination with erlotinib. The reasons for this finding are unclear. A phase III trial now under way is using this assay to prospectively enroll patients. Thus, with the help of a novel diagnostic assay, a drug that appeared to be negative in the initial analysis was shown to be potentially active and worthy of further study. Unfortunately, the design of the phase III study will not help confirm or refute the suggestion that “low MET” patients appear to be harmed by a combination of onartuzumab and erlotinib. The benefit from onartuzumab did not seem to be driven by EGFR mutation or FISH status, nor by imbalances in the randomized patient populations.30

Onartuzumab is also now under clinical evaluation in randomized, double-blind phase II trials in combination with paclitaxel and bevacizumab in triple-negative breast cancer and in combination with FOLFOX and bevacizumab in colorectal carcinoma.

Figure 2. MET Staining in NSCLC by IHC

Scores are from left to right, 1+, 2+, 3+.

MET Staining in NSCLC by IHC

Photos courtesy Adjei A.

NSCLC indicates non-small cell lung cancer; IHC, immunohistochemistry.

 

Receptor Tyrosine Kinase Inhibitors (TKIs)

Various small-molecule inhibitors of the MET receptor tyrosine kinase have been evaluated in the preclinical setting and several have reached the clinic. Some inhibitors are selective, with no other known targets at achievable concentrations in humans, while others inhibit a panel of kinases.

Selective MET TKIs

There are a number of selective MET TKIs in the clinic, including EMD 121406, EMD 1204831, INCB028060, and tivantinib.28Tivantinib (previously called ARQ197): Tivantinib is probably the most advanced oral MET inhibitor under clinical evaluation. Unlike most other TKIs, tivantinib does not compete for ATP binding and hydrolysis, but blocks the MET receptor in its nonphosphorylated, inactive conformation via an as yet undisclosed mechanism.31

Tivantinib was well tolerated in phase I trials, and pharmacodynamic activity, including reduced total MET and MET phosphorylation, was demonstrated in tumor biopsies from 15 of 51 patients. Common toxicities were fatigue, nausea and vomiting, mucositis, palmar-plantar erythrodysesthesia, hypokalemia, and febrile neutropenia.32

A randomized, placebo-controlled, double-blind phase II clinical trial evaluating the combination of erlotinib/tivantinib compared with erlotinib/placebo in second- and third-line NSCLC has recently been published.33 Progression-free survival, the primary endpoint, was similar in both arms. However, a preplanned exploratory survival analysis demonstrated a trend toward benefit from erlotinib/tivantinib in both PFS and OS in nonsquamous histology, as well as in EGFR wild-type NSCLC patients. Interestingly, in the 15 patients with KRAS mutations, there was also significant benefit in PFS and OS, with poor outcomes reported for KRAS-mutated patients in the erlotinib/placebo arm. There was a trend toward benefit in patients with MET-amplified tumors, with the benefit growing in magnitude with increasing copy number in the erlotinib/tivantinib arm. Consistent with the role of MET in metastases, there was a trend toward delayed development of metastases in patients who received erlotinib in combination with tivantinib.

Based on these results, a phase III randomized trial comparing erlotinib/tivantinib with erlotinib/placebo in nonsquamous NSCLC was activated and has completed accrual.

Non-Selective c-MET TKIs

A number of non-selective MET inhibitors are in clinical testing (Table 2). These include crizotinib, which has been developed and marketed as an ALK inhibitor and is now being evaluated for its MET inhibitory activity; foretinib; and cabozantinib. The agent most advanced in its development as a multitargeted MET inhibitor is cabozantinib.Cabozantinib (previously called XL184): Cabozantinib is a multikinase inhibitor acting on MET, VEGFR2, AXL, Tie2, KIT, FLT3, and RET. In the phase I dose-escalation study in patients with advanced solid tumors, 85 patients were enrolled, including 37 with medullary thyroid carcinoma (MTC). The maximum tolerated dose was 175 mg daily. Dose-limiting toxicities were grade 3 palmar-plantar erythrodysesthesia, mucositis, and AST, ALT, and lipase elevations and grade 2 mucositis that resulted in dose interruption and reduction. Ten (29%) of 35 patients with MTC with measurable disease had a confirmed partial response. Overall, 18 patients experienced tumor shrinkage of 30% or more, including 17 (49%) of 35 patients with MTC with measurable disease.34 A phase II randomized discontinuation study evaluated the activity of cabozantinib in patients with breast, gastric/gastroesophageal junction, SCLC, NSCLC, ovarian, pancreatic, hepatocellular, and prostate cancers, or melanoma. In the NSCLC cohort of patients who had failed up to three prior systemic treatments, there were two partial responses and eight stable disease among 20 evaluable patients. The overall disease control rate was 50% at 12 weeks, and one patient with prior exposure to sunitinib achieved a 61% decrease in tumor growth. Another patient previously treated with platinum-based chemotherapy and an EGFR inhibitor achieved a 32% reduction in tumor size. Diarrhea, fatigue, asthenia, and pain in the extremities were the most frequently observed adverse events. In the melanoma cohort, one partial response and 11 stable disease were reported in 24 evaluable patients. The disease control rate was 50%. A total of 12 patients with previously-treated hepatocellular cancer (HCC) and a Child-Pugh score of A were enrolled: seven were evaluable. Two of these patients achieved a partial response, and five achieved stable disease.

Preliminary results from a subset of patients with castration-resistant prostate cancer (CRPC) have also been presented. Accrual was halted after 168 patients had been enrolled, and the study was unblinded due to high rates of observed clinical activity. Objective tumor shrinkage occurred in 84% of patients. There was an unprecedented complete or partial resolution of bone metastases in most men with metastatic CRPC in this study. These findings support the putative role of MET in bone metastasis development and propagation. Based on these results, in addition to the phase III study of cabozantinib in prostate cancer, there are studies in breast cancer and in multiple myeloma in which the primary outcome measure is bone scan response rate. A phase III study in patients with medullary thyroid carcinoma is ongoing.

Clinical Pearls

The MET signaling pathway is involved in all of the key processes of cancer growth and dissemination, and has been implicated in resistance of cancer cells to cytotoxic chemotherapy, as well as targeted agents such as EGFR inhibitors and VEGFR inhibitors.

  • MET inhibitors have therefore been seen as exciting drugs for cancer therapy.
  • While MET is expressed in a majority of cancers, molecular abnormalities in the MET gene (mutation, translocations, amplification) are rare, suggesting that abnormalities in MET are not oncogenic drivers. Thus, it is unlikely that objective antitumor responses will be seen with the use of MET inhibitors as single agents.
  • The promise of these compounds is likely to be seen in combination therapies, with patients selected by predictive biomarkers, all of which are currently under investigation.
  • Unlike the highly selective MET inhibitors, some of the multitargeted MET inhibitors may possess single-agent activity.

Conclusions

MET inhibitors remain a very promising class of compounds for cancer therapy. While the preclinical data and knowledge of the biology of MET suggest that inhibiting MET may have a profound effect on cancer therapy, results from clinical trials to date suggest that MET inhibitors as single agents may be important only in a subset of patients. For instance, there were very few responses to foretinib in hereditary papillary RCC (which harbors c-MET mutations), and the few responses that were seen were not clearly connected to c-MET mutation status. This may imply that while many c-MET mutations have been described, a number of them may not be activating mutations that sensitize the tumors to MET inhibitors.28 Currently, the most robust single-agent activity in unselected patients has been seen with the multikinase inhibitors, such as cabozantinib. There is an urgent need to identify biomarkers that may be predictive of single-agent activity with the selective inhibitors. MET mutations, amplification, and receptor, as well as ligand expression are all being evaluated. The phase III study of onartuzumab is selecting patients based on MET expression by IHC. While this biomarker is not yet validated, it appears to be the only marker that will provide definitive information, at the end of the phase III study. There are multiple other clinical trials with MET inhibitors. Results in the coming years will help define their role in cancer therapy.


References
  1. Cooper CS, Park M, Blair D, et al. Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature. 1984;311: 29-33.
  2. Nakamura T, Nawa K, Ichihara A. Partial purification and characterization of hepatocyte growth factor from serum of hepatectomized rats. Biochemical Biophysical Research Communications. 1984;122:1450-1459.
  3. Nakamura T, Nishizawa T, Hagiya M, et al. Molecular cloning and expression of human hepatocyte growth factor. Nature. 1989;342: 440-443.
  4. Schmidt, C. Bladt F, Goedecke S, et al. Scatter factor/hepatocyte growth factor is essential for liver development. Nature. 1995;373:699-702.
  5. Uehara Y, Minowa O, Mori C, et al. Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature. 1995;373: 702-705.
  6. Matsumoto K, Nakamura T. Hepatocyte growth factor: renotropic role and potential therapeutics for renal diseases. Kidney Int. 2001;59:2023-2038.
  7. Michalopoulos GK, DeFrances MC . Liver regeneration. Science. 1997;276:60-66.
  8. Nakamura T, Mizuno S, Matsumoto K, et al. Myocardial protection from ischemia/reperfusion injury by endogenous and exogenous HGF. J Clin Invest.  2000;106:1511-1519.
  9. Rabkin R, Fernanza F, Tsao T, et al. Hepatocyte growth factor receptor in acute tubular necrosis. J Am Soc Nephrol. 2001;12:531-540.
  10. Weidner KM, Di Cesare S, Sachs M, et al. Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis. Nature. 1996;384:173-176.
  11. Bonine-Summers AR , Aakre ME , Brown K, et al. Epidermal growth factor receptor plays a significant role in hepatocyte growth factor mediated biological responses in mammary epithelial cells. Cancer Biol Ther. 2007;6:561-570.
  12. Bauer TW , Somcio RJ, Fan F, et al. Regulatory role of c-Met in insulin-like growth factor-I receptormediated migration and invasion of human pancreatic carcinoma cells. Mol Cancer Ther. 2006;5:1676-1682.
  13. Trusolino L, Bertotti A, Comoglio PM. A signaling adapter function for alpha6beta4 integrin in the control of HGF-dependent invasive growth. Cell. 2001;107:643-654.
  14. Wang X, D Frances MC , Dai Y, et al. A mechanism of cell survival: sequestration of Fas by the HGF receptor Met. Molecular Cell. 2002;9:411-421.
  15. Rosen EM , Carley W, Goldberg ID . Scatter factor regulates vascular endothelial cell motility. Cancer Invest. 1990;8:647-650.
  16. Sharma N, Adjei AA . In the clinic: ongoing clinical trials evaluating c-MET -inhibiting drugs. Ther Adv Med Oncol. 2011;3(1 suppl):S37-50.
  17. Tanyi J, Tory K, Rig J, et al. Evaluation of the tyrosine kinase domain of the Met proto-oncogene in sporadic ovarian carcinomas. Pathol Oncol Res. 1999;5:187-191.
  18. Di Renzo MF, Olivero M, Martone T, et al. Somatic mutations of the MET oncogene are selected during metastatic spread of human HN SC carcinomas. Oncogene. 2000;19:1547-1555.
  19. Park WS, Dong SM, Kim SY, et al. Somatic mutations in the kinase domain of the Met/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas. Cancer Res. 1999;59:307-310.
  20. Wasenius VM , Hemmer S, Karjalainen-Lindsberg ML , et al. MET receptor tyrosine kinase sequence alterations in differentiated thyroid carcinoma. Am J Surg Pathol. 2005;29:544-549.
  21. Tjin EPM, Groen RW , Vogelzang I, et al. Functional analysis of HGF/MET signaling and aberrant HGFactivator expression in diffuse large B-cell lymphoma. Blood. 2006;107:760-768.
  22. Jagadeeswaran R, Ma PC, Seiwert TW , et al. Functional analysis of c-Met/hepatocyte growth factor pathway in malignant pleural mesothelioma. Cancer Res.2006;66:352-361.
  23. Kong-Beltran M, Seshagiri S, Zha J, et al. Somatic mutations lead to an oncogenic deletion of met in lung cancer. Cancer Res. 2006;66:283-289.
  24. Ma PC, Kijima T, Maulik G, et al. c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions. Cancer Res. 2003;63:6272-6281.
  25. Puri N, Ahmed S, Janamanchi V, et al. c-Met is a potentially new therapeutic target for treatment of human melanoma. Clin Cancer Res. 2007;13:2246-2253.
  26. Zhuang, Z, Park WS, Pack S, et al. Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. Nat Genet. 1998;20:66-69.
  27. Jeffers M, Schmidt L, Nakaigawa N, et al. Activating mutations for the met tyrosine kinase receptor in human cancer. Proc Natl Acad Sci USA. 1997;94:11445-11450.
  28. Peters S, Adjei AA . MET : a promising anticancer therapeutic target. Nat Rev Clin Oncol. 2012. In press.
  29. Giordano S. Rilotumumab, a mAb against human hepatocyte growth factor for the treatment of cancer. Curr Opin Mol Ther. 2009;11:448-455.
  30. Spigel D. Final efficacy results from OAM 4558g, a randomized phase II study evaluating MetMA b or placebo in combination with erlotinib in advanced NSCLC . J Clin Oncol. 2011;29(suppl; abstr 7505).
  31. Adjei AA , Schwartz B, Garmey E. Early clinical development of AR Q 197, a selective, non-AT Pcompetitive inhibitor targeting MET tyrosine kinase for the treatment of advanced cancers. Oncologist. 2011;16:788-799.
  32. Yap TA , Olmos D, Brunetto AT , et al. Phase I trial of a selective c-MET inhibitor AR Q 197 incorporating proof of mechanism pharmacodynamic studies. J Clin Oncol. 2011;29:1271-1279.
  33. Sequist LV , von Pawel J, Garmey EG, et al. Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer. J Clin Oncol. 2011;29:3307-3315.
  34. Kurzrock R, Sherman SI, Ball DW , et al. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer [published online ahead of print May 23, 2011].


Dr. D. Ross Camidge Corresponding Author:

D. Ross Camidge, MD, PhD

University of Colorado
Comprehensive Cancer Center,
Anschutz Medical Campus,
Aurora, CO;

ross.camidge@ucdenver.edu

Abstract



Frequency of ALK positivity in non-small cell lung cancer (NSCLC) varies depending on the presence or absence of several key clinical and pathologic factors; groups with a true 0% chance of positivity are hard to define. Only a small proportion of ALK-positive (ALK+) cases manifest intrinsic resistance to crizotinib, a small-molecule inhibitor of ALK recently licensed for treatment of ALK+ NSCLC by the FDA. The majority demonstrate rapid and dramatic responses to this therapy. Although in general crizotinib is well tolerated, several common mild side effects and a few rare severe side effects require specific management. Despite its remarkable clinical activity, acquired resistance to crizotinib is predicted to develop in all ALK+ cases, just as epidermal growth factor receptor (EGFR)-mutant NSCLC develops resistance to treatment with EGFR tyrosine kinase inhibitors. Multiple mechanisms of intrinsic and acquired resistance to crizotinib in ALK+ NSCLC have been described, and treatment options in this setting are discussed.

The anaplastic lymphoma kinase (ALK) gene encodes a transmembrane tyrosine kinase receptor involved in a number of developmental processes.1 Oncogenic ALK gene rearrangements are characterized by chromosomal translocations that place one of a series of different 5’ fusion partners and their associated promoter upstream of the 3’ kinase domain of the ALK gene. These rearrangements were originally described in a subset of non-Hodgkin lymphoma2; hence, the new gene was named anaplastic lymphoma kinase. In 2007, an ALK gene rearrangement involving EML4 as the 5’ partner was discovered by looking for cDNAs with the potential to transform cells isolated from a lung adenocarcinoma occurring in a Japanese male smoker.3 Although other 5’ partners for ALK in non-small cell lung cancer (NSCLC), notably KIF5B and TFG, have since been described, EML4-ALK is by far the most common ALK rearrangement seen in NSCLC.4,5 In series dominated by adenocarcinomas, ALK positivity has been reported to occur in approximately 4% of NSCLC.6

Finding ALK-Positive Lung Cancer

Patients in all of the initial crizotinib studies were proven to be ALK-positive (ALK+) using the Vysis Break-Apart fluorescence in situ hybridization (FISH) Probe Kit.7,8 With this assay, the FISH probes flank the common breakpoint in ALK and separate when a rearrangement occurs (Figure 1).9 Immunohistochemistry and reverse transcriptase-polymerase chain reaction are also being explored as alternative diagnostic techniques.10,11 Whether insurers will mandate one test over another to cover access to crizotinib is unclear. When considering different testing methodologies, false-positive results will reduce the benefit from the drug. However, the greater fear is of false-negative results that would deny patients with a high chance of benefit from getting access to the drug. Studies directly comparing techniques and the benefit from crizotinib in patients who are ALK+ according to different criteria are planned.

Figure 1. Break-Apart FISH Probe Kit Used to Detect ALK Positivity

Detection of ALK Positivity

Red and green FISH probes flank the common breakpoint in the native ALK gene. When no rearrangement is present, the probes appear fused together (yellow arrows in panel A). When an ALK rearrangement occurs, the probes separate, either appearing as a classic "split" pattern (red and green arrows in panel B) or a "single red" pattern where red signals outnumber green signals, suggesting that both a rearrangement and loss of the 5' probe (non-kinase encoding) binding site has occurred (red arrows in panel C). Increases in both rearranged (double red and green arrows in panel D) and native ALK copy number can occur. Copy number gain (CNG) of rearranged signals has been associated with acquired resistance to crizotinib, but CNG of the native gene is not currently considered of any clinical significance.

ALK=anaplastic lymphoma kinase; FISH=fluorescence in situ hybridization.

Adapted with permission from Camidge DR, Kono SA, Flacco A, et al. Clin Cancer Res. 2010;16(22):5581-5590.

In addition to the issue of how to test, the issue of who should be tested is also under discussion. Recognizing that ALK positivity in NSCLC is associated with adenocarcinoma histology, never-smoking status, and absence of other common molecular drivers such as epidermal growth factor receptor (EGFR) and K-ras mutations, clinical enrichment using some or all of these factors has clearly been shown to increase the positivity rate from screening.9 However, no groups with a 0% chance of positivity stand out. Therefore, a policy of only screening an enriched population has to weigh both (1) the cost savings in terms of reducing the absolute numbers of patients screened and the reduced cost per positive found within an enriched population and (2) the number of true positives missed by any preselection approach.12

To illustrate the second of these points, in one recent modeled example, screening only patients who were never-smokers with adenocarcinoma was predicted to result in missing 50% of all possible ALK+ cases in NSCLC.12

Treatment With Crizotinib

Crizotinib is supplied in 250-mg and 200-mg capsules. The standard starting dose of crizotinib is 250 mg taken twice a day either with or without food. The activity of crizotinib 250 mg twice daily in ALK+ NSCLC is striking.7,8,13 In the phase I study, the objective response rate was 61%, with most patients achieving some degree of tumor shrinkage from the drug (Figure 2).13 Median progression-free survival was 10 months, with estimated overall survival rates at 6 and 12 months of 90% and 81%, respectively.13 Crizotinib received accelerated approval in the US in August 2011, but this approval is conditional upon the results of ongoing randomized studies comparing crizotinib with standard first- and second-line chemotherapies in ALK+ NSCLC (PROFILE 1014 and 1007 trials, respectively) (Figure 3).

Figure 2. Waterfall Plot Showing Activity of Crizotinib in ALK-Positive NSCLC

Objective response details
(all evaluable patients)
N=116
ORR (95% CI) 61% (52-70)
Median response duration 48 weeks
Median time to response 8 weeks
Disease control rate at 8, 16 weeks 79%, 67%
Updated median PFS: 10 months.
6-month OS rate (from 1st dose) = 90%,
12-month = 81%.


ALK=anaplastic lymphoma kinase; CI=confidence interval; NSCLC=non-small cell lung cancer; ORR=overall response rate; OS=overall survival; PFS=progression-free survival.
Camidge DR, Bang Y, Kwak EL, et al. J Clin Oncol. 2011;29(suppl; abstr 2501). Used with permission from Camidge DR.

Figure 3. Schema of Ongoing Randomized Trials of Crizotinib versus Chemotherapy in ALK-Positive NSCLC

First-Line Setting

PROFILE 1014: Phase III Study in Previously Untreated NSCLC Protocol
Trial Design Endpoints Stratification Study Sites
Multicenter, randomized, open-label Primary: PFS
Secondary: 6- and 12-month OS, ORR, DCR, DR, safety, quality of life, biomarkers, HCRU
ECOG PS (0/1 vs 2) Ethnicity (Asian vs non-Asian) Brain metastases Worldwide
ALK=anaplastic lymphoma kinase; DCR=delayed cutaneous reaction; DR=delayed reaction; ECOG= Eastern Cooperative Oncology Group Performance Status Scale; EGFR TKI=epidermal growth factor receptor tyrosine kinase inhibitor; FSFV=first subject first visit; HCRU=health care resource utilization; NSCLC=non-small cell lung cancer; ORR=overall response rate; OS=overall survival; PFS=progression-free survival.

www.clinicaltrials.gov (NCT01154140)
 
Key Entry Criteria

  • Positive for ALK gene
  • Metastatic non-squamous cell carcinoma of the lung
  • No prior treatment
 
Randomize
N=334
 
 
 
N=167 Crizotinib 250 mg twice daily administered on a continuous dosing schedule
N=167 Pemetrexed/cisplatin or pemetrexed/carboplatin, Day 1 of a 21-day cycle
 

Second-Line Setting

PROFILE 1007: Phase III Study of PF-02341066 (Crizotinib) versus Pemetrexed or Docetaxel in NSCLC Patients With a Translocation or Inversion Event Involving the ALK Gene Locus
Trial Design Endpoints Stratification Study Sites FSFV
Multicenter, randomized, open-label Primary: PFS
Secondary: ORR, DR, DCR, OS, safety, quality of life, biomarkers
ECOG PS (0/1 vs 2) Previous EGFR TKI treatment Brain metastases Worldwide Ongoing
www.clinicaltrials.gov (NCT00932893)
 
Key Entry Criteria

  • Positive for ALK gene translocation (Abbott)
  • Brain metastases allowed
  • 1 prior chemotherapy (platinum-based)
 
Randomize
N=318
 
 
 
N=159 PF-02341066 250 mg twice daily administered on a continuous dosing schedule
N=159 Pemetrexed 500 mg/m2, infused over 10 minutes on day 1 of a 21-day cycle (first choice) or docetaxel, 75 mg/m2, infused over 1 hour on day 1 of a 21-day cycle
 
With regard to safety and tolerability, common side effects include visual disturbance, nausea and vomiting, diarrhea and/or constipation, peripheral edema, dizziness, anorexia, dysgeusia, alanine transaminase (ALT) increase, and fatigue.7,8,13 In most cases, side effects are mild and develop quickly, with only peripheral edema worsening over time.13 Severe side effects are rare and include aspartate aminotransferase (AST) and ALT increases, pneumonitis, and neutropenia.7,8,13 Although discontinuing dosing with the drug followed by rechallenge at a lower dose (eg, 200 mg twice daily or 250 mg every day) may allow treatment after severe neutropenia or transaminitis, permanent drug discontinuation for severe adverse events is occasionally required.7,13 Anecdotally, nausea and vomiting are significantly reduced by taking crizotinib after food. Visual disturbances appear to be characteristic. In most cases, visual disturbances develop within days of starting the drug and involve brief light trails, flashes, or image persistence occurring at the edges of the visual field, most often when there is a change in the ambient lighting. These visual changes seem to improve over time and appear to be fully reversible on cessation of dosing (Figure 4).13 Recently, rapid-onset hypogonadism in male patients taking crizotinib has been noted, and serum testosterone levels should be routinely checked and replaced as appropriate.14

Disease Progression on Crizotinib



All patients treated with crizotinib will eventually manifest acquired resistance. Some patients’ disease will initially progress exclusively within the brain, possibly as a result of low central nervous system (CNS) penetration of crizotinib.15 In such situations, local CNS therapy (eg, radiotherapy) and continuing crizotinib to maintain extracranial control should be considered. Other patients will manifest extracranial resistance to crizotinib. Multiple secondary ALK kinase domain mutations that reduce sensitivity to crizotinib are now being identified in patients.16 ALK copy number gain (CNG)—increases in the number of copies of the rearranged gene in the cancer cell—either alone or in conjunction with kinase domain mutations, is also emerging as an additional mechanism of acquired resistance.17-19

A series of different second oncogenic drivers (coexisting in the same cell with the ALK rearrangement) and separate oncogenic drivers (when these new changes exist in unique clones that no longer demonstrate evidence of the original ALK rearrangement) have also been described in crizotinib-resistant patients. In contrast to ALK mutations and ALK CNG, which preserve the dominance of ALK signaling in the crizotinib-resistant state, these second and separate drivers should, in theory, degrade or destroy the dominance of ALK signaling.16 Examples of these second and/or separate drivers include both EGFR and K-ras mutations, CNG of KIT, and ligand-driven activation of wild type EGFR and HER2.17,18,20 Conservative estimates place the frequency of these non-ALK–dominant crizotinib resistance mechanisms in approximately equal balance with ALK mutations and ALK CNG.

Therapies in Development



New ALK tyrosine kinase inhibitors (TKIs) are in development, with several showing preclinical activity against both ALK CNG and some of the common ALK mutations that may drive clinical resistance to crizotinib therapy.21,22 In addition, experimental heat shock protein 90 (Hsp90) inhibitors such as ganetespib (formerly STA-9090; Synta Pharmaceuticals) and retaspimycin (IPI-504; Infinity Pharmaceuticals) also appear to show clinical activity against crizotinib-naïve ALK+ NSCLC and preclinical activity against some of the common crizotinib resistance mutations in ALK.23,24 A number of these new drugs—including the Hsp90 inhibitors ganetespib and retaspimycin, and the new ALK TKIs LDK378 (Novartis) and AP26113 (ARIAD)—are being explored in ongoing early-phase clinical trials. In theory, adopting a purely ALK-based therapeutic strategy in a non-ALK–dominant resistance setting is unlikely to be significantly effective, and many of the studies exploring new agents in the crizotinib resistance setting are considering mandating post-crizotinib re-biopsies to explore whether the exact mechanism of resistance will indeed affect outcomes.16 In a non-ALK–dominant situation, combination therapy with agents directed against different drivers or nonmolecularly focused cytotoxic chemotherapy may be required. Of note, in the pre-crizotinib setting, preliminary data suggest that pemetrexed, alone or in combination, may be particularly effective in ALK+ NSCLC.25,26 However, whether the different mechanisms of acquired resistance to crizotinib will impact this sensitivity remains unknown. Regardless of the mechanism of resistance, just as isolated CNS progression may be addressed with radiotherapy, isolated extracranial progression (so-called “oligoprogressive disease”) may in some circumstances be suitable for local ablative therapy (eg, with stereotactic body radiation therapy or metastasectomy) with continuation of the crizotinib to preserve control in other nonprogressing sites of disease.13

Summary



Crizotinib represents a major breakthrough in the treatment of ALK+ NSCLC. In general, the drug is well tolerated, allowing protracted use in those who are benefiting. Determining whom to test and how to test for an ALK rearrangement in NSCLC continues to be debated. Multiple different mechanisms of resistance to crizotinib have now been described. Optimal treatment in this setting is now being explored and may well depend on the specific resistance mechanism that manifests in individual patients.


References
  1. Webb TR, Slavish J, George RE, et al. Anaplastic lymphoma kinase: role in cancer pathogenesis and small-molecule inhibitor development for therapy. Expert Rev Anticancer Ther. 2009;9(3):331-356.
  2. Le Beau MM, Bitter MA, Larson RA, et al. The t(2;5)(p23;q35): a recurring chromosomal abnormality in Ki-1-positive anaplastic large cell lymphoma. Leukemia. 1989;3(12):866-870.
  3. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448(7153):561-566.
  4. Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007;131(6):1190-1203.
  5. Takeuchi K, Choi YL, Togashi Y, et al. KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res. 2009;15(9):3143-3149.
  6. Weickhardt AJ, Camidge DR. The therapeutic potential of anaplastic lymphoma kinase inhibitors in lung cancer: rationale and clinical evidence. Clin Invest. 2011;1(8):1119-1126.
  7. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363(18):1693-1703.
  8. Crinò L, Kim D, Riely GJ, et al. Initial phase II results with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): PROFILE 1005. J Clin Oncol. 2011;29(suppl): abstr 7514.
  9. Camidge DR, Kono SA, Flacco A, et al. Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment. Clin Cancer Res. 2010;16(22):5581-5590.
  10. Camidge DR, Hirsch FR, Varella-Garcia M, Franklin WA. Finding ALK-positive lung cancer: what are we really looking for? J Thorac Oncol. 2011;6(3):411-413.
  11. Shaw AT, Solomon B, Kenudson MM. Crizotinib and testing for ALK. J Natl Compr Canc Netw. 2011;9(12):1335-1341.
  12. Atherly AJ, Camidge DR. The cost-effectiveness of screening lung cancer patients for targeted drug sensitivity markers. Br J Cancer. 2012;106(6):1100-1106.
  13. Camidge DR, Bang Y, Kwak EL, et al. Progression-free survival from a phase I study of crizotinib (PF-02341066) in patients with ALK-positive non-small cell lung cancer. J Clin Oncol. 2011;29(suppl): abstr 2501.
  14. Weickhardt AJ, Rothman MS, Salian-Mehta S, et al. Rapid onset hypogonadism secondary to crizotinib use in men with metastatic non-small cell lung cancer. Cancer. In press.
  15. Costa DB, Kobayashi S, Pandya SS, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol. 2011;29(15):e443-e445.
  16. Camidge DR, Doebele RC. Treating ALK-positive lung cancer—early successes and future challenges. Nat Rev Clin Oncol. In press.
  17. Doebele RC, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012;18(5):1472-1482.
  18. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med. 2012;4 (120):120ra17.
  19. Katayama R, Khan TM, Benes C, et al. Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A. 2011;108(18):7535-7540.
  20. Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res. 2008;14(13):4275-4283.
  21. Zhang S, Wang F, Keats J, et al. Crizotinib-resistant mutants of EML4-ALK identified through an accelerated mutagenesis screen. Chem Biol Drug Des. 2011;78(6):999-1005.
  22. Heuckmann JM, Hölzel M, Sos ML, et al. ALK mutations conferring differential resistance to structurally diverse ALK inhibitors. Clin Cancer Res. 2011;17(23):7394-7401.
  23. Sequist LV, Gettinger S, Senzer NN, et al. Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer. J Clin Oncol. 2010;28(33):4953-4960.
  24. Wong K, Koczywas M, Goldman JW, et al. An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) as monotherapy in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2011;29(suppl): abstr 7500.
  25. Camidge DR, Kono SA, Lu X, et al. Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed. J Thorac Oncol. 2011;6(4):774-780.
  26. Lee JO, Kim TM, Lee SH, et al. Anaplastic lymphoma kinase translocation: a predictive biomarker of pemetrexed in patients with non-small cell lung cancer. J Thorac Oncol. 2011;6(9):1474-1480.


Dr. Leyland-Jones

Brian Leyland-Jones, MD, PhD

Treatment of breast cancer is becoming “horrendously complicated,” said Brian Leyland-Jones, MD, PhD, director of the Winship Cancer Institute at Emory University in Atlanta, Georgia. According to Leyland-Jones, as research on breast cancer progresses, the disease is seen as a set of many different diseases, each with distinct molecular and clinical features.

In February, Leyland-Jones spoke at the 9th Annual Northern New Jersey Breast Cancer Conference, held at the John Theurer Cancer Center, Hackensack, New Jersey, where he gave a broad overview of the current progress and direction of optimal therapies for breast cancer—individualized treatment based on specific molecular targets. Leyland-Jones noted that research in the field, both clinical trial data and new preclinical studies, is progressing so rapidly that it is almost impossible to remember all of the new, targeted areas. “It is becoming clear that breast cancer has 50 to 80 targetable drivers,” he said. “This is a time of massive knowledge change in the entire field.”

The genetic research is identifying new subpopulations of breast cancer to allow for better treatment options—some of the new subtypes could benefit from existing targeted agents and chemotherapy. This new breast cancer subtype clustering based on genetic and transcription data is also identifying new molecular drivers.

Translational research is using the new genetic data to develop drugs from a range of many newly identified targets. Advances in both basic research and translational research are producing a plethora of new targets, according to Leyland-Jones. “The number of targets is shooting up, but fortunately we are getting the drugs to handle those targets,” he said.

It is becoming clear that breast cancer has 50 to 80 targetable drivers. This is a time of massive knowledge change in the entire field. ”
–Brian Leyland-Jones, MD, PhD
Although identification of driver mutations such as HER2 overexpression in breast tumors has allowed for tailored therapies, many aggressive tumor types have no distinguishing genetic characteristics on which to base treatments. Research in this field is very active. A recent study published in the journal Nature characterized over 2000 breast tumors. The study revealed new breast cancer subgroups based on both genomic and transcription analyses.1 The authors of the study identified three new deletion mutations that correlated with already known breast cancer subtypes. Researchers can now take advantage of this knowledge to identify patients with these mutations and test specific drugs that target specific mutations. These types of genomic breast tumor studies will lead to more precise diagnoses and tailored treatments that target the specific molecular defects of a patient’s tumor. Mapping the genetic landscape of a tumor allows for identification of biomarkers, which can be used to predict response to treatment or better predict patients with high-risk disease or recurrence. For example, a research team at the Dana-Farber Cancer Institute in Boston, Massachusetts, has identified a marker of DNA damage in patients with triple-negative breast cancer that may be able to predict whether a patient has the potential to respond to platinum-based chemotherapy agents such as carboplatin and cisplatin.2

Currently, triple-negative breast cancer does not have any targeted therapy options because the subtype is actually a heterogeneous group of tumor types that is characterized by what they lack (no expression of estrogen or progesterone receptor and no HER2 overexpression) rather than distinct and targetable genetic aberrations. Platinum-based chemotherapy is widely used as a treatment, but it exposes the patient to toxicity and does not help all patients. Identifying patients who would benefit would save many patients from the toxic effects of systemic therapies that will not be efficacious—and lower unnecessary costs of treatment.

Dr. Dennis Slamon

Dennis Slamon, MD, PhD

HER2 Targeting: Advancements Beyond Trastuzumab

Approximately 20% of breast cancers produce too much HER2. These HER2-positive breast cancers are typically more aggressive compared with other types of breast cancer and are fast-growing. “When amplified, the expression of HER2 goes way beyond its normal dynamic range—there is a wide range of normal HER2 expression—so that you get pathologic overexpression. When overexpressed to this extent, it plays a dominant role in proliferation and motility and resistance to hormonal control,” said Dennis Slamon, MD, PhD, director of Clinical/Translational Research, director of the Revlon/UCLA Women’s Cancer Research Program, and chief of the Division of Hematology/Oncology at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles.

The HER2 gene was discovered in the late 1970s and cloned in 1985 by scientists at Genentech. That same year, scientists at the National Institutes of Health discovered that the gene is frequently present in multiple copies in human breast tumors. Trastuzumab (Herceptin, Genentech) was created at Genentech in 1990. The antibody specically binds to the extracellular domain of the HER2 receptor. The drug was approved for metastatic breast cancer that overexpresses the HER2 protein in 1998—either as a monotherapy for patients who have received at least one chemotherapy treatment or as a first-line therapy in combination with paclitaxel. Phase III trials showed the antibody reduced rates of recurrence by about 50%. Since then, it has become one of the most common therapeutic agents used in the treatment of breast cancer. Trastuzumab was subsequently approved as an adjuvant treatment for HER2-overexpressing, early-stage breast cancer.

HER2 Signaling Basics

HER2 is a receptor tyrosine kinase that is part of a signaling network that controls important cellular processes such as cell survival, proliferations, angiogenesis, invasion, and metastasis. HER2 belongs to the human epidermal growth factor family of receptors, along with HER1 or EGFR, HER3, and HER4. The basic signaling mechanism for this family involves dimerization—the coming together of two of the same receptors (homodimerization) or two different receptors (heterodimerization) within the plasma membrane. Heterodimers of HER2 and HER3 have been shown to be more potent compared with homodimers in activation of downstream targets. Activation results in intracellular signaling through an important pathway also frequently mutated in cancer: the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway.

Dr. Carlos Arteaga

Carlos L. Arteaga, MD

“HER2-HER3 dimerization is a particularly important aspect of HER2 signaling, as these dimers potently signal to the PI3K survival pathway and are the main mechanism driving HER2-positive cancers,” said Carlos L. Arteaga, MD, director of the Breast Cancer Research Program at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. Arteaga’s research focuses on the role of signaling by oncogenes in the progression of breast tumor cells and molecular therapies in breast cancer.

Next-Generation HER2 Therapies in Development

Although it was a great advance that led to improvement in survival of patients with an aggressive form of breast cancer, trastuzumab is not a “magic bullet.” Significant problems of resistance to the therapy and relapse require next-generation solutions, despite the availability of trastuzumab and lapatinib (Tykerb, GlaxoSmithKline), another inhibitor of the HER2 pathway.

HER2-HER3 dimerization is a particularly important aspect of HER2 signaling, as these dimers potently signal to the PI3K survival pathway and are the main mechanism driving HER2-positive cancers. ”
–Carlos L. Arteaga, MD
One of the mechanisms of resistance to trastuzumab may be an incomplete blockade of HER2 signaling. Trastuzumab blocks ligand-independent signaling, but not ligand-dependent signaling that results in HER2-HER3 dimerization. The monoclonal antibody pertuzumab, also developed by Genentech, may overcome this form of resistance. Pertuzumab binds to a different region of the HER2 extracellular domain and can block ligand-dependent HER2 dimerization. As a single agent, trastuzumab is more effective than pertuzumab in inhibiting HER2-dependent growth in vitro and in vivo, according to Slamon, who had played a major role in the development of trastuzumab.

Related: Leading Researcher Sees Turning Point in Breast Cancer: An Interview With José Baselga, MD, PhD

“But when you hit the receptor twice, it appears you have even better activity. We had preclinical data from our lab from several years ago that demonstrated this. So, it appears that two assaults on the receptor gives you synergistic activity,” Slamon explained.

Pertuzumab is currently being studied in patients with early and advanced HER2-positive breast cancer and advanced HER2-positive gastric cancer.

Pertuzumab has limited activity as a single agent, but the synergistic effect of trastuzumab plus pertuzumab that was demonstrated in preclinical studies has been confirmed in phase II trials in patients who had disease progression after trastuzumab monotherapy.

The phase II NeoSphere (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) trial showed higher pathologic complete response (pCR) rates in newly diagnosed patients with HER2-positive breast cancer treated with a triple combination of pertuzumab, trastuzumab, and chemotherapy.3 The trial demonstrated that chemotherapy may not be necessary, as pertuzumab plus trastuzumab without chemotherapy also produced higher pCR rates. These results suggest that if it were possible to predict which patients would respond to the dual HER2-targeted combination, it may be possible to treat patients effectively without chemotherapy.

Subsequently, the phase III CLEOPATRA (CLinical Evaluation Of Pertuzumab and TRAstuzumab) trial compared the triple combination of pertuzumab, trastuzumab, and docetaxel chemotherapy to trastuzumab and docetaxel alone in 808 patients with HER2-positive metastatic breast cancer who had not been previously treated.4 Patients who received the triple combination had a 38% reduction in the risk of their disease worsening. The median progression-free survival (PFS) was 18.5 months for the triple combination compared with 12.4 months for trastuzumab plus chemotherapy (P < .0001)— an increase of 6.1 months. The overall survival data were still immature when the trial data were presented but favored the triple combination. The objective response was 80.2% in the triple-therapy group compared with 69.3% in the control group.

HER2-Positive Studies Featured at the 2012 ASCO Annual Meeting

  • Results of the EMILIA phase III study of trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in patients with HER2-positive locally advanced or metastatic breast cancer who have previously been treated with trastuzumab and a taxane.
  • Results of the phase I/IB dose-escalation study of BEZ235 in combination with trastuzumab in patients with PI3K or PTEN altered HER2-positive metastatic breast cancer.
  • Results of the SU2C phase Ib study of pan-PI3K inhibitor BKM120 with letrozole in ER-positive/HER2-negative metastatic breast cancer.
  • A 13-gene signature to predict rapid development of brain metastases in patients with HER2-positive advanced breast cancer.
  • The National Surgical Adjuvant Breast And Bowel Project (NSABP) protocol, evaluation of lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer.
Leyland-Jones called the survival impact demonstrated in the study “practice-changing.” Arteaga believes that the results are due to a comprehensive blockade of HER2 signaling. “Frankly, I think these results were expected and, as strongly suggested by the mechanistic and preclinical data, the results could almost have been written before the trial,” he added.The CLEOPATRA trial results were published in The New England Journal of Medicine in January. The combination was submitted for approval in both the US and in Europe for previously untreated, HER2-positive, metastatic breast cancer and the decision to approve the combination was made by the Food and Drug Administration (FDA) on June 8, 2012, based on a priority review (Find out more).

The pertuzumab, trastuzumab, and chemotherapy combination is also being investigated in a phase III trial as adjuvant therapy in nearly 4000 patients with HER2-positive breast cancer.

In addition to trastuzumab and pertuzumab, other agents such as HER2 dimerization inhibitors are in development. “Overall, these represent an important class of agents as they disrupt a central mechanism of signaling by the HER2 receptor,” said Arteaga. These therapies include the monoclonal antibody MM-21 (SAR256212; sanofi-aventis and Merrimack Pharmaceuticals), which disrupts HER3-ligand-induced HER2-HER3 dimerization. MM-121 is under clinical development in a variety of settings, including in combination with cetuximab and irinotecan in colorectal, head and neck, non-small cell lung, and triple-negative breast cancers.

Another agent is a fully human anti-HER3 monoclonal antibody, U3-1287/AMG-888 (Daiichi Sankyo Co Ltd, U3 Pharma, and Amgen), which is currently being studied in a phase Ib/II trial in combination with trastuzumab and paclitaxel in patients with newly diagnosed HER2-positive metastatic breast cancer.

Additionally, Arteaga highlighted data on a novel HER3 antibody developed by Novartis that has shown the ability to block both ligand-dependent and ligand-independent formation of HER2-HER3 dimers. “The preclinical data suggested this monoclonal antibody could be mechanistically superior to the other two HER3 antibodies, but it has not been tested in patients yet,” he said.

Other dual HER2-blockade approaches include trastuzumab in combination with a PI3K inhibitor. “The ‘dual’ approach targets different molecules or nodes in the HER2 pathway, the HER2 receptor, and PI3K immediately downstream,” said Arteaga.

Another approach is the combination of trastuzumab plus lapatinib used in the phase III NeoALTTO trial in women with HER2-positive primary breast cancer.5 This trial demonstrated that the combination of trastuzumab plus lapatinib is more efficacious in achieving pCR compared with lapatinib alone.

A Novel Approach to Combining a HER2-Targeted Drug With Chemotherapy

Another promising agent for HER2-positive disease is T-DM1 (trastuzumab emtansine, Genentech). This novel therapeutic is an antibody drug conjugate that combines trastuzumab with the chemotherapy agent DM1 through a linker designed to stabilize the antibody-chemotherapy combination. The goal is for the T-DM1 to specifically reach its HER2 target without significant off-target effects, as occur with the administration of chemotherapy.

Results of a phase II trial, presented at the San Antonio Breast Cancer Symposium (SABCS), in December 2011, compared the combination of trastuzumab plus docetaxel with T-DM1 in HER2-positive metastatic breast cancer as a first-line therapy. T-DMI significantly improved PFS (median PFS for trastuzumab/docetaxel was 9.2 mo vs 14.2 mo for T-DM1; HR = 0.594; P = .0353) compared with the trastuzumab/docetaxel combination. Toxicity was significantly less with T-DM1, presumably because the chemotherapy was delivered specifically to HER2-expressing tumors (Find out more).T-DM1 has since shown efficacy in a phase III trial. Roche, Genentech’s parent company, announced at the end of March that the phase III EMILIA trial in 991 patients met one of its primary endpoints: T-DM1 showed a significant improvement in PFS of 3.2 months. The overall data for the trial are still immature. The trial compared T-DM1 therapy to a combination of capecitabine and lapatinib. The full trial results were presented as a late-breaking abstract at the plenary session of the American Society of Clinical Oncology (ASCO) Annual Meeting, held in June 2012 (Find out more). Patients in the trial were previously treated with trastuzumab and chemotherapy. Roche and Genentech will submit applications for approval of T-DM1 to both the FDA and the European Medicines Agency (EMA) this year.

Another ongoing three-arm, phase III study is the MARIANNE trial comparing T-DM1 with and without pertuzumab to trastuzumab plus a taxane chemotherapy in 1000 patients with HER2-positive, previously untreated metastatic breast cancer. The primary endpoint of the trial is PFS.

Other Pathway Targets

Many additional targets are under development for breast cancer therapies, including poly(ADP-ribose) polymerase (PARP) inhibitors. PARP inhibitors may have efficacy in BRCA-associated cancer. In a phase III trial published in January 2011, the PARP inhibitor iniparib (BiParSciences/sanofi-aventis) did not meet the primary dual endpoints of overall survival (OS) and PFS in metastatic triple-negative breast cancer. However, a prespecified subgroup analysis suggested improvements in OS and PFS in the second- and third-line settings. Researchers are continuing to investigate potential uses for iniparib and to discover which patients will most likely respond to PARP inhibitors.

Iniparib is considered a relatively weak PARP inhibitor, said Leyland-Jones. Other PARP inhibitors under development include rucaparib (Clovis), for BRCA-positive, post-neoadjuvant, triple-negative breast cancer; olaparib (AstraZeneca), for BRCA-positive breast cancer; and veliparib (ABT-888; Abbott), for BRCA-positive, triple-negative breast cancer.

Advances in basic research are leading to a greater understanding of the tumor microenvironment, noted Leyland-Jones. New therapeutic targets as a result of these advances include metabolic pathways (serine, glycine synthesis); JAK2 in triple-negative and potentially other breast cancers; androgen receptors in HER2-positive breast cancer; and Src in trastuzumab resistance.

The use of large-scale siRNA screens to identify and validate targets is also under way. Translational research has recently facilitated research to overcome endocrine therapy resistance, overcoming HER2-targeted therapy resistance, and classification and prognosis in triple-negative breast cancer.

Over the next five years, therapy will be increasingly based on genome sequencing, said Leyland-Jones. As the cost of sequencing keeps dropping, genetic analysis of a patient’s tumor could become routine, with results available as quickly as two weeks.

While the approach to treatment of breast cancer continues to rapidly evolve, and our understanding of the drivers of the disease increase, there is still a long way to go. Many more academic studies are needed on the genetics of breast cancer—particularly on understanding the many types of diseases within the current category of triple-negative breast cancer.


References

  1. Curtis C, Shah SP, Chin SF, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups [published online ahead of print April 18, 2012]. Nature. 2012.doi:10.1038/nature10983.
  2. Birkbak N, Wang ZC, Kim J-Y, et al. Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discovery. 2012. doi: 10.1158/2159-8290.CD-11-020.
  3. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial [published online ahead of print December 6, 2011]. Lancet Oncol. 2012;13:25-32.
  4. Baselga J, Cortés J, Kim S-B, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer [published online ahead of print December 7, 2012]. N Engl J Med. 2012;366:109-119.
  5. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial [published online ahead of print 17 January 17, 2012]. Lancet. 2012;379:633-640. doi:10.1016/S0140-6736(11)61847-3.


Dr. Nikhil I. Khushalani Corresponding Author:

Nikhil I. Khushalani, MD

Associate Professor of Oncology, Roswell Park Cancer Institute,
Department of Medicine,
Elm & Carlton Streets,
Buffalo, New York;

nikhil.khushalani@roswellpark.org

  1. Department of Medicine, State University of New York, Buffalo, NY
  2. Department of Pharmacy, Roswell Park Cancer Institute, Buffalo, NY
  3. Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY

Abstract



Metastatic melanoma has historically been one of the most therapeutically challenging malignancies, with poor 5-year survival. Until recently, dacarbazine and high-dose interleukin-2 were the only agents approved by the FDA for metastatic melanoma. The year 2011 witnessed the approval of an anti-CTLA-4 antibody, ipilimumab, and a BRAF-targeted agent, vemurafenib, in advanced melanoma, which has led to a renaissance in melanoma therapeutics. This is an exciting phase for melanoma immunotherapy and holds important implications for clinicians, due to novel paradigms of treatment, assessment of response, and management of immune-related toxicities. This review seeks to summarize the data on approved immunotherapeutic options in metastatic melanoma, with a special focus on ipilimumab.

The incidence of cutaneous melanoma has been steadily rising in the United States, especially in Caucasian women under 40 years of age, in whom an increase of 50% occurred from 1980 until 2004. Approximately 9200 deaths from melanoma are estimated in 2012.1 Thickness of the primary tumor, ulceration, and nodal metastatic status are the most important determinants of prognosis for localized disease, for which surgery remains the mainstay of therapy. A selected subset of oligometastatic stage IV patients also may benefit from surgical resection. Metastatic melanoma has a dismal prognosis, with a median survival of 7 months and a 5-year survival rate of 15%.2,3

Until recently, therapeutic options centered on dacarbazine (DTIC), the only FDA-approved chemotherapeutic agent for metastatic melanoma since 1975.4 An active regimen that was commonly used until recently is carboplatin and paclitaxel, with response rates ranging from 11% to 26%.5-7 In 2011, ipilimumab and vemurafenib gained regulatory approval in the United States for the treatment of advanced melanoma based on positive randomized trials, ushering in a new era in melanoma therapy. This in turn has initiated a cascade of clinical trials that hopefully will build on this improvement and improve the outlook for this disease.

This review will summarize the role of immunotherapy in advanced melanoma, with a focus on the use of ipilimumab in the community practice setting.

Immunotherapy Options in Advanced Melanoma

Melanoma is a highly immunogenic tumor. Clinical observations of a higher incidence in organ transplant recipients, as well as rare spontaneous tumor regressions, have led to investigations into harnessing the immune system in therapy against melanoma. It is well known that melanomas exhibiting a brisk lymphocytic infiltrate have a better prognosis than those lacking this, and that melanomas are often associated with areas of histologic regression that correlate with lymphocytic infiltration.8 Several biologic agents, vaccines, and checkpoint agents have been tested in clinical trials.

Interleukin-2 (IL-2)



IL-2 is a glycoprotein that binds to IL-2 receptors on T-cells and augments lymphocyte mitogenesis and cytotoxicity. It is essential for T-cell immunity and exerts its anticancer activity by acting as a growth factor for T lymphocytes, increasing interferon-gamma production, stimulating antigen-independent natural killer cells, and facilitating movement of lymphocytes to sites of malignancy.9-11 It was first identified in 1976, and received FDA approval in 1998 for the treatment of metastatic melanoma based on its ability to produce durable, complete responses in this disease.12-14

The Cytokine Working Group described its findings for a patient database of 270 patients with metastatic melanoma who were entered into eight clinical trials assessing the efficacy and toxicity of the high-dose IL-2 regimen.13 The overall response rate (ORR) was 16% (95% confidence interval [CI], 12%-21%); there were 17 complete responses (CR; 6%) and 26 partial responses (10%). Of the responders, 28% (including 59% who achieved CR) were progression-free at a median follow-up period of 62 months.

In an attempt to improve responses to IL-2, Schwartzentruber et al randomized patients with advanced melanoma to receive IL-2 with or without a synthetic peptide vaccine, gp100, based on prior encouraging data from their group.15,16 Although the combination arm significantly improved ORR (16% vs 6%; P = .03) and progression-free survival (PFS; 2.2 months vs 1.6 months; P = .008), the improvement in overall survival (OS; 17.8 months vs 11.1 months; P = .06) was not statistically significant.16

Attempts at intensifying biological therapy with the addition of chemotherapy or the use of other immunotherapeutic agents (so-called “bio-chemotherapy”) has resulted in improved ORR, but without survival benefit and with greater toxicity.17 Phenotypic and laboratory parameters have been shown to be associated with antitumor response to IL-2.18

A prospective tissue collection trial (High-dose IL-2 SELECT Study) is currently under way, aiming to identify genotypic and tumor-specific predictors of response to IL-2 in melanoma (NCT01288963). This effort is critical, as IL-2-related toxicity has restricted its use to carefully selected patients in highly specialized centers of care. These effects mainly stem from vasodilation and the capillary leak syndrome, resulting in significant hemodynamic consequences.19 Appropriate patient selection, with the exclusion of high-risk patients with pre-existing cardiopulmonary comorbidities and poor performance status, is essential to enhance the safety of this treatment regimen.

Skeptics may argue about the lack of evidence supporting a survival benefit from IL-2 in melanoma and the absence of a randomized controlled phase III clinical trial with this toxic biologic agent. However, the persistent “tail” of the Kaplan-Meier survival curve in nearly every published study of this drug attests to its distinct benefit, albeit in a small subset of patients in whom the disease would typically be fatal.

Ipilimumab

Ipilimumab is a human monoclonal antibody specific for the cytotoxic T-lymphocyte antigen-4 (CTLA-4) that was approved by the FDA for the treatment of unresectable or metastatic melanoma in March 2011. A key co-stimulatory signal for effective T-cell activation is the binding of CD80 or CD86 on antigen-presenting cells (APCs) to CD28 on T-cells. CTLA-4 is a cell surface molecule closely related to CD28, with a greater binding affinity towards CD80 and CD86. This prevents co-stimulation, and thereby acts as a negative regulator of T-cell activation (Figure). Ipilimumab binds to CTLA-4 and blocks its interaction with CD80 or CD86, thereby augmenting T-cell activation and proliferation.20

It is important for clinicians to understand the mechanism of action of ipilimumab, as adverse events from this agent follow similar principles. The presence of autoimmune disease is considered a contraindication to ipilimumab therapy, and these patients have been excluded from trials involving this agent. At baseline, a complete blood count, serum chemistries (including liver function tests), and thyroid profile are recommended. In our practice, we also obtain additional endocrine markers for a pituitary profile, including serum adrenocorticotropic hormone, follicle-stimulating hormone, luteinizing hormone, cortisol, and testosterone levels.

Ipilimumab is administered intravenously at a dose of 3 mg/kg over 90 minutes every three weeks for a total of four doses. Because ipilimumab contains only human protein sequences, infusion reactions are rare and premedications are not required. Prior to each subsequent dose, clinical questions evaluating immune-mediated symptoms and laboratory value checks that include liver and thyroid functions are recommended. Other parameters should be rechecked based on clinical symptomatology.

Early Experience With Ipilimumab

Initial experience with ipilimumab highlighted low, though durable, ORR and the development of immune-related adverse events (irAEs) that appeared to correlate with response.21,22 It demonstrated promising activity as monotherapy in phase II trials in advanced melanoma, giving impetus to larger-scale testing.23-25

A recent report from the National Cancer Institute provides the longest follow-up data on 177 patients treated in three trials with ipilimumab alone or in combination with gp-100 peptides or IL-2.26 The ORR ranged from 13% to 25%, with complete response rate from 6% to17%. Nearly all patients with CR (14/15) have had a durable duration of response ongoing at 54+ to 99+ months. The 5-year survival rate was 13% to 25%, which highlights the delayed kinetics of response that clinicians in practice should appreciate with the use of this and similar drugs.

The Response Evaluation Criteria In Solid Tumors (RECIST), which are utilized to assess objective response in therapeutic trials of cytotoxic drugs, may not be suitable for immunotherapy trials. The infiltration of the tumor by cytotoxic T-cells may result in no change in the size of the tumor, or, paradoxically, an initial increase in the tumor size (which may equate progressive disease at the initial timepoint of response assessment per RECIST).

With the recent reporting of long-term follow-up and the noted improved survival (vs historical controls) from the initial ipilimumab trials, it is clear that measurable response may be delayed as compared with conventional chemotherapy. Hence, in the absence of obvious clinical deterioration at the time of first evaluation after ipilimumab, continuing observation is reasonable, even in the presence of radiographic progression.Wolchok and colleagues have proposed a new set of immune-related response criteria (irRC) to assess response in patients treated with immunotherapy.27 These criteria are based on total tumor burden, which is calculated by summation of the product of the perpendicular diameters of measurable index lesions and new lesions. However, one should be mindful of the fact that the irRC criteria can potentially overestimate response to therapy and lead to unnecessary prolongation of nonbeneficial, toxic treatment.

Phase III Trials of Ipilimumab

Previously treated melanoma



In a randomized phase III trial, 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma whose disease had progressed on one prior therapy were randomly assigned in a 1:1:3 ratio to receive either ipilimumab (n = 137), gp100 vaccine (n = 136), or a combination of the two (n = 403).28 Most patients had M1c disease (73%) or an elevated lactate dehydrogenase (LDH) level (38%), both adverse prognostic factors. Twenty-three percent of patients had previously received IL-2. Ipilimumab dosed at 3 mg/kg was administered intravenously with or without gp100 every three weeks for up to four treatments, and patients were eligible for reinduction at progression if they had experienced an initial benefit to therapy.

In this trial, ipilimumab plus gp 100 significantly improved OS compared to gp100 (10 months vs 6.4 months; P < .001), and this was independent of age, sex, baseline LDH levels, metastatic stage, and previous IL-2 therapy. A similar improvement was noted in the ipilimumab-alone arm as well. PFS was similar in all three groups at week 12, but the curves separated thereafter, favoring the ipilimumab arms. This observation underscores the fact that responses to ipilimumab may be delayed, as the 2-year survival in the gp 100 group was 14% compared with 22% to 24% in the two ipilimumab arms. The ipilimumab-only arm had the highest response rate (11%), and 60% of these responses were durable at 2 years. Although this trial was conducted in patients who had failed prior therapy, the FDA approved ipilimumab for the first-line and beyond setting based on preliminary results from a concurrent trial in treatment-naïve patients discussed below.29

Therapy-naïve metastatic melanoma



Robert et al29 randomized 502 patients to combination ipilimumab (dosed at 10 mg/kg) plus dacarbazine every three weeks versus dacarbazine in a phase III trial for therapy-naïve patients with advanced melanoma. Patients with stable disease received ipilimumab every 12 weeks as maintenance therapy. The 10-mg/kg dose of ipilimumab was chosen based on a randomized phase II study that reported a dose-response relationship for the drug.24 The combination improved OS compared with dacarbazine alone (11.2 months vs 9.1 months), a benefit that spanned all subgroups of patients, including those with M1c disease. However, only 37% of patients in the combination arm completed all four induction cycles, and hepatotoxicity was higher than anticipated. Elevated transaminase levels occurred in a third of patients, with approximately 15% of those being grade 3 or higher, likely due to the addition of dacarbazine. Given this, the use of this combination is not recommended.It is difficult to directly compare the two randomized trials due to inherent differences in study population, dose of ipilimumab, and the partner drug. Although a dose-response relationship has been suggested with ipilimumab, this may come at the cost of greater toxicity, as demonstrated in the randomized phase II study by Wolchok et al.24 In that trial, the ORR was 11%, 4%, and 0% for patients receiving ipilimumab dosed at 10 mg/kg, 3 mg/kg, and 0.3 mg/kg every three weeks, respectively. The respective rates of grades 3 and 4 toxicity were 25%, 7%, and 0%.

Until additional data from ongoing clinical trials are available, the use of ipilimumab should be only at the FDA-approved dose of 3 mg/kg every three weeks. In the absence of significant toxicity, it is reasonable to consider reinduction for patients whose disease progresses after an initial response, or following a prolonged period of stability.

Ipilimumab-Related Toxicity and Management

As CTLA-4 blockade overcomes tolerance to “self” antigens, adversity from ipilimumab is similarly immune-mediated. Although the types of autoimmune toxicity are predictable, their onset and duration vary considerably. The most common side effects include diarrhea, rash, and endocrine-related adverse immune events.30 Diarrhea and colitis have been reported in 10% to 35% of study patients and are the most commonly seen grade 3/4 toxicities in the majority of clinical trials. Most patients with colitis present within two weeks of starting treatment, although time of onset varies considerably. Colitis can be potentially life-threatening and should be treated with bowel rest, supportive care, high-dose steroids, and/or infliximab.31

The use of budesonide to prevent colitis in patients receiving ipilimumab was studied in a phase II clinical trial. Prophylactic use of budesonide did not affect the rate of grade 2 or higher diarrhea, which occurred in 33% of patients who received budesonide and in 35% of patients who did not receive it.23 Hepatitis or transaminitis has been reported in 2% to 20% of patients treated with ipilimumab. Ipilimumab should be discontinued for > grade 3 hepatotoxicity (AST or ALT > 5 X ULN; bilirubin > 3 X ULN), and a prolonged course of oral corticosteroids may be warranted.25,32

Hypophysitis, adrenal insufficiency, and thyroid dysfunction are the most commonly reported endocrine immune events associated with ipilimumab therapy. Dysfunction of the adrenal axis is often an irreversible adverse event that requires long-term replacement corticosteroid therapy. Virtually every organ can be affected by ipilimumab-associated inflammation, and education of the provider and patient is paramount in its safe administration. The immune-related toxicity of ipilimumab requires prompt diagnosis and intervention, as this can become life-threatening.

The algorithms outlined in the FDA-approved Risk Evaluation and Mitigation Strategy (REMS) for ipilimumab are an invaluable source of information for healthcare providers. General guidelines suggest the use of steroids for moderate to severe irAEs (prednisone at 1-2 mg/kg/day or equivalent), with a slow taper over four to six weeks or longer, if necessary. Lower doses (prednisone at 0.5 mg/kg/day or equivalent) can be considered for lesser degrees of toxicity.

Ipilimumab therapy is an “all or none” phenomenon. Dose reductions during a course are not undertaken, and the following circumstances mandate permanent discontinuation of ipilimumab:
  1. Severe or life-threatening toxicity
  2. Inability to wean corticosteroid dose to 7.5 mg prednisone or equivalent per day
  3. Inability to complete the entire course of ipilimumab within 16 weeks from the first dose

Ipilimumab Activity in Brain Metastases From Melanoma

Melanoma has a high propensity for brain metastases. Most therapeutic trials typically exclude this poor-prognosis cohort of patients. In a multicenter phase II trial of two cohorts of melanoma patients with brain metastases (cohort A: asymptomatic and not on steroids at study entry; cohort B: symptomatic and on stable steroid dosing at entry), ipilimumab dosed at 10 mg/kg every three weeks was shown to have similar level of activity in the brain and non-central nervous system lesions.33 The global disease-control rate at 12 weeks was 18% in cohort A versus 5% in cohort B, while the median OS was 7 months and 3.7 months, respectively. These intriguing data suggest that ipilimumab may have activity in some patients with small, asymptomatic brain metastases from melanoma, and further investigation is warranted.

Increasing Options: Sequence of Therapy

With increasing options for treatment in melanoma, it becomes incumbent to understand the nuances associated with each therapy and aim to streamline an evidence-based approach to the metastatic patient. Immunotherapy offers the only chance for durable disease control and should preferably be the first-line therapy for the patient with advanced, unresectable melanoma in the absence of any obvious contraindication (eg, active autoimmune disease). Tumors from these patients should be tested for the BRAFV600 gene mutation.

The following algorithm offers a reasonable approach in decision making:

  1. For younger, fit patients without cardiopulmonary comorbidity, high-dose IL-2 remains an appropriate first choice, including patients whose tumors harbor the BRAFV600 mutation.
  2. Ipilimumab is also a reasonable option for those unfit for, or unwilling to get, high-dose IL-2, or whose disease progresses after IL-2 therapy.
  3. Vemurafenib should be considered for patients with BRAFV600 mutation with bulky, symptomatic disease at presentation, or those in whom immunotherapy is contraindicated or has failed (including toxic effects).
  4. Cytotoxic chemotherapy can be used in patients with BRAF-wild type melanoma after failure of immunotherapy, or as a possible bridge to immunotherapy in case of symptomatic disease.
  5. At any point in therapy, participation in a clinical trial is an accepted standard of care.

Conclusions: “Pandora’s Box” in Immunotherapy

The discovery that cancer cells express tumor-specific antigens lent impetus to the development and testing of various therapeutic agents targeted against these antigens. The recent success of anti-CTLA-4 agents in melanoma has spawned renewed clinical interest in cancer immunology. Multiple phase II/III clinical trials testing various combinations of immune agents with other cytotoxic, targeted, and biologic agents are under way, including temozolomide, melphalan, dactinomycin, fotemustine, and bevacizumab, among a few others. The results of these trials are eagerly awaited.

Table. Selected Immune Agents Under Investigation in Melanoma

Class Type Agent(s)
Cytokines IL-2, IL-15, IL-21, GM-CSF
Immune Checkpoint Blockade
Anti-CTLA-4 Ipilimumab, tremelimumab
Anti-PD-1/PD-L1 MDX-1106, CT-011, MDX-1105
Targeting tumor necrosis factor BMS 663513
Vaccines gp 100, MAGE-A3
Potential agents that might be predicted to synergize with ipilimumab are those targeting other immunological molecules, such as antibodies blocking PD-1 and agonistic antibodies activating OX40, a co-stimulatory receptor that promotes T-cell survival and expansion. A list of agents under investigation is outlined in the Table.The overarching goal is to obtain a sustained immune response that can facilitate longer survivorship. Importantly, the concurrent search for predictive markers of outcome is essential in order to help target patients who are most likely to benefit from the intervention and to minimize irAEs. Despite the optimism surrounding the newer agents from this “Pandora’s box” of melanoma therapeutics, this disease remains fatal in the vast majority of advanced cases in 2012. Participation in clinical trials should be strongly encouraged—and, in fact, accepted as a standard of care in advanced melanoma.


References

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10-29.
  2. Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27:6199-6206.
  3. SEER Cancer Statistics Review, 1975-2008, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2008/, based on November 2010 SEER data submission, posted to the SEER website, 2011. Accessed March 30, 2012.
  4. Hill GJ, 2nd, Krementz ET, Hill HZ. Dimethyl triazeno imidazole carboxamide and combination therapy for melanoma. IV. Late results after complete response to chemotherapy (Central Oncology Group protocols 7130, 7131, and 7131A). Cancer. 1984;53:1299-1305.
  5. Rao RD, Holtan SG, Ingle JN, et al. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer. 2006;106:375-382.
  6. Hauschild A, Agarwala SS, Trefzer U, et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009;27:2823-2830.
  7. Kim KB, Sosman JA, Fruehauf JP, et al. BEAM: A randomized phase II study evaluating the activity of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated advanced melanoma. J Clin Oncol. 2012;30:34-41.
  8. Oble DA, Loewe R, Yu P, Mihm MC, Jr. Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human melanoma. Cancer Immun. 2009;9:3.
  9. Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol. 2006;6:595-601.
  10. Malek TR. The biology of interleukin-2. Annu Rev Immunol. 2008;26:453-479.
  11. Doyle MV, Lee MT, Fong S. Comparison of the biological activities of human recombinant interleukin-2(125) and native interleukin-2. J Biol Response Mod. 1985;4:96-109.
  12. Parkinson DR, Abrams JS, Wiernik PH, et al. Interleukin-2 therapy in patients with metastatic malignant melanoma: a phase II study. J Clin Oncol. 1990;8:1650-1656.
  13. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17:2105-2116.
  14. Tarhini AA, Kirkwood JM, Gooding WE, Cai C, Agarwala SS. Durable complete responses with high-dose bolus interleukin-2 in patients with metastatic melanoma who have experienced progression after biochemotherapy. J Clin Oncol. 2007;25:3802-3807.
  15. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med. 1998;4:321-327.
  16. Schwartzentruber DJ, Lawson DH, Richards JM, et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011;364:2119-2127.
  17. Hamm C, Verma S, Petrella T, Bak K, Charette M. Biochemotherapy for the treatment of metastatic malignant melanoma: a systematic review. Cancer Treat Rev. 2008;34:145-156.
  18. Phan GQ, Attia P, Steinberg SM, White DE, Rosenberg SA. Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. J Clin Oncol. 2001;19:3477-3482.
  19. Margolin KA, Rayner AA, Hawkins MJ, et al. Interleukin-2 and lymphokine-activated killer cell therapy of solid tumors: analysis of toxicity and management guidelines. J Clin Oncol. 1989;7:486-498.
  20. Salama AK, Hodi FS. Cytotoxic T-lymphocyte-associated antigen-4. Clin Cancer Res. 2011;17:4622-4628.
  21. Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2003;100:8372-8377.
  22. Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol. 2005;23:6043-6053.
  23. Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res. 2009;15:5591-5598.
  24. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155-164.
  25. O’Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010;21:1712-1717.
  26. Prieto PA, Yang JC, Sherry RM, et al. CTLA-4 Blockade with Ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res. 2012;18:2039-2047.
  27. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412-7420.
  28. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.
  29. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-2526.
  30. Thumar JR, Kluger HM. Ipilimumab: a promising immunotherapy for melanoma. Oncology (Williston Park). 2010;24:1280-1288.
  31. Johnston RL, Lutzky J, Chodhry A, Barkin JS. Cytotoxic T-lymphocyte-associated antigen 4 antibody-induced colitis and its management with infliximab. Dig Dis Sci. 2009;54:2538-2540.
  32. Weber J. Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events. Oncologist. 2007;12:864-872.
  33. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial [published online ahead of print March 27, 2012]. Lancet Oncol. 2012;13(5):459-465. doi:10.1016/S1470-2045(12)70090-6.


Dr. David Spigel

David Spigel, MD

Two novel therapies designed to improve survival outcomes in patients with advanced non–small cell lung cancer (NSCLC) are now being evaluated in multisetting, international phase III trials after showing promise in earlier trials by slowing disease progression in distinct subgroups of study participants.

Both MetMAb (onartuzumab; Genentech), a monoclonal antibody, and ARQ 197 (tivantinib; ArQule and Daiichi Sankyo), a small-molecule inhibitor, are targeted therapies that block signaling pathways in cancer cells. Specifically, they inhibit c-MET, a cell membrane receptor molecule implicated in both tumor progression and metastasis in several cancers, including NSCLC.

“It’s an oncogenic pathway that drives cancer growth. The goal is to shut this pathway down,” said David Spigel, MD, director of Lung Cancer Research at the Sarah Cannon Research Institute in Nashville, Tennessee, and the principal investigator for the MetMAb trial.

The drugs, which are being tested in late-stage patients who have already received one or two lines of standard therapy, represent a paradigm shift in lung cancer treatment. (Related: MET Inhibitors in Cancer Therapy)

Dr. Alan Sandler

Alan Sandler, MD

“In addition to surgery and radiation, the historical approach to lung cancer is chemotherapy, a broad, nonspecific approach that damages DNA and has accompanying toxicities,” said Alan Sandler, MD, division chief of Hematology and Medical Oncology at Oregon Health & Science University and one of the principal investigators for the tivantinib trial, along with Giorgio Scagliotti, MD, PhD, of the University of Torino in Italy. “The concept of personalized medicine is to develop targeted therapies that inhibit specific pathways in specific tumors. These therapies generally don’t affect bone marrow, do not cause hair loss, and, in general, have more benign side effects.”

In each trial, the drugs are being tested in combination with another targeted cancer treatment, erlotinib (Tarceva; Genentech). Erlotinib is a receptor tyrosine kinase inhibitor that blocks the signaling pathway of the epidermal growth factor receptor (EGFR), a cell surface receptor implicated in cancer cell growth. MET has been implicated in part in erlotinib resistance.

Dr. Reinhard von Roemeling

Reinhard von Roemeling, MD

“In these two trials, the combined therapies work to delay and overcome resistance in tumors that initially respond to the other drug but then develop a resistance to it. Synergistic effects can be strong drivers of efficacy and patient benefit,” said Reinhard von Roemeling, MD, vice president of Clinical Development Oncology at Daiichi Sankyo, Inc, which is sponsoring the tivantinib trial with ArQule, Inc.“Each drug has anticancer properties, and when we combine them there may be at least additive activity. It’s not clear how additive, although there appears to be a benefit in preclinical models,” Spigel noted of the MetMAb/erlotinib combination.

MetMAb Trial

MetMAb is being tested in a randomized, double-blind, phase III study that will assign nearly 500 patients who have already been treated with standard chemotherapy for advanced or metastatic disease into two groups. One group will take MetMAb in combination with erlotinib. The other group will take erlotinib with a placebo.

The study, which began in January 2012, has an estimated completion date of December 2015. The primary outcome measure is overall survival, while secondary endpoints are progression-free survival, overall response rate, and safety.

Based on results in a phase II study with 137 patients, participation in the phase III trial is restricted to patients whose tumors are characterized as either MET diagnostic-positive or expressing high levels of the MET receptor protein on the cell surface. Patients will be classified as MET diagnostic-positive (high MET) or MET diagnostic-negative (low MET) based on the results of tissue studies from a companion diagnostic test that is also part of the phase III study.

In the phase II study, the addition of MetMAb to erlotinib tripled the amount of time people with high-MET tumors lived compared with participants who received erlotinib alone. Median overall survival was 12.6 months for the group receiving MetMAb, compared to 3.8 months for erlotinib alone. With MetMAb, the high-MET population also lived twice as long without their cancer progressing or dying from any cause (2.9 months) compared with the control group (1.5 months). Patients with low-MET tumors, however, had worse outcomes when given MetMAb and erlotinib than when they were given erlotinib alone.

In general, patients with low-MET tumors have a better prognosis, Spigel said, adding that in the MetMAb/erlotinib trial, survival outcomes for patients with high-MET tumors (and a poor prognosis) were raised to the level of the low-MET group treated with erlotinib alone.

Tivantinib Trial

Tivantinib is being tested in a randomized, double-blind, phase III study that assigns nearly 1000 patients with advanced or metastatic nonsquamous lung cancer who have been treated with one or two systemic therapies to one of two groups. One group will take tivantinib with erlotinib; the other will take erlotinib with a placebo. The study began in November 2010 and should be completed in July 2013. The primary outcome measure is overall survival.

“Earlier clinical trials established the role of tyrosine kinase small-molecule inhibitors on the EGFR pathway, and now we’re evaluating the impact of inhibiting two pathways on patients with previously treated nonsquamous NSCLC,” Sandler said. “We know that the oncogene c-Met makes the cancer more likely to be metastatic, to grow and divide, and to be more invasive. What we’re hoping for is that by impacting and inhibiting the c-Met and EGFR pathway, patients will live longer and have a better quality of life.”

Secondary and exploratory objectives of the trial include a measure of progression-free survival and overall survival in molecular subgroups, including patients whose tumors show mutations to EGFR or to KRAS (a gene that plays a role in tissue signaling), overexpression of MET, and overexpression of serum hepatocyte growth factor. All participants will be tested for biomarkers. Tivantinib is also being evaluated for safety.

Based on the results of a smaller phase II study with 167 participants, the current trial is restricted to patients with nonsquamous cell tumors.“When we looked at the data [in the phase II study] on progression-free survival, the tivantinib arm did better than the control arm, at 3.7 months compared with 2.2 months, which is more than a 50% improvement. But when we looked at the nonsquamous patients compared with the control, the results were even more dramatic—4.4 months compared to 2.3 months,” Sandler said. “We are trying to define the population that will respond best to this combination, and histology may be a way to determine that.”

The Need for New Therapies

Both studies are being watched closely because few therapies are available for late-stage lung cancer patients. “Half of patients who have already received one or even two therapies don’t make it to another therapy, and the remaining half have the option of chemotherapy or Tarceva. At that point, with single-agent chemotherapy there is a 10% response rate, and with Tarceva alone, approximately a 5% response rate in unselected patients,” Spigel said.

Dr. Chris Bowden

Chris Bowden, MD

The hope for both drugs is that they will be relevant for large populations of patients with NSCLC, the most common type of lung cancer. “Non–small cell lung cancer represents approximately 85% of all lung cancers and of those, nonsquamous tumors comprise 75%,” Sandler said.

Approximately half of all people with NSCLC have high levels of the MET protein on the surface of their cancer cells, said Chris Bowden, MD, vice president for Product Development in Clinical Oncology at Genentech, a sponsor of the MetMAb trial with Hoffman- LaRoche. He added that overexpression of MET correlates with poor prognosis, making the tumor type “a good candidate” for MET-targeted medicines.

“A lot of great advances recently have affected select groups of patients, as few as 2% to 4% in some cases. The potential here is as high as 50%, and so that would be a big step forward,” Spigel said.

Role of MET in Cancer

MET was first identified in the 1980s when a mutant form was discovered, Bowden said. Further research led to the classification of the gene encoding c-MET as a proto-oncogene, a gene that has the potential to cause cancer if it is mutated or expressed in increased amounts.

Researchers liken the MET receptor to a switch. By attaching to the molecule, the targeted therapies help prevent it from turning on. “MET activation plays key roles in enabling cell movement and invasive growth, as is required during embryonic development and in wound healing in adults, but is also frequently found in cancer,” Bowden said. “The MET protein resides on the cell surface and acts as a receptor for HGF (hepatocyte growth factor). When HGF binds to MET, it sets off a series of signals that tell cells to multiply and spread to other parts of the body.”

Overactive MET signaling has been observed in a range of cancers, including lung, colorectal, breast, gastric, liver, and bladder tumors, and its activity may also partially explain why some cancers worsen after initially responding to certain targeted therapies, Bowden added. “For these cancers, it is believed that MET signaling can bypass the targeted signaling pathways, allowing cells to grow and spread again.”

Molecular Markers and Biomarkers

The sponsors of both trials said they will closely analyze outcomes among patients belonging to molecular subgroups. “Within the overall study population, there are some patients who may benefit more, and being able to determine who gets more treatment benefit is the goal of personalized medicine,” von Roemeling said of the tivantinib trial. “We will analyze results by several biomarkers. Patients who exhibit overexpression of c-MET by IHC (immunohistochemistry) testing may benefit more. Also, patients with a higher c-MET gene copy number may see a larger benefit. By looking at specific molecules and features of tumors, determining who is most likely to benefit from tivantinib and selecting patients accordingly, the goal is to maximize benefits.”

Other molecular markers are being explored in the MetMAb trial, as well as various methods of MET assessment, Spigel said.

Table. MetMAb and Tivantinib Trials

A Study of Onartuzumab (MetMAb) in Combination With Erlotinib (Tarceva) in Patients With MET Diagnostic-Positive Non–Small Cell Lung Cancer Who Have Received Chemotherapy for Advanced or Metastatic Disease A Study of Tivantinib (ARQ 197) Plus Erlotinib (Tarceva) Versus Placebo Plus Erlotinib for the Treatment of Nonsquamous Non– Small Cell Lung Cancer
ClinicalTrials.gov Identifier: NCT01456325. ClinicalTrials.gov Identifier: NCT01244191.
Primary outcome measure: Overall survival. Primary outcome measure: Overall survival.
Secondary outcome measures: Progressionfree survival, with tumor assessments according to Response Evaluation Criteria in Solid Tumors (RECIST); overall response rate; safety. Secondary outcome measures: Progression-free survival in the intent-to-treat population; overall survival in subjects with epidermal growth factor receptor wild type non–small-cell lung cancer.
Study start date: January 2012. Study start date: November 2010.
Estimated completion date: December 2015. Estimated completion date: July 2013.
Estimated enrollment: 480. Estimated enrollment: 988.
Patients: Adults age 18 years or older. Patients: Adults age 18 years or older.
Histologically or cytologically confirmed incurable stage IIIb/IV non–small cell lung cancer tumor. Histologically or cytologically confirmed surgically unresectable locally advanced or metastatic (stage IIIB/IV) nonsquamous non–small-cell lung cancer.
MET diagnostic-positive status tested by immunohistochemistry.
Results of epidermal growth factor receptor– activating mutation testing.
Radiographic evidence of disease.
Measurable disease and documented disease progression following last prior therapy according to Response Evaluation Criteria in Solid Tumors (RECIST).
Prior treatment with at least one platinum-based line of treatment (for stage IIIb/IV) and no more than one additional line of chemotherapy treatment; the last dose of chemotherapy must have been administered ≥21 days prior to day 1.

Availability of tissue sample for diagnostic testing is required.
Have received one or two prior lines of systemic anticancer therapy for advanced or metastatic disease, one of which must be a platinumdoublet therapy. Patients who received only adjuvant treatment will be eligible only if disease progression occurred <6 months after completion of adjuvant therapy. Prior maintenance therapy is allowed and will be considered as the same line of therapy when continued without discontinuation after initiation of a treatment regimen.
Eastern Cooperative Oncology Group performance
status 0-1.
Eastern Cooperative Oncology Group performance
status 0 or 1.
Dosages: Dosages:
Arm A: Onartuzumab (MetMAb), repeating intravenous dose; erlotinib (Tarceva), repeating oral dose. Arm A: Tivantinib (ARQ 197), 720 mg daily (360- mg oral tablets twice a day); erlotinib (Tarceva), 150-mg oral tablets once a day.
Arm B: erlotinib (Tarceva), repeating oral dose; placebo, repeating intravenous dose. Arm B: Tivantinib (ARQ 197) oral placebo tablets given twice a day; erlotinib (Tarceva), 150-mg oral tablets given once a day.
Adverse effects: Edema is one effect that will be expected and monitored closely. Adverse effects: Rash, diarrhea, and fatigue are possible side effects.
Adherence: Compliance with oral therapies. Adherence: Compliance with oral therapies.
Note to oncologists and lung cancer patients: Staining tumors for MET is not standard and must be done in a central laboratory. Note to oncologists and lung cancer patients: In the phase II trial, patients in the placebo arm were allowed to cross over at the time of progression, but they are not permitted to do so in the phase III trial.

Role of Combination Therapy

Sponsors of both trials said they expect to test their respective drugs in combination with other therapies.In addition to the ongoing phase III study comparing erlotinib and onartuzumab with erlotinib alone, a number of trials are ongoing or soon to be initiated in the firstline treatment of NSCLC, gastrointestinal malignancies, glioblastoma multiforme, and breast cancer, Bowden said, adding, “The clinical development for onartuzumab includes combinations with approved chemotherapy, antibodies, and small-molecule TKIs (tyrosine kinase inhibitors). Combination trials of onartuzumab with other investigational agents are planned as well.”

von Roemeling also indicated that other combinations will be explored. “There may be other ways to make the benefit larger. We need to select targeted therapies and figure out how they will work together to support each other. The combinations might differ for different cancer types,” he said, adding, “If we can give an active drug at earlier stages of the disease, there may also be a better chance to see a bigger benefit. This is the hope.”

Participant Eligibility

Patients with nonsquamous histology are eligible for the tivantinib trial, while in the MetMAb trial all histologies are eligible, but patients must be tested for c-MET expression and have overexpression to take part, Sandler said.

“From a practical viewpoint there is no way to clinically examine a patient and say he or she is better suited for a particular therapy,” Spigel said, adding that if the trial results are positive, oncologists would use the same eligibility criteria to select patients for treatment.


Tracey Regan is a freelance medical writer.


Oncology Fellows aims to provide timely and practical information that is geared toward fellows from a professional and lifestyle standpoint—from opportunities that await them after the conclusion of their fellowship training, to information on what their colleagues and peers are doing and thinking right now.

This issue contains articles on:

  • When Patients Refuse Treatment for Their Cancer
  • (Never) A Typical Day in the Life of a Pediatric Hematologist/Oncologist
  • Using QOPI to Improve Quality Within Your Fellowship Program
  • Providing Oncology Services in Impoverished Countries


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.

Oncology Fellows aims to provide timely and practical information that is geared toward fellows from a professional and lifestyle standpoint—from opportunities that await them after the conclusion of their fellowship training, to information on what their colleagues and peers are doing and thinking right now.

This issue contains articles on:

  • Finding Time: A Day in the Life of an Academic Oncologist
  • Balancing Clinical Education with Scientific Research
  • Medical Writing Basics: Cringe-Worthy Errors and How to Avoid Them
  • The Art of Analogies in the Clinic


This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.



Bone remodeling is the constant process of removing and rebuilding bone tissue and driven by osteoblasts and osteoclasts. In a healthy person, the communication and binding (between RANK and RANK-L) activity is regulated to balance bone formation and resorption. In cancer patients, tumors can often stimulate osteoblasts to overexpress RANK-L causing excessive osteoclast activity. The result is rapid deterioration of bone tissue. Denosumab inhibits RANK-L communication and returns osteoclast resorption to a normal level.



The epidermal growth factor receptor (EGFR) is often activated in several types of cancer leading to abnormal cell reproduction. Cetuximab was developed to block EGFR in order to stop tumor growth and cause it to regress. Cetuximab prevents EGFR from receiving the necessary survival signal and blocks angiogenesis at the source (tumor cells). Cetuximab also binds onto natural killer cells in the bloodsream, direct them to the cancer cells and block DNA repair of EGFR. The synergy of all functions of cetuximab allows the drug to be effective.

Maurie Markman, MD

Maurie Markman, MD

Editor-in-Chief of OncologyLive

Senior vice president for Clinical Affairs and National Director for Medical Oncology

Cancer Treatment Centers of America, Eastern Regional Medical Center

The presence or absence of lymph node involvement has long been recognized as a critically relevant prognostic factor in solid tumor oncology. While local and regional lymph nodes are no longer viewed as serving a “barrier function,” the documented presence of cancer within these anatomical areas provides important data regarding the statistical likelihood that a particular malignancy has spread to distant sites.

At the same time, it is also well understood that individual cancers may have metastasized at the time of diagnosis, even without the documented presence of malignant cells within local nodes. This well-established observation raises the provocative question of whether the disease involved nodes prior to further dissemination or, conversely, whether the finding of “negative nodes” is often simply an artifact of the inherent insensitivity of existing diagnostic tools.

The question is highly clinically relevant in colorectal cancer, since adjuvant chemotherapy is known to improve both progression-free and overall survival in patients with lymph node–positive nonmetastatic disease. Thus, patients labeled as having “node-negative” disease, when the cancer is actually more advanced, will be denied the opportunity to receive systemic antineoplastic therapy at a point in the natural history of the malignancy where the ultimate survival outcome may be most favorably impacted by its use.

This issue was recently addressed in an interesting analysis involving a group of patients with “node-negative” colorectal cancer. Hyslop et al noted that approximately one-fourth of patients with negative-node status experience a recurrence of disease and set out to explore the relationship between molecular tumor burden in lymph nodes and outcomes (Clin Cancer Res. 2011;17(10):3293-3303).

In this particular research effort, the “noncancer bearing” lymph nodes were examined for the presence of guanylyl cyclase 2C (GUCY2C), a family of proteins that synthesizes cyclic guanosine monophosphate. GUCY2C is a previously documented sensitive marker of the presence of malignant colorectal cancer, established through the technique of reverse transcriptase polymerase chain reaction (PCR).

The study included 291 patients (55% male), with 84% having >12 nodes removed at the time of surgery. The tumor grade was well or moderately differentiated in 85% of cases, and 15% were classified either as poorly differentiated or the grade was unknown. Lymphovascular invasion was present in 20% of the population.

Based on the laboratory findings, the patients were divided into 3 groups with a predicted quantitative tumor burden. The low, intermediate, and high tumor burden populations comprised 60%, 31%, and 9% of the total, respectively. Of considerable interest, the recurrence rates documented within these 3 groups (median follow-up of 2 years) was found to be 2.3%, 33.3%, and 68%, respectively. Not surprisingly, the 3 patient populations were also shown to experience different overall survival rates consistent with their relative observed risk of recurrence.

Finally, the investigators concluded that in this analysis the molecular tumor burden was an independent predictor of outcome.It is important to emphasize that the results in this analysis will need to be confirmed by other investigators evaluating independent data sets. However, assuming that such studies reveal similar outcomes, it would be reasonable to suggest that this type of quantitative molecular analysis may play an important role in routine management of colorectal cancer patients discovered on initial histopathology review to have no evidence of malignant involvement of local or regional lymph nodes. In addition to providing refined prognostic data for a specific patient, the results of this study strongly support the conclusion that this type of molecular analysis of lymph node involvement is associated with a far more accurate assessment of the population of individuals who would be predicted to benefit from adjuvant chemotherapy following definitive surgical staging and tumor removal.

Finally, it is also reasonable to speculate that future research efforts will be successful in defining specific molecular markers in other malignancies that may more definitively separate patient populations with and without local/regional nodal involvement, permitting both more meaningful prognostic data regarding the ultimate risk of recurrence and—of greatest importance— predictive information that can be used by clinicians to select a management program to optimize outcome.

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Alex A. Adjei, MD, PhD, Professor and Chair, Department of Medicine, Katherine Anne Gioia Chair in Cancer Medicine, Senior Vice President, Clinical Research, Roswell Park Cancer Institute, discusses the evolution of cancer therapeutics.

Adjei discusses the old and simplistic approach to fighting cancer vs. the new method. Previously, chemotherapy was thought to be the best way to fight cancer as it targeted tumor DNA. Newer targeted antibodies and angiogenesis inhibitors have becoming available and also agents that direct attack aberrations within the tumor. However, Adjei believes that the best and most stable approach may be the microenvironment rather than the tumor itself.

Clinical Pearls:



  • Historically tried chemotherapy and bone marrow transplants
  • Immune system important, had success with antibodies and angiogenesis
  • Learning now, not just the tumor cells but also the microenvironment
  • Success targeting molecular abnormalities in the tumor
  • Microenvironment may be more stable than tumor


Dr. Belani

Chandra P. Belani, MD

In the era of personalized medicine, paradigms for treating non-small cell lung cancer (NSCLC) are evolving. With the discovery of mutation drivers for NSCLC—including EGFR, KRAS, and EMLA 4-ALK—targeted therapies directed to those mutations are beginning to make a difference. While more work needs to be done to improve outcomes, advances thus far were discussed by Chandra P. Belani, MD, deputy director of the Penn State Hershey Cancer Institute in Pittsburgh, Pennsylvania.

Lung cancer is still the leading cause of cancer deaths in 2011. NSCLC currently accounts for about 87% of all cases and small cell lung cancer (SCLC) for about 13%. Adjuvant chemotherapy is now the standard of care for early resectable (<4 cm) NSCLC, Belani said. Adjuvant chemotherapy has improved overall survival (OS) from 4.1% to 15%.

Cisplatin/vinorelbine has been the most common doublet used in all clinical trials, but up to 50% of patients are not able to get the recommended 4 cycles, and there is a clear need to reduce toxicity, improve dose delivery, and improve compliance. An adjuvant therapy trial by Winton et al compared standard cisplatin/ vinorelbine versus cisplatin/pemetrexed. The feasibility of cisplatin/pemetrexed compared favorably with that of cisplatin/ vinorelbine, with fewer toxicities and fewer dose delays. This regimen has been incorporated into the ECOG1505 trial for nonsquamous NSCLC, which will compare 1 of 4 chemotherapy regimens with no bevacizumab versus chemotherapy plus bevacizumab in the adjuvant setting.

“Maintenance therapy for NSCLC has become the new paradigm for about 50% of physicians, based on available data,” Belani continued. The other 50% are skeptics, he added. “The criticism [of maintenance therapy] is that about 40% of patients are unable to receive it. If we are going to change the paradigm from acute disease to chronic disease in stage IV NSCLC, we need to give less toxic maintenance therapy,” he stated.

Two strategies have been studied: switch maintenance therapy and continuation maintenance therapy. Switch maintenance with pemetrexed following initial therapy with a platinumcontaining regimen improves survival in all patients. Switch maintenance with erlotinib also improves overall survival. However, only patients with good performance status are candidates for maintenance therapy.

Continuation maintenance therapy was studied in the PARAMOUNT trial, in which patients with stage IV NSCLC who responded to front-line cisplatin/ pemetrexed were randomized to continuation pemetrexed or placebo. Progression-free survival (PFS) was improved with pemetrexed continuation maintenance; OS data have not yet been presented.

“Pemetrexed continuous maintenance has had similar results to switch maintenance therapy, and we await the overall survival data,” Belani said.

ECOG 5508 is accruing 1282 patients with stage IV nonsquamous NSCLC who respond to 4 cycles of carboplatin/paclitaxel/bevacizumab and randomizing them to pemetrexed, bevacizumab, or the combination of pemetrexed/ bevacizumab, following carboplatin, paclitaxel, and bevacizumab therapy. “The next step is to personalize maintenance therapy using molecular selection. Patients with EGFR mutations can get erlotinib,” Belani continued.Research by the Lung Cancer Mutation Consortium looked at 10 driver mutations in patients with stage IV adenocarcinoma. Fifty-four percent of patients had 1 or more of these mutations; the most common ones were KRAS (22%), EGFR (17%), and EMLA 4-ALK (7%).

“These mutations were almost all mutually exclusive, since 97% of patients had only one of them. This work just scratches the surface, because lung cancer is a heterogeneous disease,” Belani explained.

The European Randomized Trial of Tarceva vs Chemotherapy (EURTAC) trial compared front-line chemotherapy with a platinum-based doublet versus erlotinib in 174 patients with EGFR mutations (EGFR+). Erlotinib was superior for PFS, and all subsets of patients with EGFR+ status benefited from erlotinib. There was no improvement in OS, but Belani said that this was attributable to the fact that patients in the chemotherapy arm received second-line erlotinib.

“The new treatment paradigm is to test patients with NSCLC adenocarcinoma for EGFR-mutated status and treat with erlotinib if EGFR mutations are present,” he said.

Newer targeted therapies are being studied. Crizotinib (an ALK and MET inhibitor) is approved for ALK-positive NSCLC, representing a second targeted approach. Afatinib (HER-1 and -2 inhibitor) plus cetuximab shows promise in patients with EGFR+ status who develop resistance to EGFR tyrosine kinase inhibitors. This drug is not yet approved.

There is a long list of other novel personalized agents in earlier phases of development, including MetMAb, ARQ 197, Hsp90 inhibitors, talactoferrin, farletuzumab, and hedgehog inhibitors.

Robert Pirker, MD

Robert Pirker, MD

Investigators reported that high tumor epidermal growth factor receptor (EGFR) expression is a predictive biomarker that defines patients with advanced non–small cell lung cancer (NSCLC) who are most likely to derive a survival benefit from the addition of cetuximab to platinum-based, first-line chemotherapy. “To our knowledge, this is the first study to show that tumor EGFR expression level is associated with survival benefit for a targeted therapy given concurrently with firstline chemotherapy in patients with advanced NSCLC,” said Robert Pirker, MD, with the Medical University of Vienna in Austria, and associates.

For their study, the group examined the association of tumor EGFR expression level with clinical outcome in patients enrolled in the phase III First- Line Erbitux in Lung Cancer (FLEX) study.

They pointed out that attention has been increasingly focused on the identification of predictive tumor biomarkers in order to improve the benefit-risk ratio of anticancer treatments. Ultimately, these biomarkers can help refine the selection of patients who are likely to benefit most from treatment.

The FLEX study had already shown that patients with EGFR-expressing, advanced NSCLC who had been randomized to the EGFR inhibitor cetuximab on top of chemotherapy involving cisplatin and vinorelbine had an overall survival (OS) superior to patients assigned to chemotherapy alone (hazard ratio [HR], 0.871; 95% CI 0.762-0.996; P =.044).

In the present analysis, the researchers used an immunohistochemistry scoring system in which a score <200 indicated low EGFR expression while a score ≥200 denoted high EGFR expression.

High EGFR expression was scored for 345 (31%) of 1121 patients in whom tumor EGFR expression data were available and low EGFR expression for 776 (69%) patients.

Median OS was longer in the high EGFR expression group in the cetuximab-pluschemotherapy arm compared with the chemotherapy-alone arm (median of 12.0 mo [95% CI, 10.2-15.2] vs 9.6 mo [CI, 7.6-10.6]; HR, 0.73; CI, 0.58-0.93; P =.011).

The improved OS in the cetuximabplus- chemotherapy, high-EGFR group was achieved without an appreciable increase in side effects.

There was no OS benefit in the low- EGFR-expression group (a median of 9.8 mo [CI, 8.9-12.2] vs 10.3 mo [CI, 9.2-11.5]; HR, 0.99; CI, 0.84-1.16; P =.88).

Extended OS in the chemotherapyplus- cetuximab group was observed for patients with high EGFR expression in all major NSCLC histological subgroups that were examined.

The authors said that the clinically meaningful improvements in survival and benefit-risk ratio in patients with high tumor EGFR expression in the diverse population of patients enrolled in the FLEX study provide a strong rationale for the use of EGFR expression in clinical practice to identify which patients with advanced NSCLC will benefit from the addition of cetuximab to first-line chemotherapy.

Oliver Sartor

Oliver Sartor, MD
Medical Director
C.E. and Bernadine Laborde Professor of Cancer Research
Professor, Department of Medicine
Department of Urology
Tulane Cancer Center
New Orleans, LA

Men with prostate cancer now have an array of treatments, which was not the case a decade ago. The radiopharmaceutical radium-223 will probably be approved by the FDA for metastatic castration-resistant prostate cancer (CRPC). That likely approval is based on the overwhelmingly positive findings in the Alpharadin in the Treatment of Patients With Symptomatic Prostate Cancer (ALSYMPCA) trial. Another experimental agent, XL-184 (cabozantinib), has shown encouraging results in disease stabilization in men with metastatic CRPC and significant effects on bone scans. A third agent undergoing clinical trials is a neutraceutical, pomegranate extract, which appears to slow prostate-specific antigen (PSA) doubling time in men with rising PSA levels, but it is not clear if that will translate to improved outcomes. These prostate cancer treatments were discussed by different speakers at the 2011 Chemotherapy Foundation Symposium.

“Radium-223 promises to become a new standard of treatment for men with CRPC who have bone metastasis,” said Oliver Sartor, MD, director of the Tulane Cancer Center in New Orleans, Louisiana. This radiopharmaceutical is not only effective in improving survival, but its safety profile is at least as benign as placebo, according to results of the phase III, multicenter, randomized, placebo-controlled ALSYMPCA trial. Results of this trial were reported at the September 2011 meeting of the European Multidisciplinary Cancer Congress in Stockholm, Sweden.

The study included 922 patients with CRPC and at least 2 bone metastases and no known visceral metastasis who were randomized to radium-223 or placebo. At a pre-planned interim analysis, radium-223 had a clear survival benefit. Median overall survival was 14 months for radium-223 versus 11.2 months for placebo. The study was halted, and men in the placebo group were allowed to cross over to radium-223. Radium-223 also reduced the risk of time to first skeletal-related event by 39%. All subgroups benefited from this approach, including those who received prior docetaxel treatment. Amazingly, the placebo-treated patients had more side effects and a higher number of patients who discontinued treatment.

“We now have a variety of agents [for CRPC] that prolong survival. In the future we will need to learn how to combine them and sequence them,” Sartor said.

Dr. Smith

David C. Smith, MD

XL-184 (cabozantinib) is a dual inhibitor of mesenchymal epithelial transition factor (MET), a proto-oncogenic receptor, and vascular endothelial growth factor receptor 2. Theoretically, cabozantinib may block osteolytic lesions, said David C. Smith, MD, professor in the Department of Urology at the University of Michigan, Ann Arbor.A phase II, randomized, discontinuation trial of cabozantinib versus placebo was conducted in 171 men with metastatic CRPC with measurable disease and evidence of disease progression. Median age was 68 years; 54% had bone pain, and 42% were taking narcotics for their pain. About 40% were pretreated with docetaxel. Results were good, so randomization to placebo was discontinued.

After 12 weeks of treatment, 68% had disease control (complete response, partial response, and stable disease). “Almost every patient had some evidence of activity [of the drug] on bone scan,” Smith said.

The major toxicities were fatigue (63%), thrombocytopenia (8%), and gastrointestinal perforation (1%). Fifty percent of patients required dose reductions. No significant effect was observed in patients who received prior docetaxel.

The moderator of the session, William K. Oh, MD, chief of the Division of Hematology and Medical Oncology at the Mount Sinai School of Medicine in New York City, said that both radium-223 and cabozantinib target the microenvironment. “Radium-223 will be transformative, because of its efficacy and favorable toxicity. Cabozantinib should also be transformative. It had a remarkable effect on bone scans, but we need to see more studies,” Oh stated.

A randomized, phase II study of 2 different dose levels of pomegranate extract showed that the extract, which is more potent than pomegranate juice, increased the PSA doubling time by about 6.6 months, from 11.9 months at baseline to 18.5 months after 6 months of treatment (P <.001). No dose response was observed. The study included 104 patients with a rising PSA without evidence of metastasis; at baseline, median age was 72, median Gleason score was 6-7 (44% were Three-quarters of patients with a PSA doubling time <3 months moved to a higher doubling time after taking pomegranate extract.

“The study met its primary endpoint but we did not see a dose response. Pomegranate extract may play a role in the treatment of older men who are looking for alternative therapies. I don’t recommend it to my patients, but if a patient of mine wants to take it and defer hormonal therapy, I tell him that the extract is safe,” stated lead author Michael A. Carducci, MD, professor of Urologic Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland.

Debu Tripathy

Debu Tripathy, MD
Co-Leader, Women’s Cancer Program
Professor of Medicine
Priscilla and Art Ulene Chair In Women’s Cancer
USC/Norris Comprehensive Cancer Center
University of Southern California
Los Angeles, CA

Although the use of tumor markers to evaluate patients with breast cancer is well established, the nuances involved in such testing are growing, along with the emergence of novel assays and fresh research findings.

Debu Tripathy, MD, has made novel therapeutics in breast cancer the focus of his clinical research. He is delving into biomarkers that predict sensitivity and resistance to therapeutics, as well as growth factor receptor pathways that might be promising candidates for targeted therapies.

In this interview, Tripathy discusses practical implications of biomarker research.

How do you use gene profiling in clinical practice?

The primary area where gene profiling such as the Oncotype DX score helps is in patients who have estrogen receptor (ER)–positive or progesterone receptor (PR)–positive and HER2/neu–negative early-stage cancers.

It is primarily used in patients with negative nodes because in those patients the benefit of chemotherapy on the average is very small. Those with a high or intermediate-to-high recurrence score—perhaps a little more than a quarter of the patients—derive almost all of the benefit of chemotherapy, and most of the other patients do not.

More recently, there have been some studies to suggest that maybe in patients with positive nodes, even though the risk of recurrence is higher, the recurrence score may still tell us who is likely to benefit from chemotherapy. There may even be patients with positive nodes who really don’t benefit much from chemotherapy. The studies supporting that are not as robust, so that area is a little more controversial.

In fact, there’s an ongoing prospective study right now for patients with 1 to 3 nodes and hormone receptor–positive, HER2/neu–negative tumors to use the Oncotype assay and randomize those who have a score of less than 25 to hormonal therapy alone versus chemotherapy followed by hormonal therapy. In that study, patients with a recurrence score greater than 25 automatically get chemotherapy.

How do you use biomarkers when tumors recur?

When patients have a local or distant recurrence, the standard now is to do a biopsy if feasible and send these biomarker assays, because the markers can change.

For estrogen and progesterone receptors, they may change up to 10% to 20% of the time. For HER2, it’s probably less, maybe in the 5% to 10% range, but it is important in decision making. It may affect the therapy options that you would have in recurrent disease.

Many times, biomarkers from the original tumor that may have been determined years earlier are used, and we now know that sometimes those can change and affect tumor biology.

What role does tumor heterogeneity play?

Tumor heterogeneity is becoming an increasingly recognized phenomenon, and it’s very difficult to incorporate that into decision making. As the tumors grow, different cells within the tumor may start to acquire or select for different genetic changes, and then a certain part of the tumor may grow, expressing a different set of proteins than another part of the tumor. If you’re giving the patient a drug that might select out one of these subclones, you end up getting differences in markers across the tumor due to selective pressures.Now we’re seeing that when we perform estrogen, progesterone receptor, or HER2 analysis, we may find that the whole tumor doesn’t behave uniformly.

It’s still a controversial notion, but we do know that tumor heterogeneity exists, and now the problem is how do we deal with it, how do we use that information? Certainly, it is not something we’re routinely using. If you look at all the guidelines for how a pathologist should score ER, PR, or HER2, it’s by counting a lot of cells and then averaging them. There really isn’t accounting for these sorts of patches over larger segments of tumor. What do you do if you have just a small patch of HER2– positive cells and the rest of the tumor is HER2–negative? Should those patients get trastuzumab?

These are questions that we simply cannot answer at the moment. So tumor heterogeneity is an evolving area. We think it’s a very interesting window of opportunity to learn about mechanisms of resistance in the research setting. But for clinical decision making, it is really bedeviling us.

Dr. Silver

Daniel P. Silver, MD, PhD

PARP inhibitors, which are a group of pharmacologic inhibitors of the enzyme poly ADP ribose polymerase (PARP), are gaining ground as a potential strategy for treating triple-negative breast cancer. The data are more promising in hereditary triple-negative breast cancer than for sporadic triple-negative breast cancer, but more research is needed, according to a presentation at the Chemotherapy Foundation Symposium held in New York City.

“It is still in the early days [of studying PARP inhibitors]. We still need results of clinical trials with veliparib, MK4827, and AGO14699, but research thus far suggests that PARP inhibition is likely to be active in hereditary triple-negative breast cancer,” stated Daniel P. Silver, MD, PhD, medical oncologist at the Breast Cancer Treatment Center at the Dana-Farber Cancer Institute, Boston, Massachusetts. However, Silver said, PARP inhibition is “not likely to be active as monotherapy in a large percentage of heavily pretreated sporadic triple-negative breast cancer, although biomarkers may identify a small subset that can benefit.”

PARP inhibition targets DNA repair in breast cancer by acting on the base excision repair DNA pathway, which acts in concert with the homologous recombination DNA repair pathway that requires BRCA1 and BRCA2, Silver explained. This provides the rationale for studying PARP inhibition in hereditary triple-negative breast cancer. BRCA1 and BRCA2 are human genes that belong to a class of genes known as tumor suppressors. Mutation of these genes has been linked to hereditary breast and ovarian cancer.

Early studies of PARP inhibitors in hereditary triple-negative breast cancer showed clinical benefit in carriers of BRCA1 and BRCA2. A recent phase II study of the PARP inhibitor olaparib in both sporadic and hereditary triple-negative metastatic breast cancer patients (Tutt A et al. Lancet. 2010;376(9737):235-244) showed the best responses in BRCA1 and BRCA2 carriers; 11 of 13 hereditary triplenegative patients had an overall response rate of 54%. “In this study, higher doses were better,” Silver commented.

“A number of investigators have found that sporadic and hereditary triple-negative breast cancer tumors share several characteristics, and they have posited that a deep relationship exists between these tumors. Sporadic triple-negative cancers appear to have a ‘BRCA-ness,’ meaning that something is wrong with the BRCA pathway,” Silver explained.

PARP inhibitors are also being studied in sporadic triple-negative breast cancer. A phase II trial of olaparib in advanced ovarian cancer and triple-negative breast cancer found no objective response in 16 sporadic cases, and that arm of the study was closed (Gelmon K et al. Lancet Oncology. 2011;12(9):852-861). Looking at a waterfall plot, which shows tumor shrinkage (not objective response rates), 63% of patients with BRCA1 or BRCA2 showed some tumor shrinkage and stable disease for more than 8 weeks, while only 13% of sporadic tumors had any degree of tumor shrinkage.

“Clearly, more large trials are needed, but it is unlikely that a proportion of metastatic, heavily pretreated sporadic triple-negative cancers will respond to PARP inhibitor monotherapy. It is entirely possible that there may be small subsets of patients identified by biomarkers that might respond,” Silver said.Combinations of PARP inhibitors with chemotherapy are being studied as well. It appears that PARP inhibition may potentiate other chemotherapies, such as carboplatin, cisplatin, cyclophosphamide, and irinotecan, Silver commented.

Unexplored issues include the optimal rational combinations of therapy with PARP inhibitors, which are the best of these agents to combine with other therapies, timing, doses, and whether PARP inhibitors can act as radiosensitizers. Chemoprevention in carriers of BRCA1 and BRCA2 is an attractive option, but the safety of this approach needs to be established. PARP inhibitors in combination with chemotherapy or as part of other approaches may be useful in postneoadjuvant therapy for triple-negative breast cancer patients who failed to achieve good response and are otherwise destined for poor outcomes.

Dr. Petrylak

Daniel P. Petrylak, MD
Professor of Medicine, Co-Leader, Prostate Cancer
Program Director, Genitourinary Oncology Section, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY

The options for treating patients with prostate cancer are mushrooming, presenting fresh questions for clinicians seeking to select and combine therapies for the best possible outcomes.

In April 2011, the FDA approved Zytiga (abiraterone acetate), an oral CYP17 inhibitor, for use in combination with prednisone in patients with metastatic castration-resistant prostate cancer who have received prior docetaxel therapy.

In recent months, positive trial data have been reported about Alpharadin (radium-223 chloride), which emits alpha radiation targeted to bone metastases, and MDV3100, an androgen receptor signaling inhibitor.

These developments come on top of the 2010 approvals of Jevtana (cabazitaxel), an injectable microtubule inhibitor, and Provenge (sipuleucel-T), a vaccine custom-made for each patient. In an interview, Daniel P. Petrylak, MD, discussed key points in evaluating therapies.

What are the challenges facing clinicians?

It’s a very difficult issue. We have some drugs that are approved in very, very similar clinical niches. For example, there is cabazitaxel as well as abiraterone, and now MDV3100, which will probably be approved as therapy post-docetaxel, so there are 3 drugs in the space. Then there is Alpharadin, which will probably be approved for patients ineligible for docetaxel, as well as those patients who have failed docetaxel. And, if you consider the fact that you can administer Provenge to patients who fail docetaxel, that’s 5 different agents.

How do we sequence them? We don’t understand the biology as well as we should. We need good tests to tell us which drug or treatment is the best one to use in a given situation. Right now, it’s a bit of guesswork. If a patient is rapidly progressive, one tends to go toward chemotherapy, although there’s really no evidence to use that at this particular point. That’s just basically what a lot of clinicians are accustomed to using. If you’ve had chemotherapy and you’ve tolerated it poorly, one would tend to go to some of the other hormonal agents such as abiraterone or MDV3100.

Is it frustrating to have new tools but many questions?

I’m happy that we have all these drugs. If you look back to a review that I wrote with Alan Yagoda in 1993, we were labeled as being nihilist because we said nothing worked at that point. We went from that to Taxotere [docetaxel] in 2004. Our study supported the approval of that drug for castrationresistant disease. So that’s a big leap at that point. In an 11-year period, the field changed. And then for 7 years it’s been quiescent and now we’ve had this explosion of new drugs.

So I’m really happy for the patients. It’s up to us to figure out how to use these drugs properly, and I think I have good confidence that we’ll be able to do that.

stephane oudard

Stéphane Oudard, MD

Treatment with denosumab achieved delay in the onset of bone metastasis in men with hormoneresistant prostate cancer compared with placebo in the first large-scale clinical trial to demonstrate this effect.

“Up to 90% of men with hormoneresistant prostate cancer will develop bone metastases, suggesting that the cancer is entering the terminal phase,” said Stéphane Oudard, MD, of Georges Pompidou Hospital in Paris, France. “Currently, there is a gap in the treatment plan for these patients who have not yet developed bone metastases. Being able to delay this turning point is very significant. We have shown that the use of denosumab in patients with hormone-resistant prostate cancer can impede the onset of bone metastases by just over 4 months.”

Denosumab is a RANK ligand (RANKL) inhibitor, which prevents the formation of osteoclasts (ie, cells involved in bone destruction). The phase III international, double-blind, placebo-controlled trial randomized 1432 men with hormone-resistant prostate cancer in a 1:1 ratio to receive denosumab 120 mg via subcutaneous injection every 4 weeks or placebo injections. All patients took calcium and vitamin D supplements. As of July 2010, more than 660 patients developed bone metastases or died, and the trial was stopped and unblinded.

The primary end point was bone metastasis–free survival; secondary endpoints were time to development of first bone metastasis and overall survival. The median bone metastasis-free survival was 25.2 months for placebo versus 29.5 months for denosumab, which represents a 15% risk reduction (P = .028). The effect of denosumab in delaying bone metastasis was observed across all subgroups, including age, geographical region, race, Gleason score, and prostate-specific antigen (PSA) stratum.

Denosumab also resulted in fewer skeletal-related events (SREs): 15% for placebo versus 10% for denosumab, representing a 33% reduction in risk of SREs (P = .01). Most adverse events were similar in both groups, with the exception of osteonecrosis of the jaw, which occurred in 5% of denosumab-treated patients versus 0% of placebo-treated patients. Oudard pointed out that patients received about 20 cycles of denosumab.

“We can conclude that no matter what the patient characteristics are— either a high PSA level or a short PSA doubling time—denosumab can delay the appearance of bone metastasis,” said Oudard. “In a condition where there is currently no effective treatment, this is a highly significant finding.”

Joaquim Belmunt, MD, of Hospital del Mar in Barcelona, Spain, said, “Denosumab, being the first agent to delay the onset of bone metastasis in castrate-resistant prostate cancer, represents a paradigm shift in our beliefs about the limited efficacy of the presently available antimetastatic strategies. The way this activity will translate into survival benefit will require future investigation.”

Dr. William G. Wierda

William G. Wierda, MD, PhD
Associate Professor
Medicine and Internist
Department of Leukemia
The University of Texas
MD Anderson Cancer Center
Houston, TX

Genetic markers are becoming a more integral part of diagnosing cancer and determining which patients will encounter more aggressive forms of their disease. For patients with leukemia, recently approved diagnostic tests may revolutionize the way their treating physicians evaluate their disease.

In October, the FDA approved the Vysis EGR1 fluorescence in situ hybridization (FISH) Probe Kit for detecting a chromosomal deletion in bone marrow that usually is associated with a poor prognosis for patients with acute myeloid leukemia.

It was the second new in vitro diagnostic test for leukemia that the FDA approved this year. In August, the agency approved the Vysis FISH Probe Kit for patients with chronic lymphocytic leukemia (CLL). The kit includes a panel of 5 individual FISH probes intended to detect deletion of the LSI TP53, LSI ATM, andLSI D13S319 probe targets and gain of the D12Z3 sequence in peripheral blood specimens from untreated patients with B-cell CLL.

Abbott Molecular, which developed the tests, said the assays are intended to help clinicians determine disease prognosis.

“When patients are given these tests, there are things that we can do differently in terms of treatment,” said William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

Wierda works most closely with patients who have CLL. For these patients, Wierda said that performing a FISH analysis allows him to detect deletions of the 17p, 11q, and 13q chromosomes and trisomy of chromosome 12. All of these deletions and mutations have been shown to predict poorer outcomes for patientswith CLL.

For patients who have the 11q deletion, Weirda said he might use combination therapies such as fludarabine, cyclophosphamide, and rituximab (FCR) along with an alkylating agent.

In the case of patients with a chromosome 17p deletion, Wierda said that effective treatment options are very limited or nonexistent. For those patients, Wierda said the diagnostic tests can be good predictors of who would be an appropriate candidate for clinical trials of new therapies.

While these diagnostic tests are helpful to patients, Wierda said he hopes the detection of chromosomal abnormalities and other biomarkers eventually will be used to develop targeted therapies that help patients with these very specific mutations.

Dr. Jerald P. Radich

Jerald P. Radich, MD

Several molecular markers for acute myelocytic leukemia (AML) are now used at top-tier cancer centers for prediction, treatment selection, and monitoring response.

But there is room for progress and more research is needed to identify markers beyond simple cytogenetics, said Jerald P. Radich, MD, in the Division of Cancer Research at the Fred Hutchinson Cancer Research Center in Seattle, Washington. Radich spoke at the National Comprehensive Cancer Network’s 6th Annual Congress on Hematologic Malignancies in New York, September 9-10.

Conventional prognostic factors include age, performance status, and cytogenetics. In AML, as people get older they accumulate more cytogenetic risk factors. In clinical practice, 3 different cytogenetic markers are used at Fred Hutchinson and other research centers: Flt3-ITD, NPM1, and CEBPA mutations. The presence of Flt3-ITD predicts increased rates of relapse and lower overall survival rates (ie, poor progno selecsis), while NPM1 and CEBPA mutations predict improved prognosis. There can be overlap of these markers in a given AML patient, Radich explained.

In good-risk patients, the presence of C-kit mutations (occurring in 20% to 50% of AML) downgrades risk status to intermediate risk, with a 4-year survival of 40%, he said. In patients with intermediate risk AML and normal karyotypes, about 84% will have mutations; about 50% will have NPM1, about 31% will have Flt3-ITD, and these can overlap. About 14% of patients will have CEBPA mutations. The presence of all 3 mutations predicts improved outcomes.

Radich said that a further refinement in predicting clinical course is quantifying the amount of Flt3-ITD present; patients with high amounts of this mutation will have worse outcomes. “We think it is important to identify the presence of Flt3-IDT and to measure the amount that is present,” he said.

Patients with NPM1 mutations have a better clinical course, and those with Flt3-ITD wild-type and NPM1 mutations fare the best, Radich said. “This drives them from intermediate risk to improved risk,” he commented. Poor-risk patients are those with deletions of 5q and 7. Patients with 2 or more monosomy karyotypes have a poor prognosis.

The presence of minimal residual disease (MRD) predicts relapse, even in a patient with complete response (CR) to induction and/or consolidation chemotherapy. Quantification of MRD defines the level of risk, Radich said. Molecular assays for MRD allow selection of therapy, he added. Flow cytometry should be used to measure MRD, because “it is exquisitely sensitive to phenotype,” he said.

MRD pretransplant also predicts outcome. Posttransplant, MRD-negative patients have a good prognosis, while those who are MRD-positive have a poor prognosis. “Just because you identify MRD early does not mean you can improve outcome,” Radich told attendees.

The field is moving toward use of cytogenetics and molecular testing for risk stratification of patients enrolled in clinical trials. “Using this testing up front allows you to choose the appropriate regimen 48 hours later,” he said. A major problem is lack of funding for this research.

He cited the following areas for improvement: the need for better prognostic and diagnostic markers; the ability to identify a priori the 15% of AML patients who will be nonresponders to conventional chemotherapy; and a method for figuring out how to change therapy according to development of new clones as the disease progresses.

Dr. Heather Wakelee

Heather Wakelee, MD

Assistant Professor, Oncology
Member, Stanford Cancer Institute
Stanford University School of Medicine
Stanford, CA

Since the mid-1990s, researchers have studied whether adjuvant chemotherapy for patients with non-small cell lung cancer (NSCLC) provides any added survival benefit. Initial studies appeared to find that adjuvant therapy did not provide any significant benefit in lung cancer patients, yet further studies have seemed to confirm that additional therapy might be helpful in certain patient populations.

Studies are under way to find predictive markers that could determine which patients with NSCLC are best suited for adjuvant therapy.

“Most of [the markers] have to do with DNA repair enzymes,” said Heather Wakelee, MD, during a presentation at the 12th International Lung Cancer Congress in Carlsbad, California, in August. “If they’re high, the tumor is able to repair any DNA damage and is therefore resistant to the chemotherapy.”

For example, Wakelee said that patients with higher concentrations of ERCC1, a DNA repair protein, tend not to benefit from platinum treatment as much as patients whose protein levels are low. A retrospective trial showed that patients did benefit from this treatment, but Wakelee said she would like to see a prospective study before recommending this treatment for her patients.

Adjuvant therapy trials that have studied the delivery of 4 cycles of cisplatin- based treatment after surgery showed a 5% to 10% improvement in survival among patients 65 years and older. However, Wakelee has concerns about which patients within that older population would benefit from treatment.

“I think we need to be very aware of the toxicities of the chemotherapy,” Wakelee said. “We know from patients with metastatic disease that well-selected elderly patients do just as well as younger patients. “However, that’s looking at 65 or 70 [years old] as the cut point,” she said. “When we get into the octogenarians, there are very few patients in their eighties who are fit for chemo. However, we do know that for those who are fit, giving combination chemotherapy can be done.”

When discussing adjuvant therapy with patients, Wakelee said that in most cases the surgery has already “cured” their case of lung cancer, depending on the stage of the malignancy that has been treated.

“I tell them that if we were to give them the adjuvant chemotherapy that their likelihood of being cured is going to be improved by 5% to 10%, meaning that there will still be patients who go through the chemotherapy and are not cured,” said Wakelee. “That number will vary by stage and other factors that we really don’t know how to look at yet.”

Dr. Katherine S. Virgo

Katherine S. Virgo, PhD

New data show that patients treated for lung cancer at high safety-net burden hospitals undergo curative-intent surgery significantly less often than individuals treated at low safety-net burden facilities.

The Institute of Medicine of the National Academies defines healthcare safety-net facilities as institutions that deliver a significant level of medical care and other services to vulnerable patients, such as those who lack health insurance or who are on Medicaid.

Katherine S. Virgo, PhD, with the American Cancer Society in Atlanta, Georgia, and colleagues examined the relationship between hospital safety-net burden and receipt of curative-intent surgery for both black and white adults with earlystage non–small cell lung cancer (NSCLC). All patients had been treated between 2003 and 2005 at institutions that were accredited by the American College of Surgeons’ Commission on Cancer.

Roughly 85% of incident lung cancers are categorized as NSCLC, and surgical resection can be curative provided that treatment starts at an early stage.

Research has shown that black patients diagnosed with early-stage NSCLC are less likely than white patients to undergo surgery and are more likely to undergo resection at low-volume hospitals and to die in the hospital or within 30 days of their operation. However, there is scant information on the impact of hospital safety-net status on patient receipt of appropriate treatment.

In the present study, results in 52,853 evaluable patients showed that 67.1% of patients treated at high safety-net burden facilities had curative-intent surgery versus 77.1% of those treated at low safety-net burden centers (odds ratio 0.69; 95% CI, 0.62-0.77).

The results were maintained even after the investigators adjusted for multiple factors that decreased the likelihood of curative-intent surgery, including race, insurance status, disease stage, female gender, and other hospital characteristics.

Virgo and associates pointed out that the lack of consensus on the definition of safety-net status may represent a possible shortcoming of their study. They defined safety-net burden as “the percentage of uninsured and Medicaid-insured patients that hospitals treat, categorized as low, medium, and high,” and maintain that their definition is the one that is closest to that proposed by the Institute of Medicine. A lack of information on individual surgeon characteristics, such as volume or specialty, may also be a limitation.

The authors said that more studies are needed to determine if the relationship between hospital safety-net burden and curative-intent surgery is the same for other cancer sites besides lung cancer, and whether safety-net burden is associated with receipt of multimodality therapy for patients with advanced disease. It would also be helpful to explore the link between hospital safety-net burden and hospital characteristics, such as bed size, ownership type, revenue margins, availability of diagnostic equipment, case mix, referral patterns, and staffing patterns.

Dr. Brian I. Rini

Photo by © ASCO/Todd Buchanan 2012

Brian I. Rini, MD

The FDA has approved axitinib (Inlyta) for the treatment of patients with advanced renal cell carcinoma (RCC) who have failed to respond to another drug.

The FDA approved axitinib on January 27, 2012, based on the strength of a clinical trial that demonstrated an improvement in progression-free survival (PFS). The randomized, open-label, multicenter study involved 723 patients from 22 countries who had RCC and progressed despite receiving sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or a cytokine as firstline therapy. Patients were randomly assigned to receive either axitinib or sorafenib.

The axitinib arm demonstrated a median PFS of 6.7 months (95% CI, 6.3-8.6) compared with 4.7 months (95% CI, 4.6- 5.6) for those receiving sorafenib. The results of the study, first published in The Lancet in December 2011, demonstrated a 33.5% improvement in PFS (hazard ratio [HR] = 0.665; 95% CI, 0.544-0.812; P <.0001).

Treatment was discontinued in 14 of 359 patients receiving axitinib and in 29 of 355 patients receiving sorafenib. The most common side effects reported were diarrhea, hypertension, and fatigue in the axitinib arm, and diarrhea, palmar-plantar erythrodysesthesia, and alopecia in the sorafenib arm. The FDA warned that patients with hypertension should have their blood pressure well controlled before taking axitinib, and patients with untreated brain tumors or gastrointestinal bleeding should not take axitinib.

Axitinib is an oral kinase inhibitor designed to selectively inhibit vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, which have been known to promote angiogenesis and tumor progression.

“Through studying this drug we have learned that a VEGFR-targeted therapy can be effective following prior treatment options, including another VEGFR- targeted agent. This is important in helping physicians understand where these medications fit in the treatment armamentarium,” said Brian I. Rini, MD, associate professor of Medicine in the Department of Solid Tumor Oncology at the Cleveland Clinic in Ohio, lead author of the axitinib study and a consultant to Pfizer Oncology. Pfizer Inc will release the drug under its brand name Inlyta.

The FDA noted that this is the seventh drug approved for metastatic or advanced RCC since 2005. The other drugs that have been approved are sorafenib, sunitinib, temsirolimus, everolimus, bevacizumab, and pazopanib.

“Collectively, this unprecedented level of drug development within this time period has significantly altered the treatment paradigm of metastatic kidney cancer, and offers patients multiple treatment options,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, in a statement concerning the approval of axitinib.

In a statement released by the manufacturer, Pfizer noted that the drug is also being investigated in treatmentnaïve and previously treated advanced RCC patients. Additionally, a randomized phase II trial is being conducted to test its efficacy in hepatocellular carcinoma (HCC).

The National Cancer Institute estimates that 64,770 new cases of kidney cancer will be diagnosed in 2012, and 13,570 people will die from the disease. Between 40% and 65% of patients whose disease progresses after receiving firstline therapy will receive some form of second-line therapy.

Dr. Eric J. Sherman

Eric J. Sherman, MD
Head and Neck Oncology
Memorial Sloan Kettering Cancer Center, New York, NY

Caprelsa (vandetanib) is the first approved treatment for patients with metastatic medullary thyroid cancer (MTC) who are not candidates for surgery and have disease that is advancing and causing symptoms. It is a tyrosine kinase inhibitor with multiple targets.

The drug, which is administered orally, was approved on the basis of a single randomized study among 331 participants that demonstrated a median progressionfree survival of at least 22.6 months in the vandetanib arm versus 16.4 months for those on placebo (published online ahead of print November 21, 2011. J Clin Oncol).

To prescribe the drug, physicians must register with a Risk Evaluation and Mitigation Strategy program.

Eric J. Sherman, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York City, discussed the drug during the 7th Annual Multidisciplinary Symposium on Head and Neck Cancer, a Physicians’ Education Resource (PER) conference held in Philadelphia on November 19.

“One of the concerns the FDA had was an increase in QTc interval and whether that can lead to further cardiac events,” said Sherman in an interview. “Very few people actually had a cardiac event in the study, but it still was a major concern of the FDA. Because of that concern, the FDA mandated that in order to be able to prescribe vandetanib, physicians would need to undergo registration, which basically involves a short online course.”

Sherman said dosing and timing are issues. “It is not completely clear that the starting dose used in the study of 300 mg daily is the best dose for the treatment of medullary thyroid cancer,” he said.

“It’s still not clear when it is the perfect time to start [Caprelsa] because people with metastatic medullary thyroid carcinoma, even those who have some progression, can live quite a number of years before any event,” said Sherman. “It shouldn’t be started just because someone has metastatic disease, and it shouldn’t be started just because tumor markers are increasing. However, it is very reasonable to start when there is a significant progression (not minor) on the scans or when symptoms due to the disease develop.”

For late-stage head and neck cancers, a category that includes cancers of the nasal cavity, sinuses, lips, mouth, salivary glands, throat, or larynx, oncologists can now consider Erbitux (cetuximab) in combination with chemotherapy.

In 2006, Erbitux gained approval as a treatment for advanced squamous cell carcinoma of the head and neck in combination with radiation therapy, or as a single agent after prior platinum-based therapy. Studies showed prolonged survival and delay in tumor growth compared with radiation therapy alone (N Engl J Med. 2006;354[6]:567-578).

The study that led to its latest approval demonstrated that patients treated with cetuximab and chemotherapy (cisplatin or carboplatin and 5-fluorouracil) had a median overall survival of 10.1 months compared with 7.4 months on chemotherapy alone (N Engl J Med. 2008;359[11]:1116-1127). Everett E. Vokes, MD, chairman of the Department of Medicine and physicianin- chief at the University of Chicago Medical Center in Illinois, said the study of cetuximab combined with chemotherapy represents “a major breakthrough” for that patient population because it was the first to show an increase in survival.

“That is really where there is measurable impact directly derived from cetuximab at this point,” said Vokes, who also spoke at the PER conference.

“When moving into the curative-intense setting, we want to use it as a radiation sensitizer or as a chemotherapy sensitizer, so we add it to what we know to be curative modalities at this point,” Vokes continued. “The landmark study that was done was a comparison of radiation versus radiation and cetuximab. And the survival with cetuximab was improved, statistically and clinically. But in terms of where that leaves us as clinicians or the patient, it’s really in the middle of nowhere because radiation alone is not something we use frequently.”

“I think if I’m a community oncologist and I stick to evidence-based medicine, then I will give it with first-line chemotherapy for patients who have recurrence,” he said. “That is the indication with chemotherapy. Every other use with chemotherapy or chemoradiation up front would be on experimental trials.”

hair stylist New survey results suggest that some cosmetologists and barbers inspect their customers’ scalps, necks, and faces for the presence of skin lesions that they think may be cancerous.

Elizabeth E. Bailey, MD, with Brigham and Women’s Hospital in Boston, Massachusetts, and colleagues analyzed responses to questionnaires completed by 203 hair professionals from 17 salons in a single chain in the greater Houston area. The chain was selected because its clientele are both male and female and reside in economically and geographically diverse areas. The questionnaire focused on skin cancer knowledge, attitudes, and behaviors of hair professionals working in a salon.

Melanoma of the scalp and skin were responsible for 6% of all melanomasand 10% of all melanoma deaths in the United States between 1973 and 2003, and had a 5-year survival probability of 83.1% for stage I melanoma of the scalp and neck compared with 92.1% for stage I melanoma of other sites. The relatively high mortality rate for melanoma of the scalp and neck is probably due to the difficulty in detecting suspicious lesions during self-examination by patients and during routine examination by doctors.

While nonmelanoma skin cancer has a fairly low mortality rate, it may cause significant cosmetic disfigurement and functional impairment when the scalp, neck, and face are affected.

According to Bailey and associates, hair professionals have a “natural view of difficult- to-see areas,” and they also meet with their customers on a regular basis and may discuss such subjects as health and illness, diet, and medical care, all of which make them well suited for identifying skin cancer “that is otherwise unseen by the customer and customer’s physician.”

The primary outcome measure was the frequency with which hair professionals looked for lesions on their customers’ scalps, necks, and faces during the prior month.

Overall, 37.1% of survey respondents reported looking at more than 50% of their customers’ scalps, 28.8% maintained that they looked at more than 50% of their customers’ necks, and 15.3% said that they looked at more than 50% of their customers’ faces. Fifty-eight percent of hair professionals claimed that they had recommended at least once that a customer see a health professional for an abnormal mole.

Bailey and colleagues warned that the results may not be broadly generalizable given that the cohort was drawn from a single salon chain in a single city. Also, the study did not provide longitudinal data, which would have made it possible to determine causality.

The investigators are now conducting a prospective study examining the impact of a 20-minute education session about skin cancer and the role that hair professionals can play in its early detection and prevention. Pamphlets and customer information cards are used to facilitate the discussion of skin cancer.

Dr. Angela Fagerlin

Angela Fagerlin, PhD

Researchers are urging oncologists to improve the communication of complex medical information to their patients.

Angela Fagerlin, PhD, with the University of Michigan and the VA Ann Arbor Center for Clinical Management Research, and colleagues cited 10 recommendations “that have shown strong evidence for improved patient understanding and decision making.”

Their methods, they said, are tailored to patients who need to make a decision that involves trade-offs (eg, between quality and length of life or between different aspects of quality of life), in which the right choice depends on how important the patient finds these trade-offs.

The team issued its recommendations because of concern that while patients are increasingly being required to make difficult decisions about cancer screening, prevention, and treatment, they are frequently not able to understand the types of health information needed to make such decisions.

Patients may, for example, lack the “health literacy” required to understand what their physician is saying to them, and they may also be unable to understand the educational materials issued by their healthcare providers. Low numeracy skills may also be a problem, meaning that patients may not be able to use numerical information discussed in educational materials (eg, risk and benefit statistics) in order to make informed decisions.

Fagerlin and associates said that the use of plain language is a must for cancer education. In short, materials should be written so that they can be understood by people with an eighth grade or lower level of education, and the use of clinical and statistical jargon should be avoided. Instead, the authors propose the use of focused information presented in a logical order coupled with a graphic design or page design involving subheadings and the use of more white space intended to make the document more readable.

They also advise oncologists to present statistical information using absolute risk instead of relative risk or number-needed-to-treat formats. In support of this recommendation, they point to evidence showing that “both in the context of making psychological and medical decisions…changes in risk appear larger when presented using risk and that the treatments were viewed more favorably when presented in terms of relative risk.” The use of relative risk information may convince patients that a treatment is more effective than has been empirically demonstrated.

Additional strategies include the use of an incremental risk format to highlight how treatment changes the risk from preexisting baseline levels, along with the use of summary tables that include all of the risks and benefits for each treatment option.

Clinicians should also be aware that the order in which risks and benefits are presented can affect perceptions.

Andrew D. Zelenetz, MD

Andrew D. Zelenetz, MD
Chief, Lymphoma Service
Department of Medicine
Memorial Sloan-Kettering Cancer Center
Associate Professor of Medcine
Weill Cornell Medical College
New York, NY

Maintenance therapy for follicular lymphoma (FL) remains an option but is not mandatory for patients in remission. The decision for initiating postremission therapy in asymptomatic patients should be based on discussions with the patient, said Andrew D. Zelenetz, MD, chief of Lymphoma Service at Memorial Sloan- Kettering Cancer Center (MSKCC), New York City. In addition, newly diagnosed patients with low tumor burden can have their initial treatment delayed, since living with asymptomatic disease is similar to being in remission.

“Taking a bird’s-eye view, the quality of life for FL patients who are asymptomatic and living with their disease is similar to that of patients in remission. No maintenance therapy has been shown to have an effect on transformation of the disease or on overall survival [OS],” Zelenetz told attendees at the National Comprehensive Cancer Network 6th Annual Congress on Hematologic Malignancies.

Follicular lymphoma is an indolent B-cell lymphoma that accounts for about 25% of patients with lymphoma in the United States. “Consultations for FL are the longest ones in my practice,” Zelenetz said. “The disease has a long natural history, with a median survival of 12 to 16 years. Survival has been dramatically improved due to rituximab, but relapse is inevitable over time.”

The decision to initiate therapy in an asymptomatic patient basically falls to patient preference. “From the patient’s perspective, there are 2 camps: ‘I can’t live my life fully knowing I have active lymphoma,’ or, ‘I feel fine now. You will treat me when I need it,’” Zelenetz explained.

Although a number of clinical trials using different regimens have shown that maintenance therapy after chemotherapy with or without rituximab with either radioimmunotherapy or rituximab dramatically improves progression-free survival (PFS) in FL, no therapy has shown a significant improvement in OS, which would be the gold standard. These trials include EORTC, SAAK, PRIMA, RESORT, and FIT. “Delaying therapy is effective,” Zelenetz said.

Using the PFS endpoint in clinical trials is not as optimal as OS. Achieving improvement in PFS delays the time to initiating the next therapy, but treatment may increase resistance to further treatment, and the impact of PFS on quality of life has not been explored, Zelenetz told attendees. Achieving improvement in OS would preserve future treatment options and delay the potential toxicities of subsequent treatments.

“Treatment decisions are currently based on clinical trials using PFS as an endpoint, but PFS is not the ideal surrogate,” Zelenetz noted. “We need better surrogate markers to predict the depth and quality of remission,” he stated. Newly diagnosed patients who require treatment are those with symptoms, massive disease (ie, tumor burden >3 cm), cytopenia, concurrent disease transformation, compromised endorgan function, and who are candidates for ongoing clinical trials.“Please do not treat every newly diagnosed patient with FL,” Zelenetz told the audience during a questionand- answer session. “Four prospective randomized clinical trials that have compared treatment versus observation in newly diagnosed asymptomatic patients (ie, candidates for observation) failed to show improved OS with chemotherapy.”

Disease proliferation is currently being studied at MSKCC as a marker for when to initiate treatment of FL. The technique used is a quantitative assessment based on image analysis of MIB-1/Ki-67 staining [Kedmi et al. Blood. 2010;116(suppl abstr 4149)]. Studies showed that median time to need for treatment was 5 years in FL patients with disease proliferation <30%, while median time to treatment initiation was 18 months in those with disease proliferation >30%.

In the current health care environment, cost of therapy is an important consideration. Cost of single-agent rituximab, the mainstay of FL treatment, is about $36,000 per year.

“If this treatment has no impact on OS, then the cost of quality-adjusted life-years will be tens of millions of dollars,” Zelenetz said. “Currently, we have the luxury of using therapy that doesn’t impact OS, but I can’t predict the future. It might be difficult to get paid for maintenance rituximab [in the future].”

Gordon B. Mills, MD, PhD.

Gordon B. Mills, MD, PhD.

Although personalized medicine has seen some exciting advancements in identifying tumor targets through genomic sequencing and developing treatments aimed at those targets, other successes, such as trastuzumab for HER2- positive breast cancer and imatinib for chronic myelogenous leukemia and gastrointestinal stromal tumor (GIST), do not tell the whole story. The Holy Grail may be in sight, but it remains elusive.

“While there is incredible excitement about the potential implementation of personalized cancer therapy, it is easy to contend that the excitement is massively overblown by the press,” said Gordon B. Mills, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, at the recent European Multidisciplinary Cancer Congress in Stockholm, Sweden.

“The number of successes—and in most cases these are only found in small subpopulations of patients and are transient—are outnumbered by spectacular failures,” he continued. “The cost of targeted therapy has added a tremendous burden to health care for a minor improvement in outcomes in small subpopulations. We are far from overcoming the hurdles associated with the implementation of personalized cancer therapy.”

Mills added, “We are coming closer to having scientific underpinnings for personalized medicine, but integrating our discoveries is an art. We have to ask ourselves whether we are overpromising successful treatments for cancer. Is this hype? Is this fund raising? Will there be repercussions if we don’t deliver on our promises?”

For trials of personalized medicine, each patient represents an “n” of 1. The therapy has to work with the specific patient’s genomics. Just identifying mutations does not mean that they are actionable and druggable; even if a tumor has actionable mutations, many responses to targeted therapy are in small subpopulations of patients and are shortlived. Also, regulatory hurdles need to be overcome for approval of targeted therapies.

In lieu of an ability to treat individual patients based on the changes in the genomes, experts are moving toward stratified therapy and treating groups of patients with similarities in their tumors, but Mills acknowledged that this is fraught with challenges. “Breast cancer is leading the way [in tumor stratification],” he said. “Ductal carcinoma used to be considered 1 disease; now 8 subclasses have been identified. Some of these subgroups are orphan diseases and too small for clinical trials.”

Only subpopulations of patients with a particular biomarker show a response to targeted therapy, and the response is typically not durable. “We need to convert these short-lived responses to durable ones,” he said. He gave the example of the targeted agent crizotinib, which achieved a remarkable response in a subpopulation of lung cancer patients with the ALK mutation, “but every patient has recurred.”

Challenges in Personalized Medicine

The success of any cancer therapy is partly determined by the patient’s nongenetic makeup, the tumor characteristics, and the drug’s therapeutic index and toxicity. Tumor heterogeneity represents a challenge because characteristics of the primary tumor often change at relapse and at metastasis, signaling the need for rebiopsy at stages of disease progression. In some cases, the primary tumor itself may be heterogeneous at different sites. Therapy should be sequenced based on the shift in characteristics at disease progression, Mills told the attendees.With improved ability to characterize tumors in greater depth, multiple mutations are being identified, posing another hurdle to targeted therapy. When a mutational target is identified and targeted treatment is initiated, compensatory pathways may be activated, causing the emergence of resistance.

One focus of research is to distinguish between “passenger” mutations and “driver” mutations. “Not all mutations are targetable,” said Mills.

The price of mutational testing is considerable. There is the cost of genomic sequencing, and then the costs of handling and storing data, which can be much more expensive than genomic sequencing itself. Targeted therapies themselves are also quite expensive, and, as mentioned, responses are typically not durable. Further, genomic testing is not 100% accurate, Mills said. Only 70% of tests are true positive and 70% are true negative. “The best deep-sequencing technologies come with increased cost,” he said.

Ethical considerations also come into play. Patients may not want to know their germ-line aberrations. Regulatory issues are another challenge. Validated assays for tumor testing are not available, and genomic testing is not reimbursed by about 95% of carriers. “We need to make genomic testing billable and payable,” stated Mills.

Also, physicians and patients need to be educated about genomic testing. “Most physicians at MD Anderson don’t understand what all the sequencing tests mean,” he said. There are many unknowns, including whether a mutation present in only 1 tumor cell has any significance. “Patients hear about ‘cures’ and ‘nontoxic therapy,’ and we need to be more realistic about what we present to patients,” said Mills.

Pilot Program at MD Anderson

MD Anderson Cancer Center has launched a personalized medicine pilot program that services about 30,000 patients per year. The goal is to identify targetable and druggable genetic aberrations versus no aberrations. “Then we go to ‘n’ of 1 clinical trials to determine if a patient will benefit from a targeted therapy,” said Mills.

In the pilot program, 996 patients underwent testing with a mass array of 44 genes to identify activating mutations. There are 457 cancer-associated genes; 122 of them occur at a significant frequency in epithelial tumors. Less than 25% of mutations identified were actionable, and most of them were quite rare.

“We were surprised and disappointed. P53 was the most common aberration, but there is no targeted treatment for this,” said Mills. “Fifteen percent were Ras mutations, which are markers of resistance. The percentage with actionable mutations was much lower than in the literature.”

“The patient’s underlying gene lineage is important to response,” Mills said. “You can have efficacy with a targeted therapy, but it is determined by the patient’s lineage and tumor cell aberration.”

Patients with low-grade disease and mutations are frequently cured by targeted therapy, but most patients with advanced disease tend to have p53 mutations. “So we promise all patients that we can treat them, but only a few have actionable mutations,” said Mills. The ultimate outcome of a given cancer is determined by metastatic lesions that may differ from the primary tumor, he added.

Breast cancer is “the poster child for stratified medicine.” In the pilot program, Mills and colleagues looked at 51 primary breast tumors and 56 metastases. Over 40% of the time, the dominant clone was discordant.“Patients with concordance of PTEN, estrogen receptors, progesterone receptors, and HER2 have a better outcome, while the outcome is dismal for those who are discordant,” said Mills. “Potentially, we have to obtain multiple biopsies to know what we are treating. In one study, the primary tumor had heterogeneity at different sites.” Testing for genetic aberrations does not always yield results that can be acted upon. “In 10 patients where we’ve sequenced the majority of the genome, not one new actionable mutation was found,” said Mills. “Most mutations we find are not drivers.” For example, out of the 16 mutations most common in acute myelogenous leukemia and the 237 most common mutations in lung cancer, less than 6 were targetable.

“Many mutations are only passengers, not drivers,” he emphasized. “The ‘noise’ in mutations is challenging.” A new program has been initiated at MD Anderson to distinguish between passenger and driver mutations. Thus far, investigators have identified a set of PK13R1 driver mutations.

“The future of personalized medicine will entail biopsy, biopsy, biopsy,” said Mills. “Eventually we hope to be able to move from biopsy to imaging and use of blood and circulating tumor cells to identify mutations.”

Mills envisions the process as follows: characterize the primary tumor and metastases, identify subclones, move to a trial of therapy (“n” of 1), and then biopsy at recurrence. “Personalized medicine offers great hope and many challenges. It is indeed a team science,” he said.

The Trials in Progress section is intended to stimulate discussion about ongoing clinical trials and to promote collaboration across the oncology community. Each month, Targeted Therapy News will present summaries of ongoing research in a broad range of cancer types.

Breast Cancer

Evaluating trastuzumab/capecitabine and pertuzumab in patients whose cancer has progressed

Researchers are recruiting for the multicenter, randomized PHEREXA study. The phase II, 2-arm study will examine the safety and efficacy of giving pertuzumab and trastuzumab with capecitabine in women with HER2-positive metastatic breast cancer whose disease has progressed during or following trastuzumab therapy. As of January 2011, researchers have recruited 58 patients for this open-label trial, but they hope to recruit 450 patients from 19 countries. Patients in both arms will receive trastuzumab and capecitabine, while 1 arm will also receive pertuzumab. Progression-free survival (PFS) is the primary endpoint. Overall survival, PFS, safety, and tolerability are secondary endpoints. Researchers plan to analyze HER1, -2, and -3 receptor status and downstream markers.

Sponsor: Hoffmann-LaRoche

ClinicalTrials.gov Identifier: NCT01026142

Phase II study of iniparib in breast cancer that has metastasized

Researchers plan to recruit 40 patients with triple-negative breast cancer (TNBC), which has metastasized to the brain, to evaluate the safety and efficacy of iniparib plus irinotecan. TNBC patients with brain metastases experience poor survival rates. The researchers are accepting patients with brain metastases that measure more than 0.5 cm, even if they have already received therapy with iniparib or steroids. However, those with leptomeningeal disease will be excluded. Cohort 1 will be those with new and/or progressive brain metastases following radiation of the central nervous system (CNS). Cohort 2 will be asymptomatic patients who have not received CNS radiotherapy. Patients will receive irinotecan before iniparib. Researchers will use MRI and CT scans to determine the presence of intra- and extracranial disease. Time to progression is the primary endpoint. Secondary endpoints include CNS and non-CNS response rates, progression-free survival, overall survival, quality of life, and correlative science endpoints.

Sponsor: sanofi-aventis

ClinicalTrials.gov Identifier: NCT01173497

PARP inhibition among patients with TNBC

The Hoosier Oncology Group is conducting a multicenter, randomized, phase II trial of cisplatin alone or cisplatin with the experimental compound PF 01367338 among patients with triple-negative breast cancer (TNBC) who have not achieved pathologic complete response (pCR) on anthracycline-and/ or taxane-containing neoadjuvant chemotherapy. The 2-year disease-free survival (DFS) of TNBC patients with residual disease category II or III is poor,―only about 40%. There are no standard systemic therapies for this high-risk group. The researchers chose cisplatin because of its DNA-damaging properties. Cisplatin and PF 01367338 appear to affect the PARP breast cancer cells; they inhibit the replication of DNA and their growth. After completing standard radiation therapy, patients will be randomized to cisplatin alone or with PF 01367338. The primary endpoint is 2-year DFS. Secondary endpoints include safety, 1-year DFS, overall survival, and biomarkers of tumor recurrence, resistance to chemotherapy and/or PARP inhibition. The estimated enrollment is 135 patients.

Sponsor: Hoosier Oncology Group and Pfizer

ClinicalTrials.gov Identifier: NCT01074970

Gastrointestinal Cancer

Detecting c-KIT and PDGFRA in GIST patient plasma

Researchers from Germany are actively recruiting for a biomarker study in patients with gastrointestinal stromal tumors (GISTs). In this phase III, open-label trial, patients will be placed in 2 groups. One group is an assigned intervention group (surgery or a tyrosine kinase inhibitor); the other is composed of patients whose disease has progressed irrespective of treatment. Blood will be drawn every 3 months for 2 years to look for the biomarkers c-KIT and PDGFRA (platelet-derived growth factor receptor alpha). Activating mutations of the kinases c-KIT and PDGFRA can be detected in 90% of GIST tissue samples. The researchers want to know if these markers will correlate with the clinical course of disease either under therapy or in progressive disease irrespective of the current therapy. The primary outcome is to detect tumor-specific DNA encoding for mutated c-KIT or PDGFA in the plasma of these patients at least once during the study. The estimated enrollment is 25 patients.

Sponsor: Technische Universit.t München

ClinicalTrials.gov Identifier: NCT01462994

Investigating relationship between plasma platinum levels and neurotoxicity in GI cancer patients receiving oxaliplatin therapy

French researchers are recruiting for a phase IV toxicity study in patients with gastrointestinal (GI) cancer who are taking oxaliplatin. Patients who are receiving or plan to receive oxaliplatin will be eligible for enrollment in this multicenter, open-label trial. Patients must have no pre-existing neuropathy, central nervous system disease, or cerebral metastases when enrolled. During the study, the patient’s neurological function and plasma levels will be measured at baseline after each treatment with oxaliplatin (2-hr IV infusions every 2-3 wk), and at the end of study treatment. The primary endpoint is to determine the relationship between plasma levels of residual platinum with persistent neurotoxicity in the hope that this information will help clinicians plan treatment and improve the quality of life of these patients. The secondary endpoint is to determine the pharmacokinetics of oxaliplatin in patients with GI cancer. The estimated enrollment is 58 patients.

Sponsor: Groupe Cooperateur Multidisciplinaire en Oncologie (GERCOR)

ClinicalTrials.gov Identifier: NCT00274885

Phase II trial of FOLFOX with or without vismodegib in advanced gastrointestinal cancer

Researchers are recruiting for a multicenter, phase II study of FOLFOX with or without GDC- 0449 (vismodegib) in treatment-naïve patients with advanced gastric and gastroesophageal (GE) junction carcinoma. This randomized, double-blind study will review the efficacy and safety of vismodegib plus FOLFOX versus FOLFOX alone as first-line treatment for advanced GE cancers. The hedgehog (Hh) pathway is critical in the development of both normal and malignant gastroesophageal cell growth and survival, but Hh overexpression correlates with clinical and histological features of GE tumors. Vismodegib, an oral Hh antagonist, binds to and inhibits SMO (Smoothened), a key component of the Hh pathway. By inhibiting SMO, Hh signal transduction is blocked. Patients will receive FOLFOX (leucovorin calcium, fluorouracil, oxaliplatin) with either vismodegib or placebo. Progression-free survival is the primary endpoint. Secondary endpoints are overall survival, relative risk, and toxicity rates. The estimated enrollment is 116 patients. As of June 2011, the researchers had enrolled 58 patients.

Sponsor: New York Cancer Consortium and National Cancer Institute

ClinicalTrials.gov Identifier: NCT00982592

Genitourinary Cancer

PREDICT looking for predictive biomarkers in renal cell carcinoma

The PREDICT (Personalized RNA Interference to Enhance the Delivery of Individualized Cytotoxic and Targeted Therapeutics) Consortium is conducting multicenter, single-arm phase II trials of everolimus (E-PREDICT) or sunitinib (S-PREDICT) administered around the time of the nephrectomy in patients with untreated metastatic renal cell carcinoma (mRCC). Although inhibitors of the vascular endothelial growth factor receptor (VEGFR) and the mammalian target of rapamycin (mTOR) have transformed mRCC therapy, predictive biomarkers have not been identified. The researchers plan to analyze the molecular markers of paired biopsies before and after treatment and compare them with clinical data to find predictive biomarkers. Sunitinib and everolimus will be given before and after nephrectomy and will continue until disease progression at metastatic sites. The primary clinical endpoint is the safety of peri-nephrectomy everolimus and sunitinib. Secondary endpoints include efficacy and biomarker measurements. The researchers hope to recruit 60 patients per trial.

Sponsor: The PREDICT Consortium

Hematologic Cancer

Phase II study of nilotinib in Ph+ CML patients

Researchers are evaluating patients with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) with low imatinib plasma concentrations to see if nilotinib will improve patient outcomes. Patients with low plasma concentrations of imatinib are at risk for treatment failure. Nilotinib is a second-generation Bcr-Abl tyrosine kinase inhibitor and has a higher affinity for Abl than imatinib. Researchers will enroll 50 patients with Ph+ CML-CP who have been diagnosed within the 12 months prior to recruitment and who meet other European LeukemiaNet (ELN) response milestones, but who still have a low plasma concentration of imatinib. The patients will be switched from imatinib to nilotinib and treated for up to 2 years. The primary endpoint is the number of ELN-defined failure events during the course of nilotinib therapy. Secondary endpoints include cytogenetic and molecular response, and event-free, progression- free, and overall survival. Changes in quality of life will also be considered.

Sponsor: Novartis Oncology

ClinicalTrials.gov Identifier: NCT01131325

Phase II study of elacytarabine/idarubicin as second-course remissioninduction therapy in AML

Researchers are studying elacytarabine with idarubicin in patients with acute myeloid leukemia (AML), who have more than 5% remaining blasts in the bone marrow after the first induction course of a regimen containing cytarabine. The decreased expression of hENT1 (human equilibrative nucleoside transporter 1) has been shown to contribute to cytarabine resistance. Elacytarabine, with or without idarubicin, has shown activity in refractory or relapsed patients with AML during phase I studies with a safety profile similar to the cytarabine/idarubicin regimen. In this phase II, multicenter study, researchers will biopsy bone marrow to determine the hENT1 expression level prior to beginning the new protocol. The primary objectives are to assess the biological activity of elacytarabine/idarubicin and to examine the correlation between hENT1 and overall survival.

Sponsor: Clavis Pharma, Theradex, INC Research

ClinicalTrials.gov Identifier: NCT01035502

Head and Neck

Using lyophilized black raspberries to prevent oral cancerOhio State University researchers are trying to determine the best method to administer lyophilized black raspberries as prophylaxis to patients who are at high risk for oral cancer. The use of lyophilized black raspberries may prevent oral cancer in those with previously diagnosed stage I-IV or in situ head and neck cancer. In this phase I/II trial, there will be 2 treatment arms and 2 placebo arms. Patients will be randomized to (1) placebo lozenge or lyophilized raspberry lozenge; or (2) saliva substitute placebo or lyophilized black raspberry saliva substitute. Treatment will continue for 6 months. Primary objectives are to define safety and tolerability of long-term black raspberry administration after surgery in patients with head and neck cancer, to determine the best dose and delivery vehicle, and to correlate gene expression changes within regulatory pathways and dose and delivery method. The estimated enrollment is 140 patients.

Sponsor: Ohio State University Comprehensive Cancer Center, National Cancer Institute

ClinicalTrials.gov Identifier: NCT01469429

Hematologic Malignancies

Fludarabine and busulfan with or without clofarabine for AML and MDS patients that need stem cell transplant

Researchers at MD Anderson Cancer Center are actively recruiting for a new phase III study of 2 combination therapies in patients aged 3 to 70 years with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who also must undergo stem cell transplantation. AML patients in any stage and cytogenetic risk group who have not achieved complete remission with 1 course of induction therapy, and MDS patients with intermediate or high-risk IPSS score or treatmentrelated MDS, are eligible for the trial. Some other low-risk MDS patients might be eligible. In this open-label trial, patients will be randomized to 1 of 2 arms. Arm 1 will receive busulfan, fludarabine, and clofarabine before stem cell transplantation. Arm 2 will receive busulfan and fludarabine before stem cell transplantation. Patients in both arms will also receive treatment to prevent graft-versushost disease. Patients will be followed quarterly for 5 years after treatment. The primary endpoint is progression-free survival, and the secondary endpoint is overall survival. The researchers will also review safety data of this combination therapy. The estimated enrollment is 250 patients.

Sponsor: MD Anderson Cancer Center

ClinicalTrials.gov Identifier: NCT01471444

Brentuximab vedotin and combination chemotherapy for treating older patients with Hodgkin lymphoma

TResearchers from Northwestern University are actively recruiting for a phase II, open-label trial of patients with previously untreated stage II-IV Hodgkin lymphoma. The researchers want to determine the effects of adding the monoclonal antibody brentuximab vedotin, which targets the cell membrane protein CD30, to traditional combination chemotherapy. There will be only 1 treatment arm. In the study, all previously untreated patients with stage II-IV Hodgkin lymphoma who are 60 years or older, will receive sequential therapy with brentuximab vedotin, and then receive doxorubicin, vinblastine, and dacarbazine (AVD). Primary outcome is overall response rate after sequential brentuximab vedotin therapy with AVD chemotherapy. Secondary outcomes are progression-free survival, time to treatment failure, freedom from progression, and overall survival. The estimated enrollment is 48 patients.

Sponsor: Northwestern University, Robert H. Lurie Cancer Center

ClinicalTrials.gov Identifier: NCT01476410

Lung Cancer

Finding most effective radiation therapy for SCLC patients receiving cisplatin/etoposideTA 2-part, phase III, multicenter trial is testing the most effective radiotherapy for patients with small cell lung cancer who are receiving cisplatin and etoposide. All patients will receive cisplatin/etoposide and will be randomized to 1 of 3 treatment groups. Patients in arm 1 will receive standard-dose (45 Gy) thoracic radiotherapy delivered twice daily, 5 days a week for 3 weeks; patients in arm 2 will receive 70 Gy radiotherapy once daily, 5 days a week for 7 weeks; and patients in arm 3 will receive 61.2 Gy once daily, 5 days a week for 16 days, then twice daily, 5 days a week for 9 days. The interim results will be analyzed, and the experimental arm with the most side effects will be discontinued. In part 2, standard radiotherapy will be compared with the remaining higher-dose regimen. Primary outcome measures are overall survival times. Secondary outcome measures are toxicity, complete and partial response rates, failure-free survival, local tumor progression, and rates of distant and intracranial metastases.

Sponsor: Cancer and Leukemia Group B, National Cancer Institute, Radiation Therapy Oncology Group

ClinicalTrials.gov Identifier: NCT00632853

Women's Cancer

Treatment versus observation in women with stage III/IV gynecological cancers

A phase III trial is studying how well paclitaxel performs compared with polyglutamate paclitaxel or observation only in women with stage III/IV fallopian tube, ovarian, or peritoneal cavity cancer, which is in clinical complete response (CR) after platinum and taxane-based chemotherapy. In this multicenter study, the women are being randomized to 1 of 3 interventions: paclitaxel poliglumex, paclitaxel, or clinical observation. Sometimes women who are experiencing CR do not necessarily need more treatment, but researchers do not know if observation is better than maintenance therapy in these cases. The primary outcome is overall survival. Secondary outcomes are progression-free survival (PFS), toxicity, particularly peripheral neuropathy, and quality of life issues. Researchers also want to correlate biomarkers with overall PFS. After treatment, women will be followed every 3 months for 2 years, and then every 6 months for 3 years. Estimated enrollment is 1110 women (555 patients per treatment arm).

Sponsor: Gynecologic Oncology Group, National Cancer Institute

ClinicalTrials.gov Identifier: NCT00108745

Dr. Agarwala

Sanjiv S. Agarwala, MD
Professor of Medicine
Temple University School
of Medicine
Chief, Oncology /Hematology
St. Luke’s Hospital and Health Network Bethlehem, PA

The US oncology community applauded the FDA’s approval of ipilimumab (Yervoy) in March 2011, and the European Commission supported the use of the drug for patients with previously treated advanced melanoma among European Union member nations in July.

In the United Kingdom, however, the National Institute for Health and Clinical Excellence (NICE) has issued a draft recommendation against its approval, stating that clinical trial results thus far do not demonstrate sufficient benefits to justify its costs, and that biomarkers are needed to identify patients who would benefit. The agency is scheduled to make a final decision in February, 2012.

Sanjiv S. Agarwala, MD, chief of Oncology/ Hematology at St. Luke’s Hospital and Health Network in Bethlehem, Pennsylvania, is enthusiastic about Yervoy but believes NICE’s points are well taken.

“It certainly is practice changing,” said Agarwala of the drug, noting that increasing overall survival in patients with melanoma has been quite difficult.

Agarwala agrees that focusing more efforts on genome mapping and biomarker identification research is critically important in order to deliver a more personalized therapy for melanoma patients.

At the same time, he said, the costs of the drug are certainly worthwhile to those who would benefit.

“There are about 8000 metastatic melanoma patients in the United States,” said Agarwala. “That’s a relatively small number of patients who can be helped by the drug, but if it increases their survival, then it will be worth the cost to them.”

Yervoy, which Bristol-Myers Squibb developed, is the first drug that has been shown to help patients with advanced melanoma live longer. The FDA’s approval was based on a clinical trial in which patients were randomized to receive Yervoy in combination with the investigational peptide vaccine gp100, Yervoy alone, or gp100 alone.

Patients who received Yervoy either alone or in combination had a median overall survival (OS) of approximately 10 months, compared with a median OS of 6 months for those in the vaccine-only arm. Participants had been previously treated with 1 or more of 5 drugs.

Sir Andrew Dillon, chief executive of NICE, said in announcing the draft guidance in October that “the results did show the drug could potentially be very effective for a small percentage of patients.”

He said, however, that the trial did not compare Yervoy with currently used therapeutics, and it likely would improve survival for only about 30% of patients, with about 10% of those patients experiencing long-term benefits.

In its economic analysis, NICE said the incremental cost-effectiveness ratio (ICER) would be at least £54,000 to £70,000, and possibly significantly higher, per quality-adjusted life-year (QALY). In the United States, a complete course of treatment consisting of 4 infusions of 3 mg/kg doses during a 3-month period carries an estimated cost of $30,000 per infusion, or $120,000 for the series.

NICE makes recommendations to the National Health Service that apply in varying ways in England, Wales, Northern Ireland, and Scotland. The type of guidance ultimately issued determines whether a drug or device will be covered under a mandatory funding requirement.

Pierre Hainaut, PhD

Pierre Hainaut, PhD

Pierre Hainaut, PhD, conducts research that spans basic molecular biology and molecular epidemiological studies related to the tumor suppressor gene p53, with an emphasis on its role in a variety of human cancers. His lab consistently generates important contributions on the molecular epidemiology and pathology of esophageal, breast, liver, and lung cancers.

The IARC center, in Lyon, France, is part of the World Health Organization. In January, Hainaut will take over the post of director at the International Center for Research and Training, Hospital AC Camargo, Sao Paulo, Brazil.

1

What role does p53 signaling play in normal cells?



p53 coordinates a number of antiproliferative programs in response to multiple forms of stress, including low oxygen, depletion of ribonucleotides, hyperactivation of growth signaling, and many forms of DNA damage. Among the antiproliferative programs induced by p53 are cell cycle arrest, cell differentiation, senescence, autophagy, increased DNA repair, and apoptosis. The type of program activated depends upon cell type, status (eg, stem, progenitor, or differentiated cell), and the type of stress. One interesting theory proposes that the TP53 gene may have evolved as an adaptation of cells to enable them to handle oxidative damage caused by mitochondria.

2

How important is it in the development of cancer?



It could be said that cancer cannot develop if p53 function and activity is intact and, in fact, all cancers may have altered p53 function. Many mechanisms of p53 inactivation have been identified. For example, inactivating mutations occur in around 50% of cancers, and loss of p53 alleles is detectable in 30% to 60%. Functional inactivation through interaction with inhibitory viral or cellular proteins is common in some cancers, and may account for another 5% to10% overall.

Other mechanisms include p53 promoter repression, competition with p53 homologues or with "inactive" p53 isoforms, and suppression of p53 expression by microRNA. The effects of these alterations may be very tumor-specific. In breast cancer, loss of p53 function is perhaps the most significant prognostic marker to date (with worse prognosis than ER/PR-, HER2-, or triple-negative). In lung cancer, TP53 mutation has no prognostic effect, but it may alter tumor response to adjuvant therapy, thus exerting a form of gain-of-function.

Subjects who inherit a mutant TP53 allele suffer from a familial syndrome of predisposition to multiple cancers: Li-Fraumeni syndrome (childhood solid tumors, early breast cancer, sarcomas). Long considered a rare disease, there is now evidence that it might be a much more common form of cancer predisposition.

DNA damage / Cell cycle abnormalities / Hypoxia

3

Are there any p53-targeted anticancer agents currently available or under development?

In fact, many conventional treatments (radiotherapy or chemotherapy) are at least partially p53-dependent. With respect to "targeted therapies," several approaches are in clinical trials: small drugs activating wild-type p53, small drugs "resuscitating" mutant p53, TP53-based gene therapy using viral vectors, and immunotherapy-targeting cells expressing p53 antigenic determinants. None are currently considered superior to standard treatments but there is significant hope that they may improve the effects of conventional therapy.

4

What has been the key discovery relating to p53 signaling in cancer in recent years?



The field is a goldmine for discoveries in molecular biology. In my view, the biggest recent advance is the identification of p53 as a key factor controlling oxidative metabolism (decreasing glycolysis, increasing oxidative phosphorylation in the mitochondria). Thus, loss of p53 function in cancer cells is one of the bases of the famous Warburg effect, the metabolic adaptation that allows cancer cells to thrive on glucose with no or little oxygen usage. There is now good evidence that p53 operates as a link between telomere shortening and changes in oxidative metabolism to control cellular senescence.

5

What is the future of research with regard to p53 signaling in helping our understanding of cancer or developing targeted treatments?



Firstly, monitoring p53 (mutations, loss of alleles, molecular signatures of expression of target genes) is already proving very important for prognosis and prediction (depending upon tumor type), and this type of application will become standard practice in the coming years. Secondly, although p53 might prove difficult to "repair" using small drugs, pathways upstream and downstream offer a huge number of potential targets. As these pathways have multiple entry and exit routes, combination therapy will be needed. This will take time but may well herald the next therapeutic revolution.

NeuVax mechanism of action: active specific immunotherapy (ASI)

NeuVax

Courtesy Galena Biopharma

A vaccine therapy designed to prevent breast cancer from recurring in women who have been treated for early-stage disease, but remain at high risk of forming new tumors, is now being evaluated in a multinational phase III trial after it succeeded in reducing relapse rates significantly in earlier trials.

The therapy, NeuVax, directs the immune system to target HER2 (human epidermal growth factor receptor 2), an oncogene that promotes tumor growth associated with aggressive disease and poor survival and is expressed to some extent in about two-thirds of breast cancer tumors.

The drug represents a departure from the majority of cancer therapies now in clinical trials because of the early stage at which patients are enrolled, as well as its focus on prevention. While most new therapies are evaluated in later-stage patients with metastatic disease, the patients participating in the PRESENT trial (Prevention of Recurrence in Early-Stage, Node-Positive Breast Cancer with Low-to-Intermediate HER2 Expression with NeuVax Treatment; Galena Biopharma) have newly diagnosed cancer characterized as local regional disease, or stage 2 to 3a from a clinical perspective.

Elizabeth Mittendorf, MD, PhD

Elizabeth Mittendorf, MD, PhD

“This trial is for women who have completed standard- of-care therapy and are node-positive with tumors with low to intermediate expression of HER2, defined as 1+ and 2+, for whom there are currently no additional treatment options. It’s an unmet need because these patients are node-positive and have a high risk of recurrence,” said Elizabeth Mittendorf, MD, PhD, an assistant professor in the Department of Surgical Oncology at University of Texas MD Anderson Cancer Center in Houston, and the trial’s principal investigator.

About 40,000 of the approximately 230,000 women diagnosed each year with breast cancer fit this profile, said Mark Ahn, PhD, president and CEO of Galena Biopharma. “About 55% of women are node-positive, and this is the dominant clinical factor for predicting whether their cancer will return. They have a 25% chance of recurrence within 3 years, despite there being no evidence of disease following standard-of-care therapy. These are women with a median age of about 50 who are highly active with lots of life left, and who are keen to stay in remission,” he said, adding, “Of HER2- positive tumors, 20% to 30% are 3+ (high-level expression), and these patients receive trastuzumab therapy. However, about 50% to 60% are either 1+ or 2+, and these women are currently sent home to watch, wait, and worry about recurrence.”

Mark Ahn, PhD

Mark Ahn, PhD

The trial is a randomized, double-blind study at 32 sites, with an estimated enrollment of 700 women with operable early-stage, node-positive breast cancer who have completed standard therapies that include surgery, chemotherapy, and radiation. The primary outcome measure for the trial is an assessment of disease-free survival in the vaccine and control groups at 36 months. Secondary endpoints include measurement of disease-free survival and overall survival in both groups at 3, 5, and 10 years, and data collection on time to recurrence, time to local recurrence, time to distant recurrence, and time to bone metastases, as well as an overall safety profile.

Patients seeking to enroll in this trial undergo a two-step qualification process at one of the test sites to confirm their eligibility, Mittendorf said. A blood sample is sent to a central lab to determine the patient’s human leukocyte antigen (HLA) status, as the vaccine only works in patients who are A2- or A3-positive for these alleles, molecules that package the vaccine peptide and present it on the cell surface for recognition by the immune system. Patients must also undergo a series of tests, including a mammogram, computed tomography scan, and bone scan, to show that they are disease-free.

“They must begin their vaccination series within 2 months after standard therapy is completed,” she said, noting, “We’re identifying potentially eligible trial patients while they are still completing their standard treatment. This allows us to appropriately counsel patients and complete the necessary consenting and testing so that they can start their inoculations on schedule.”

Participants in the experimental arm of the trial are inoculated with a hybrid vaccine that includes NeuVax (nelipepimut-S), an E-75 peptide derived from HER2, combined with Leukine (sargramostim), an adjuvant that boosts the immune system. The mixture is injected intradermally once a month for 6 months, followed by booster shots five more times at 6-month intervals. Participants in the control arm receive injections of Leukine at the same intervals.

Ahn described NeuVax as a clone of HER2 that trains the body’s T cells to attack the tumor-expressing cells that become the basis for breast cancer relapse. “The body has a trillion T cells and between 15% and 40% are CTLs, or cytotoxic T cells, lymphocytes that can kill cancer cells. These T cells are trainable and can be turned on and directed at HER2; we can have 2% of CTLs to run around the body for 6 months to look for HER2,” he said.

Recurrence rates were cut in half for women who were vaccinated with NeuVax over the course of the earlier clinical trials, said Col. George Peoples, MD, a developer of the vaccine who is director and principal investigator for the Cancer Vaccine Development Program at San Antonio Military Medical Center and deputy director of the US Military Cancer Institute.

Col. George Peoples, MD

Col. George Peoples, MD

Peoples, the principal investigator for the phase I and II trials, said that the figure reflected outcomes for all women participating, regardless of dosage levels and including those who did not receive boosters. He noted that a series of dosages and schedules were tried with the vaccine before investigators determined which combination produced the most robust immune response.The phase I/II clinical trial of NeuVax recently concluded, with the final patients completing their booster treatments and final follow-up visits in September 2012. Initially, patients in the earlier trials were given a series of up to six inoculations of NeuVax on a monthly basis. The trial physicians added a voluntary booster program as the trial progressed, however, when they determined that some patients’ immunity waned after the initial monthly series, translating to late recurrences of cancer in some. This declining immunity was identified by monitoring the patients’ T cells.

The results showed that at a median of 60 months, the disease-free survival for the booster group was 96% versus 80.5 % in the control group, with a recurrence rate for the booster group of about 4% versus about 19% in the control group.

“In phase III, patients are getting an optimal dose. Phase I participants were rolled into phase II, and so those patients received a variety of doses including low doses, and some did not receive boosters,” Mittendorf said.

Patients with HER2 3+ tumors participated in the earlier trials, but have been excluded from the phase III trial as they now receive trastuzumab as standard-of-care therapy. Trastuzumab is a monoclonal antibody that also targets HER2, but is reserved for women who are HER2 3+, and it has a dose-limiting toxicity of cardiotoxicity, Ahn said.

NeuVax appears to be synergistic in combination with trastuzumab, based upon the results of a phase II pilot trial that resulted in no recurrences with NeuVax plus trastuzumab after 24 months versus 12.5% with trastuzumab alone, and without added toxicity. As a result, Galena Biopharma is following up with a randomized phase IIb study that will enroll patients with low and intermediate HER2-expressing breast cancer.

While she described the treatment regimen as rigorous, Mittendorf said the side effects were minimal. “Some patients experience redness at the injection site, bone pain, and aches that are like flu symptoms, but these typically last for 4 to 5 hours only and are responsive to acetaminophen. We see these symptoms with other vaccinations,” Mittendorf said, adding, “The trial is not a hard sell, because the treatment does not replace other therapies, is easily tolerated, and has potential benefits. We’re finding that patients and their physicians are enthusiastic about this study.”

Cancer researchers describe HER2-positive breast cancers as more aggressive than other types of breast cancer and less responsive to hormone treatment. And so for these patients, the stakes are high.

“When the cancer comes back after they’ve undergone the best available therapy, the vast majority of people will succumb to the disease,” Peoples said.

Mittendorf described the years following treatment as stressful for women. These patients must be “very vigilant following care, checking in for evaluations every 3 months for 2 years, and then every 6 months for 3 years after that, and then every 5 years after that. They begin to worry as that next checkup gets closer. It’s not an easy way to live,” she said. “The women enrolling [in the PRESENT trial] don’t know if their disease will recur, but that’s the fear of all cancer patients, and their only other choice at this point is to go home and do nothing,” she said.Peoples noted that when he began his immunotherapy research nearly two decades ago, “there were no products then that used the immune system as a relevant tool. That the immune system can be actively engaged is emerging as an important modality,” he said. “People like the idea of strengthening their own immune systems and taking measures to prevent disease, rather than toxic remedies when they are already sick. And while it does make sense that late-stage patients are more willing to try experimental treatments, when we’re talking about the immune system, we can’t wait until the cancer has won.”

He added, “From the standpoint of a clinical trial, it’s not good either to vaccinate and wait 20 years to see whether a drug works. It has to be a happy medium, targeted at patients who are treated and disease-free, but at a high risk of recurrence based upon their disease profile. If we learn that we can prevent metastatic disease, it’s a natural transition to enlist this therapeutic approach earlier in the process, and that’s when we do start looking at the 20-year trials.”

Ahn characterized the marked reduction in the death rate among breast cancer patients over the past decade as “about half attributable to earlier diagnosis and half to better and more aggressive treatments with targeted therapies like Herceptin and Avastin.” He noted that with prophylactic strategies, including surgeries, “we’re entering an era where the question is what we do with the information we have, understanding that we’re often dealing with probabilities and not certainties.”

“If we could detect the presence of HER2 before it forms a tumor mass, that would be pretty smart. But we’d have to be able to determine where the cut-off levels are in asymptomatic patients with detectable levels of circulating tumor cells,” he said. “We’re just now acquiring the technology that allows us better assessments of these counts, but we need to make sure treatment is something we can define with it. If we can, this could lead to more prophylactic therapies. The challenge is to make it practical.”

Table. Efficacy and Safety Study of NeuVax Vaccine to Prevent Breast Cancer Recurrence (PRESENT Trial)

Primary outcome measure: Disease-free survival at 36 months
Secondary outcome measures: Assessment of disease-free survival and overall survival at 3, 5, and 10 years; time to recurrence, time to local recurrence, time to distant recurrence, time to bone metastases; overall safety profile
Study start date: November 2011
Estimated primary completion date: May 2015 (for final data collection on primary outcome measures)
Estimated study completion date: May 2022
Estimated enrollment: 700
Patients:
Adults 18 years or older
Pathological diagnosis of invasive adenocarcinoma of the breast
Breast cancer completely excised
Node-positive disease
Primary tumor stage T1-3
HER2-negative (HER2 1+ by IHC or HER2 2+ by IHC/FISH)
HLA-A2 or HLA-A3 haplotype
Completed NCCN-approved neoadjuvant/adjuvant chemotherapy, or both
Completed radiation therapy
No evidence of disease
No bilateral breast malignancy or suspicious mass in opposite breast
No history of prior breast cancer, ductal carcinoma in situ
No prior trastuzumab therapy
Dosages:
Arm A: Hybrid vaccine of NeuVax mixed with Leukine and injected intradermally once a month for 6 months, followed by booster injections once every 6 months for 5 months
Arm B: Leukine injected intradermally once a month for 6 months, followed by booster injections once every 6 months for 5 months
Adverse effects: Some patients experience redness at the injection site, bone pain, and aches that resemble flu symptoms typically lasting 4 to 5 hours

IHC = immunohistochemistry; FISH = fluorescence in situ hybridization; HLA = human leukocyte antigen; NCCN = National Comprehensive Cancer Network.



Trainees have sat in this hot seat at the front of the room for decades. It’s not really warm, of course. This is where the fellow sits who is asked to review the findings, come up with a differential diagnosis, and devise a plan for the case in question. A peripheral smear appears on the big screen and John, a first-year fellow, starts to tell us what he sees. He points out red cells, then platelets, then white cells. We ask him the history and physical. John then develops a differential diagnosis, makes the diagnosis, and discusses the treatment plan. Twenty to 30 minutes later, we’re on to a second case and another fellow takes John’s place. At then end of the hour, we’ve reviewed 3 cases and we’re all a little wiser. Now it’s time to see the patients.

Is There a Typical Day?

After the conference at 7:30, the rest of the day generally goes as follows, more or less:

8:30 am — Office hours

12:00 pm — Oncology conference with fellows and attendings

1:00 pm — Desk time

3:30 pm — Sign-out conference with the hematologic malignancies and stem cell transplantation team

But is there a typical day for a fellowship director? Not really. The days are crammed full of activities and responsibilities that vary based on the time of the year and the clinical responsibilities for the day. There are often changes in the schedules due to new issues that come up. Flexibility is very important. Half the time, I have clinical responsibilities. These may be inpatient or outpatient activities, and may or may not include the fellows or other trainees.

Following our conference on this particular Friday morning, I start to see outpatients with hematologic malignancies. As part of her training, Amy, one of the fellows, is doing an outpatient hematologic malignancies block and is working with me. Together with Lisa, one of a team of great nurse practitioners, we divide up the schedule and start to see our patients in the outpatient offices. Most of the patients with follow-up visits are doing well. Together with Amy and Lisa, I make plans to restage lymphoma in 2 patients, evaluate anemia and a monoclonal protein in another, sign a consent for salvage chemotherapy for another, do some long-term follow-up for a few more, and end the morning with a new patient who would like to discuss options for an allogeneic stem cell transplant for relapsed acute myeloid leukemia. It’s been a busy morning, but we got through it without any emergencies or admissions and finish with just enough time to get to our noon conference.

Our noon conference focuses on solid tumor didactics. Fellows and attendings are present, along with a student and that the fellows’ didactic conferences are up to par, so I try to attend as many as possible. Most program directors would agree that keeping tabs on the quality of the lectures and the attendance by faculty and fellows is best done if you or the associate program director regularly attend.On a good day, the afternoon will include time spent at my desk. This time is valuable (and difficult to protect) and usually includes some fellowship-related activities. My program coordinator has a folder of e-mails about elective requests and vacation coverage for the fellows, off-campus conferences a fellow would like to attend, research plans that need to be reviewed, and other papers that need signatures. Fellows’ schedules need to be revised. Online and paper evaluations must be reviewed to ensure all fellows are progressing in the right direction. Goals and objectives are updated. Process-improvement projects and plans for research projects must be reviewed and approved. I frequently visit the Web sites of the Accreditation Council for Graduate Medical Education (ACGME), American Board of Internal Medicine (ABIM), and Electronic Residency Application Service (ERAS). The ACGME page is particularly useful right now, as I prepare for a site visit. The ABIM site is visited more frequently as annual reports become due. This year, with the change in the schedule for fellowship matches, I probably won’t need to visit ERAS for awhile, but once that starts up in the fall, I’ll be reviewing applications for what will seem like weeks.

Halfway through the afternoon there’s a page. An issue has come up. Today, one of the fellows has to leave early because her 6 year old got sick at school. We call the backup fellow, arrange a quick sign-out, and 30 minutes later everything is under control. On another day, the afternoon call will be one of the fellows who needs clarification about a policy. A week later, one of the faculty members pages me with concerns about one of the fellow’s ability to manage a rapidly growing service. Sometimes, it’s a simple call to clarify the rotation or call schedule. Whether a big problem or a small one, however, everything else gets put on hold to deal with the current crisis.

Then there are meetings; these range from individual discussions with 1 fellow to full-blown conferences that include all of the fellows. There are also semiannual reviews with individual fellows, fellowship committee meetings, and meetings with faculty to review and revise rotations.

The afternoon draws to a close and it’s time to go home. But then an hour later my beeper goes off. When I call back Maria (a third-year fellow), she says, “Sorry to bother you, but I thought you should know….” So even though I’m home, I still have to deal with this next problem, clarifying how we deal with growing services at a time when service caps on the internal medicine services are changing the landscape for all of us.

A Good Fit

Five years ago, 6 months after my second child was born, my division chief walked into my office and said “We need a new fellowship program director. Motherhood seems to agree with you—I bet this would be a good fit.” We laughed, but he wasn’t completely wrong. My fellows are a family. Although no longer children, they need guidance and mentoring as they go through the training program. They need support and someone who will be available as an advocate. Being a program director is a full-time job. As program directors for fellowship programs in hematology and medical oncology, we are teachers, administrators, and counselors—not to mention physician role models. At times we are mentors and at times disciplinarians. We are advocates for our fellows; we liaise between the fellows and the faculty and administration. The most rewarding aspects of the job come from the fellows themselves. As I watch them become confident and mature hematologists and oncologists, ready to go out into practice, I commend them on their progress and share a sense of accomplishment.

Been to your college reunion? If so, you probably spent some time basking in the admiration of your classmates, all of whom were, no doubt, quite impressed (and maybe a bit envious) that you’ve become an oncologist. And while that admiration is certainly well earned, it’s quite likely that your nonphysician classmates have something you probably do not: interviewing experience.

Think about it. While you were slaving away in medical school, your classmates were interviewing for, and securing, their first “real” jobs. And as you embarked on your internship, residency, and fellowship, many of those same classmates probably changed jobs, or even careers, all the while racking up even more interviewing experience. There is, however, some good news. Like all the other skills you’ve honed so finely over the years, interviewing can be mastered with the help of some solid tips, ample preparation, and a good dose of practice.

What to Expect

Your interviewing experience will depend upon a number of factors, including the type of position you’re seeking and the type and size of facility or practice with which you’re interviewing. In general, however, plan for a busy, all-day affair. In an academic center, for example, be prepared to interview with several individuals, such as the division director, medical director, and facility administrator, as well as the department head and other faculty members from your subspecialty.

Once you’ve survived day 1 of the interviewing process, be prepared to wait. Most academic centers have selection committees, the members of which meet with several candidates over a specified time period, and then decide which of those candidates to bring back for a “second look.” Depending on the number of candidates being interviewed and the schedules of those doing the interviewing, it could be weeks or even months before you’re called back for a second (and, hopefully, final) round of interviews. In most cases, that second session will involve additional meetings with individuals higher up the chain of command (such as the cancer center director) and might also include beginning negotiations and initial discussions about laying out a proposal.

What Your Interviewers Look For

There’s no better way to prepare for an interview than to find out what your interviewers will be looking for during those all-important face-toface meetings. To that end, Oncology Fellows spoke with Marc Stewart, MD, medical director of Seattle Cancer Care Alliance, and Steven J. Cohen, MD, fellowship director for the Fox Chase/Temple University Hematology-Oncology Fellowship Program, about how they separate the wheat from the chaff while interviewing candidates for positions at their facilities.

Question: How do you decide which candidates to bring in for interviews?

Dr. Stewart : This is usually based on our personal experience (if, for example, a fellow has trained in our program). Otherwise, the decision is based largely on the candidate’s CV, along with later discussion with the program directors at the applicant’s training site.

Dr. Cohen : We start by looking at where the fellows trained, mentors who can vouch for them, and what they’ve accomplished in their area of interest, such as clinical trials and projects of their own that could potentially translate into successful careers and meaningful research findings.

Question: What are the must-haves that you look for in potential candidates?Dr. Stewart : We look for candidates who have a focused area of interest and a solid vision about the direction and future of their career and potential contributions. We also look for academic productivity and excellent clinical reviews. Good interpersonal and communication skills also are important.

Dr. Cohen: The most important quality we look for is a true commitment to the candidate’s chosen career path, along with solid ideas about how to move that commitment forward and build upon what’s already been accomplished. We also look for individuals who will work well with others. Stated differently, we’re looking for people whose egos won’t get in the way of their willingness to be mentored and work as part of a team.

Question: What, in your past interviewing experiences, have been some of the qualities that have set candidates apart and made you want to hire them?

Dr. Stewart: Two such qualities would be publications in outstanding journals and funding.

Dr. Cohen: Nothing strikes a better chord than a candidate who knows about the center at which he or she is interviewing, and can articulate what it is that attracted him or her to that particular center. But what truly impresses us is a fellow’s ability to demonstrate and discuss his own work and his unique role in generating the data from his research.

Question: What are some common mistakes made during interviews that might result in a candidate losing an opportunity for a position?

Dr. Stewart : Failure to show a focused interest in research would definitely be considered a negative attribute.

Dr. Cohen : As alluded to previously, simply describing research conducted by a mentor rather than being able to discuss the details of a candidate’s unique role in his or her research is disappointing. We’re not looking for a literature review or a summary of the field. Instead, a candidate needs to be able to discuss the details of any research and articulate a vision for the direction that research might take in the future.

Interviewing Basics

If all of this still sounds a bit daunting, the following tips will help to position you for success during that all-important “face-to-face.”

Get your materials in order. Most larger facilities will have very specific instructions about what materials to send prior to your interview and which materials to bring with you. When in doubt, it’s always better to ask than to guess. While a curriculum vitae, letters of recommendation, and all material related to research and funding are must-haves, different centers will likely request different types of materials.

Do your research. This is no time for a cold call. Well before your interview, take some time to research not only the practice or center but also those with whom you’ll be interviewing. Doing so will allow you to ask relevant questions and demonstrate your interest in the facility to which you’re applying. The center’s Web site is a good place to start, but keep in mind that the site’s information is written by media specialists rather than medical staff members and may not have been recently updated. For this reason, a search for publications about the facility and by the physicians with whom you’ll be interviewing is a must. Whenever possible, talk to physicians who have already interviewed at the facility or, better yet, have already been hired.Anticipate questions and ask your own. Be prepared to discuss your strengths and even your perceived limitations (described as areas you’d like to improve)—and to do so with candor. And, as stressed by Dr. Cohen, anticipate detailed questions about your role in research and the direction you’d like that research to take. Just as important as your ability to answer the basic “What would you bring to our facility?” questions is your ability to ask questions about the center or practice and your role as a staff physician or scientist. Failure to ask questions conveys a lack of preparedness or, even worse, a lack of interest.

Ask your friends, ask your mentors. Don’t be afraid to pick the brains of friends and colleagues who have already been through the interviewing process. Who better to tell you what to expect than someone who has already “been there, done that”? And while you’re picking brains, be sure to include your mentors, who can tell you first-hand what they, and their colleagues, look for in potential candidates.

Conduct a mock interview. More likely than not, your fellow fellows are dealing with their own interviewinduced anxieties. Talk to your colleagues about getting together for an evening of mock interviews, in which each of you has an opportunity to play the role of both candidate and interviewer, and then ask for and accept constructive criticism. This little exercise will, at the very least, give you a sense of what to expect before the big day and, even better, likely provide you with some pointers from those who will judge your interviewing skills with objectivity.

Dress for success. The rule of thumb for dressing for an interview is to wear what you’d normally wear to work once the job is yours. This, however, doesn’t mean you should go to your interview in scrubs or a lab coat. Instead, choose attire that conveys a sense of professionalism.

Be genuine. Impressive people don’t need to try to impress. Keep in mind that a successful candidate conveys confidence and an eagerness to learn. Keep your ego in check and let your work speak for itself.

With the adoption of electronic medical records (EMRs), healthcare systems in the United States are moving rapidly toward digitization. This movement is being driven by a variety of influences, including regulatory and governmental authorities, with the aim to increase accessibility to information, reduce errors, and improve compliance with quality and performance measures. The overarching objective is to allow physicians to gain control over the ever-increasing complexity of the current healthcare system. Indeed, the American Recovery and Reinvestment Act provides for both financial incentives and punitive measures that are designed to accelerate the adoption of EMRs.1

I personally welcome the introduction of EMRs into healthcare. My own research program has benefited from the advent of information technology. Our group has utilized large healthcare data sets to conduct analyses that would not be possible with clinical trials alone and has used electronic order entry alerts to improve patient outcomes.2,3 From a clinical oncology perspective, writing chemotherapy orders is perceived to be safer and easier in EMRs, and most of us appreciate not having to hunt down paper charts for writing orders or for finding patient heights and weights.

Note-Writing in the EMR

Having transitioned to an EMR at my institution earlier this year, however, I find note-writing to be the EMR’s major shortcoming, as it tends to disrupt many of the intended uses of the traditional patient-progress note. The progress note has a long and storied tradition in healthcare, and it serves many purposes. The first is documentation, as it captures essentials of the visit and reminds physicians of their discussions with the patient. A second purpose is communication, with versions of progress notes (“letters”) sent to other providers for either information or to request input. A third—and more recent—purpose is compliance, with notes documenting mandatory preventive measures (for example, thromboprophylaxis in the inpatient setting or influenza vaccination in the outpatient setting) that can later be queried for quality-of-care audits.

The EMR first causes disruption outside of the progress note itself. Patients do not feel as engaged with their physicians, who are looking at the computer screen rather than the live patient in front of them. While many of my patients are forgiving of my focus on the screen, I find it difficult to practice mindfulness when multiple items on the screen (eg, laboratory results, flagged messages, imaging results) are all vying for my attention and competing with the actual patient. One can accept disruptions if this leads to improvement over current capabilities. However, the primary uses of the progress note—documentation and communication—are disrupted as well, because EMR notes rely heavily on templates and pointand- click software applications. Although convenient for note-writing, such choices made by software designers (and not physicians) force us to reduce our patients to the “boxes” that have been provided by the software designer. For instance, if I wanted to document that the patient at a recent visit was anxious, but the choices offered by the program are “sleeping,” “active,” “cooperative,” or “distressed,” it might be easier to pick “distressed” even though it doesn’t accurately convey the situation. This is not the physician failing to write a good note; it is a software program deficiency that narrows available choices for physicians and leads to an inaccurate capture of reality.My concerns about this issue are affirmed by a recent critique of current software design by one of Silicon Valley’s own pioneers. In You Are Not a Gadget , computer scientist Jaron Lanier states that information underrepresents reality and that current software does not have the capability to capture the nuances of human interactions (let alone the complexities of physician-patient interactions).4 Even worse for future EMR development, Lanier describes the process known as software lockin, where software choices made early in program development become entrenched for all future iterations of the program.4 In other words, the choices made in currently existing programs, if accepted by end-users (physicians) as a sacrifice necessary for transitioning to EMR, will be kept for the next several generations of medical software. As Lanier points out, software lock-in “removes design options based on what is easiest to program, what is politically feasible, what is fashionable, or what is created by chance…[and] narrows the ideas that it immortalizes, by cutting away the unfathomable penumbra of meaning that distinguishes a word in natural language from a command in a computer program.”4

Take Ownership of the Note

The genie, of course, cannot be put back in the bottle. EMRs are here to stay. What, then, can physicians do to optimize note-writing in the age of EMRs? The first step is to take ownership of the note: develop EMR “etiquette” based on consensus within your own group of physicians. When you open the record on the desktop, explain to the patient exactly what you are doing. For those who are new to EMRs, apologize in advance for having your back turned. Many of my patients find it useful if I tilt the screen toward them, so they can view what I’m viewing and I can run through vitals, medications, and test results with them. This empowers the patient to be part of the record-keeping process and reduces the mysteriousness of the screen that you keep looking at as an alternate source of information. Avoid the temptation of cutting and pasting the enormous amount of data that are freely available through the EMR and are merely repeated in the note. Keep only what is essential (with a nod to the gods of billing compliance) and capture the heart of that specific interaction with the patient, so that the primary purpose—communication— is preserved. Avoid point-and-click boxes if they do not sufficiently capture the interaction; use free text instead.

All of this is, of course, harder to practice than preach. I am still learning, and my notes do not always achieve the ideal. But if we as physicians do not take ownership of the physician-patient interaction, who will?

REFERENCES 1. D’Avolio LW. Electronic medical records at a crossroads: impetus for change or missed opportunity? JAMA. 2009;302(10):1109-1111. 2. Khorana AA, Francis CW, Culakova E, Fisher RI, Kuderer NM, Lyman GH. Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol. 2006;24(3):484-490. 3. Candelario GD, Francis CW, Panzer R, et al. A computerized prompt for thromboprophylaxis in hospitalized cancer patients. Thromb Res. 2010;126(1):32-34. 4. Lanier J. You Are Not a Gadget: A Manifesto. New York, NY: Alfred A. Knopf; 2010.

Providing medical care to patients in the hospital setting has become increasingly complicated. Large amounts of clinical data need to be processed, and new rules governing resident and fellow hours have resulted in fragmented care. There have been many initiatives to improve hospital care, and it is a process that needs continuous reevaluation and updating.

Communication between physicians has been identified as an area in which many mistakes happen. These can lead to potentially negative outcomes for our patients, such as prolonged hospital stay or death.1 In 2003, the Accreditation Council for Graduate Medical Education instituted limits on the number of hours that residents can work in the hospital per 24-hour period. Although the goal was to improve patient safety by decreasing fatigue among residents, it had unintended consequences. The rules led to the increased need for multiple handoffs of patient care among residents, fellows, and attending physicians in the inpatient setting. Unfortunately, these communications are often not standardized and may lead to disastrous results.

Change-of-Care Perils

The change of physician on duty can be a perilous time for the patients, because the majority of medical errors resulting in liability have been traced to miscommunications.2,3 The errors resulting from poor handoffs can include incomplete or incorrect lists of medications, incorrect code statuses, and inaccurate laboratory results. But the most serious mistakes are errors of omission, when the events of the last 12 to 24 hours are not relayed and the new physician does not have an accurate picture of the patient’s health.

In the studies that examined liability claims, 26% to 31% of events were due to errors in communication.2,3 There are not many data that directly evaluate physician-to-physician communication at the time of patient-care handoff. Specifically, there is a lack of data about teams caring for patients on internal medicine hospital services, although a few studies report an alarmingly high rate of errors and omissions during change-of-care times.4

Over the past 5 years, the Joint Commission has made standardized communications a priority among physicians performing patient- care handoffs. However, there is no concerted effort to evaluate and recommend the most efficient and reliable methods. Individual institutions have designed their own solutions, although there are no high-quality data on which approaches lead to better outcomes in patient care and safety. Most institutions now use some form of electronic board that can be updated by various members of the team.5

Unfortunately, there is great variation among different institutions and their approach to patient-care handoffs.6 Some of the differences stem from the fact that there are many solutions to the resident-hour rules, ranging from the night-float system to residents staying overnight in the hospital and leaving early in the morning. It is disturbing to learn that the process was not standardized across institutions nor within specific programs.6 These observations call attention to the lack of high-quality data needed to help institutions implement solutions that would assure patient safety, and to the lack of education for physicians and residents on how to efficiently and thoroughly communicate patient information to other physicians.The uniform standardization of patient handoffs across all institutions might not be possible or even desirable due to the differences between academic institutions and private institutions. Also, hospital services caring for certain patient populations have their own requirements and points of emphasis specific to their specialties. Internal medicine services and especially hematology and oncology inpatient services have increasingly complex patients with multiple medical problems. It is imperative that physicians caring for these patients have up-to-date and accurate information.

Several existing studies offer recommendations to make the process safer. Face-to-face interactions between the 2 parties is essential in limiting errors.7 This allows the physicians to ask questions and clarify information, resulting in more accurate patient data being transferred. Interruption- free time was also important in ensuring an error-free transfer of care. Computerized systems that automatically pull information from patients’ charts help to reduce errors and make the process more efficient.8

Consistency in Communication

It is clear that the process of patient-care handoffs must be made safer and more efficient. The increasing implementation of sophisticated software programs will most likely improve the accuracy of the information as well as the efficiency of the process. Unfortunately, these ancillary products will not be able to replace a physician’s necessary clinical acumen. One of the most important parts of the change of care is anticipation of potential problems and designing appropriate responses. All doctors do this to some degree while caring for their patients—often subconsciously. The challenge lies in communicating this information to others. No software program will be able to replace this interaction. Medical schools and residency programs will need to introduce or expand existing programs in teaching physicians the necessary methods to effectively and concisely hand off the care of their patients to new care teams. Likewise, institutions must continually reevaluate the process to decrease the number of poor patient-care handoffs, leading directly to improved patient safety.

REFERENCES 1. Pham JG, Aswani MS, Rosen M, et al. Reducing medical errors and adverse events [published online ahead of print January 26, 2011]. Annu Rev Med. 2. White AA, Pichert JW, Bledsoe SH, Irwin C, Entman SS. Cause and effect analysis of closed claims in obstetrics and gynecology. Obstet Gynecol. 2005;105(5, pt 1):1031-1038. 3. White AA, Wright SW, Blanco R, et al. Cause-and-effect analysis of risk management files to assess patient care in the emergency department. Acad Emerg Med. 2004;11(10):1035-1041. 4. Sehgal NL, Auerbach AA. Communication failures and a call for new systems to promote patient safety: comment on “structured interdisciplinary rounds in a medical teaching unit.” Arch Intern Med. 2011;171(7):684-685. 5. Kannry J, Moore C. MediSign: using a Web-based signout system to improve provider identification. Proc AMIA Symp. 1999;550-554. 6. Horwitz LI, Krumholz HM, Green ML, Huot SJ. Transfers of patient care between house staff on internal medicine wards: a national survey. Arch Intern Med. 2006;166(11):1173-1177. 7. Alvarado K, Lee R, Christoffersen E, et al. Transfer of accountability: transforming shift handover to enhance patient safety. Healthcare Q. 2006;9 spec no:75-79. 8. Petersen LA, Orav EJ, Teich JM, O’Neil AC, Brennan TA. Using a computerized sign-out program to improve continuity of inpatient care and prevent adverse events. Jt Comm J Qual Improv. 1998;24(2):77-87.

When my alarm goes off at 5:30 am, I wake up prepared to play many roles. Juggling family life with 2 young children, caring for my patients as a fellow, and pursuing scholarly activities leaves little free time. One of the joys of being a fellow at an academic institution is that I really do not have a “typical” day. Each workday brings a different combination of patient care and research, both of which can be challenging and exciting.

By 7 am, there has already been a lot of activity in my home. Changing diapers, feeding bottles, and searching for my elder daughter’s favorite pink dress consume my early morning. Afterward, I rush to work so that I arrive on time for rounds.

If I’m on an inpatient service, by 7:30 am my rounds are starting. The residents and interns are busy gathering patients’ vital signs and orders, and I am preparing chemotherapy orders. As a fellow on rounds, I enjoy leaving issues such as uncomplicated diabetes and hypertension to the internal medicine residents while I focus on the oncologic care of the patient. After our attending hurries off the wards to clinic, I am in charge of the service and our patients. Most days on service I spend much of the morning going over plans with the residents and—most importantly—teaching the students what they must know about our oncology patients. I try to focus less on specific chemotherapeutics, which I am still learning myself, and more on treatment of complications and communication with patients. Even though I am still acquiring these skills, one of the most useful things I can teach the students is how to deliver difficult news to our patients. Medical schools and residency programs do an excellent job of teaching facts, treatment algorithms, and disease management, but the oncology ward is the ideal place for students to learn the art of communication.

If I am the hematology or oncology consult fellow during a given month, by 7:30 am my pager has already gone off a couple of times. In my experience, the busiest times in fellowship are consult services, when you never seem to be in enough places at once. On the positive side, however, this fast-paced work helps me learn the most about a wide variety of cases.

If I am not on service, which is typical now that I am a senior fellow, my morning is somewhat more relaxing. After many months of busy service as a first-year fellow, when I became a senior fellow I welcomed the opportunity to do clinical research in the comfort of my office. I can now spend my time reading and focusing on GI research. More specifically, I am working on a review article about pancreatic cancer and a clinical protocol for neuroendocrine cancers. I’m always working on multiple projects at once in hopes that at least some get published, or funded in the case of a grant. Even as a senior fellow, it is easy to be caught up in patient care at the hospital because there is always a need for a bone marrow biopsy, intrathecal chemotherapy, or orders to be written. It’s very important, though, that I make enough time to pursue scholarly activities that will help me in my career and to become a better oncologist.

By noon, I have left the residents to manage the oncology service and I squeeze in a lecture. As a fellow, finding time to attend a lecture is a daily struggle. Between clinical work and research, it is very tempting to skip it so that I can catch up on work. Most days I do try to avoid this temptation, as the lectures are essential to my learning as a fellow.After a quick bite to eat, it’s off to clinic for the remainder of the afternoon. Now that I’ve been in clinic for a couple of years, the patients are familiar to me because I’ve had the opportunity to follow many of them as they progress through their treatment. Although my attending is in clinic with me, many of my patients now view me as their oncologist. Each afternoon in clinic is usually a mix of emotions as I share both good and bad news with them. It is not uncommon that in 1 hour of clinic I have rejoiced with one patient at the completion of her chemotherapy course and in the next visit have consoled another after learning that his malignancy has recurred. For me, each of these encounters is equally fulfilling, and I always leave clinic feeling privileged to have shared in these experiences with my patients, whether joyful or sad.

By 5 pm, although I am tired, I am excited about one of the best parts of my day. After finishing at least some of my clinic notes, I hurry down the street to pick up my kids from day care. The look on their faces when they see me is always reenergizing and is a much-needed break from the hospital. Although sometimes it is impossible, I try not to do any more work when I am at home. During fellowship, the time with my husband, kids, and friends is a precious thing. My evenings consist of tea parties with my daughter, rocking my son to sleep, and catching up with my husband. I have to admit that it is not always easy balancing my family with fellowship. It is difficult to completely keep family life and work separate in oncology because many of our patients depend on us even when it is not between the hours of 8 am and 5 pm. Although I value keeping my family life the highest priority, I also hope that the dedication and time commitment I have shown to my patients and research will be a good example for my children.

By the end of the evening, fatigue has set in and I begin to prepare for the next day. There is always a recent article or textbook chapter to be read that oftentimes needs to wait until the next day. My clinic notes need to be finished too, but they will also need to wait until the next day. The beauty of oncology training is that tomorrow will offer new challenges to find enough time in the day as well as opportunities to learn more about how best to help our patients.

What is mentorship? The term “mentor” originates with the mythological character Mentor, with whom Odysseus entrusted his son, Telemachus. Mentor was responsible for educating and instilling values in Telemachus when Odysseus departed for the Trojan War. Nowadays, mentorship is a partnership or relationship focused on education, inspiration, and support between a mentor and a mentee. This type of relationship forms part of the central structure of medical education, including hematology and oncology training. Mentorship can help drive your education, whether or not you choose to pursue a traditional academic career.

What Makes a Good Mentor?

Medical education is anything but a straight line. Different forks in the path may require guidance and counsel from individuals with unique perspectives. Thus, it is common, even ideal, for someone to identify multiple mentors as their career progresses. Though one can have multiple mentors, there are several tasks often required of a mentor or mentors. These include the establishment of trust, and the provision of logistical assistance, subjective advice, and feedback.1 Overarching these tasks is the ability and willingness to inspire, support, and to invest in a mentee.2

During my training as a resident and fellow, various physicians have acted as mentors to inspire, support, and invest in my career. As a medical student and resident, I established an important relationship with a pulmonologist with whom I met periodically for career advice and general counsel. He inspired me with both his actions and his words. I learned that medicine is a lifelong education (though the tests slowly go away, you are never done learning) and part of that education is to question the status quo, to never stop asking “Why?” It was his bedside manner with patients, however, that was most inspirational to me as a young physician. His example of placing a hand on patients’ shoulders while sitting down to listen to them, explaining their x-rays, and learning more about their life outside of the hospital was invaluable to me. Patients would open up completely to this physician and trust him immensely. He inspired me to simplify the complexities of medicine by putting the doctor-patient relationship above all else.

As a hematology/oncology fellow, 2 oncologists in particular were excellent mentors and supported me on an academic and personal level. As a new mother starting a fellowship, it was very difficult learning how to balance family life with a demanding academic schedule. Both physicians had developed successful academic careers, yet, as mothers and wives themselves, had navigated these same issues throughout their training. Their support and encouragement helped me learn to balance my time at work and at home, to be more efficient, and to understand that a successful academic career need not come at the expense of a happy family life. During my most challenging moments as a physician and as a mother, their support as empathetic mentors encouraged me to continue to work toward my goals.

I have had faculty mentors who, on a daily basis, helped me to build the foundation of my academic career. Common among them was their regular availability, constant logistical feedback, and tenacity with establishing goals and meeting them. They helped open doors for me, such as those that involved educational and research opportunities. They identified areas of my training that needed enhancement. They contacted and introduced me to colleagues, wrote letters of recommendation during my job hunt, and invited me to meetings. In short, the mentors in my medical career have demonstrated that they believe in me and are invested in my success.

Why Is It Important to Have a Mentor?Medicine is not a career meant to be staked out alone. I would argue that it is difficult to be successful if you are not in a mentoring relationship. To avoid stasis and regression, we need examples to inspire us and we need the objective feedback that an invested mentor can provide. This continuous pursuit of improvement is vital in the field of medicine, where change is constant.

The mentorship relationship is surely not a one-way street. It is vital that you take the role of being the mentee just as seriously as finding the right mentor(s). You need to be open to criticism and understand that challenges provide opportunities for growth. Instead of viewing challenges as a nuisance, you should use these opportunities to prove to yourself that you are capable of more than you may have imagined. Furthermore, you as the mentee must be just as invested in the relationship as the mentor, by being available, working hard, and spending the time to improve yourself. You should also provide regular feedback to your mentor, because there is no cookie-cutter approach to the mentoring relationship.

How Do You Choose Your Mentors?

Most of the mentors in my life have been physicians with whom I got along well on a personal level. They were physicians who inspired me and after whom I hoped to pattern my own career. From a clinician’s standpoint, I chose people to emulate who I believed were excellent clinicians, had a wonderful bedside manner, and always placed the best interests of the patient above anything else.

Finally, from an academic standpoint I looked for mentors who were successful in their field, even if they were in one that was different from mine. I knew I could learn skills such as clinical trial design or grant writing, for example, that were necessary for a successful academic career and apply them to oncology and hematology. I also looked for mentors who would take the time to meet with me on a regular basis so I could be sure I stayed on the right career path. I looked to find those who were as invested in my success as I was. I also sought out individuals who had successfully mentored others in the past.

REFERENCES 1. Glanz K, Lewis FM, Rimer B, eds. Health Behavior and Health Education: Theory, Research, and Practice. 4th ed. San Francisco, CA: Jossey-Bass; 2008. 2. Tyre RH. Mentoring to reach your highest potential, or the hunting and capture of a great mentor. Radnor, PA: The Uncommon Individual Foundation; 1995.

While debt from medical school loans is inevitable for most oncology and hematology fellows, there are strategies they can consider to lessen that burden. Moreover, recent announcements from the Obama administration would cut loan debt for some medical school borrowers.

Nevertheless, many fellows and young physicians still face substantial debt when they complete their schooling. Matthew Shick, senior legislative analyst for the Association of American Medical Colleges (AAMC), told Oncology Fellows , “Medical school tuition and fees continue to rise. The amount medical students borrow to pay for medical school has averaged around $160,000 for the past 3 years (as reported by medical students graduating in 2009, 2010, and 2011).”

Similarly, the American Medical Association (AMA) estimated the average educational debt of indebted graduates of the class of 2010 at $157,944.

However, some good news has emerged to brighten the financial outlook for borrowing students. The Obama administration announced in late October that it will reduce the maximum required payment on student loans from 15% of discretionary income annually to 10%. Obama said the plan would go into effect in 2012, instead of 2014. In addition, the White House says the remaining debt would be forgiven after 20 years, instead of 25. The proposal is expected to affect some 1.6 million borrowers starting in 2012.

In other good news, AAMC’s Shick said that recent statistics indicate that “Since 2008 we’ve started to see a recent trend of medical education debt leveling off.”

Finally, the economic stimulus bill that President Obama got through Congress includes an additional $300 million for students who agree to take public service jobs, including those in medicine.

Still, many observers of healthcare trends contend that the spiraling debt burden has serious consequences for American medicine. For example, Catherine Spina, MD, a PhD candidate at Boston University School of Medicine, and immediate past chair of the Organization of Student Representatives (OSR) of the AAMC, wrote in a newsletter in February 2011: “The grim financial outlook of state-funded schools has translated to an increased burden on the learner. As a result, many matriculating medical students arrive with more debt from their undergraduate educations and are forced into deeper debt as they shoulder the expense of soaring medical school tuition.”1

One possible consequence of the crushing weight of debt, according to some observers, is to steer young physicians into the higher-earning specialties rather than lower-paying primary care medicine. S. Ryan Greysen, MD, assistant clinical professor of medicine for the Division of Hospital Medicine at University of California San Francisco, who has written on the subject for The New York Times , said that “My sense is that the rising cost of medical education may be part of a cultural shift where the practice of medicine is more of an investment than a calling. I make the argument in my [New York Times ] article that medical education is seen now as a personal investment and I hear colleagues refer to their debt as a ‘mortgage,’” especially since “obtaining medical education in the United States has become a loandependent, individual investment.”

Greysen is quick to point out that the data on how school loans affect the kind of medicine young physicians choose to take up are ambiguous, with some studies showing that it has minimal effect.“The studies here are often conflicting—some show that students with higher debt are less likely to practice primary care or work with underserved populations but others show there is no relationship with debt,” Greysen said. “Several recent studies have shown correlations between debt and stress or burnout—and these may affect students’ decisions about which specialty they enter,” he added.

Shick said of this issue: “In the 2011 AAMC Graduate Questionnaire, students reported personality fit, specialty content, work/life balance, role model influence, future family plans, fellowship training options, income expectations, length of residency, competitiveness of specialty, and expectations of family as having a higher influence on specialty choice than student debt.”

However, he added: “That being said, the cost of medical education weighs more heavily on certain cohorts of students. With the high price tag and expected debt burden, the decision to attend medical school can be daunting for socioeconomically disadvantaged and minority students who are typically more averse to taking out high loan volumes.”

Nonetheless, oncology and hematology fellows do have choices that can substantially reduce their debt.

Public Service

One of those choices is public service medicine that makes young physicians eligible to receive loan repayment programs (LRPs). Applicants for these programs must agree to commit to practicing for a specified time in a medically underserved region of the United States or in research at an approved institution.

The National Institutes of Health (NIH) is the largest provider of LRPs, recruiting physicians to practice in areas designated by the US Health Resources and Services Administration either as a Health Professional Shortage Area or a Medically Underserved Area. To qualify for this program, applicants must be willing to work full-time serving patients in the designated areas.

For example, the American Society of Clinical Oncology LRP, funded by Susan G. Komen for the Cure, provides repayment of qualifying educational debt to oncologists or oncology fellows who, after completing their training, commit to practicing oncology in a medically underserved region of the United States. The LRP will repay up to $35,000 per year for 2 years (up to $70,000 total) of qualifying education loans. For questions, contact grants@ asco.org or call 571-483-1662. [Editor’s note: For more on loan repayment programs, see Finance for Fellows in the October 2011 issue of Oncology Fellows .]

Increased Funding for Public Service Medicine.

The LRPs get funding through the National Health Service Corps (NHSC), which has been given a financial boost from Congress and the Obama Administration. The American Recovery and Reinvestment Act of 2009 (the so-called stimulus package) provides an additional $300 million in funding for NHSC, including $168 million for LRPs, to increase the physician workforce in medically underserved areas.

According to AAMC’s Shick, the expanded funding means that NHSC practice locations will increase significantly, to include urban and rural areas not previously designated as health professional shortage areas. He predicted that the program, which is already strong, is going to be even stronger, providing many more opportunities in urban areas than there were in the past.

An option for oncology and hematology fellows is military service. The Armed Forces, through the Health Professionals Loan Repayment Program (HPLRP), offer up to $40,000 per year to physicians who commit either to active duty service or to service in the National Guard or Reserves, or to the Veterans Health Administration. [Editor’s note: For more on HPLRP, see Finance for Fellows in the October 2011 issue of Oncology Fellows .]

Ideas for Reducing Student Debt The AAMC, Shick said, has advocated strongly for the following proposals:
    • Reduce the amount of interest paid on federal Stafford loans through the Department of Education. At the current 6.8% rate for graduate and professional students, medical students can expect to repay between $300,000 and $450,000 on the average $160,000 medical education debt (between $140,000 and $290,000 in interest).


    • Increase funding for the NHSC, the federal program that provides scholarships and loan forgiveness in exchange for primary care practice in underserved areas. Additionally, Shick said, the AAMC sponsors Financial Information Resources Services and Tools (FIRST) for medical education. He said this program “offers a full range of resources for medical school applicants, students, and residents to help expand their financial literacy, make smart decisions about student loans, and manage their student debt wisely.” Students and fellows can learn more about this program online at www.aamc.org/first.




REFERENCE 1. Spina C. Viewpoint: Drowning in debt: innovate or else. AAMC Reporter. https://www.aamc.org/newsroom/reporter/ feb11/174772/viewpoint.html. February 2011. Accessed November 30, 2011.

At first glance, you might be struck by the seemingly odd distribution of oncology salaries in the United States. For example, why would oncologists in the Mid-Atlantic region, where the cost of living is relatively high, have lower median salaries than the North Central region, where the cost of living is lower? According to Medscape’s 2011 report, it is due to the higher concentration of research hospitals and community oncology practices in the Northeast, Mid-Atlantic, and West. These institutions increase the competition for oncology positions and thus lower the median salaries. “By  

Quoting statistics seemed to be a refuge to me. The objectivity of the numbers provided a hiding place and a shelter, and they helped me maintain the emotional distance that my profession demanded.

She repeated, “Can you cure me?” I responded, “Well, I cannot guarantee a cure, but we can try.”

Her History

She had received 3 cycles of neoadjuvant chemotherapy for her breast cancer and then decided that it was not for her. She did not follow up with her subsequent appointments. Then, she arrived one day in the emergency department, extremely short of breath. She had a pleural effusion that almost completely filled her right thorax. The pleural fluid was drained and she felt much better. Next was the question of treatment of the breast cancer. The medical team discussed the issue with her, but she insisted that she did not want any more treatment. That is when I first met her, as an oncology fellow on the consultation service.

I was briefed about her by an intern. There I was, a firstyear oncology fellow in my not-so-crisp white coat, with a smile hiding my exhaustion as I walked into her room. She was a black woman in her early 50s (but looked much younger), with beautiful, carefully arranged dark hair, smiling and cheerful. She did not wear hospital clothes but rather a bright and colorful gown, matching nail polish, and somewhat large jewelry. She was bent forward in bed but was not uncomfortable.

After introducing myself, I asked her how she was doing and started my history and physical examination. As I examined her I realized she had a rock-hard right breast, with stretched skin that was warm and puckered where the lymphatics had presumably been invaded. The skin was so tight that I imagined it could break open any moment and pour forth the tumor that lurked within. She had large rock-hard lymph nodes in her axilla and in the supraclavicular region. She could not lift her right arm beyond 30 to 40 degrees. Her entire right arm and forearm were swollen. She said this had occurred only within the last 2 weeks.

She denied feeling any pain and felt well except for the shortness of breath that had brought her to the hospital. She wanted the pleurodesis because it would prevent the fluid from reforming, and she would not have to get admitted to the hospital again. After that she wanted to go home. That’s all she wanted.

Refusing Further Treatment

I pressed for reasons why she had stopped her treatment. Was she having unmanageable side effects? We could switch her to alternate drugs. Treatment options for breast cancer are numerous, I explained. Was the treatment not shrinking the tumor? We could change the regimen or send her for radiation or surgery, possibly followed by chemotherapy. Was it a long and difficult commute from home? We could arrange transportation. Did she understand her medical condition? I told her that she had triple-negative breast cancer, an aggressive form of cancer that without treatment could progress rapidly and take her life away.

“Yes, I know,” she said. “I thought about it several times, and I decided 3 months back I do not want any more treatment; the Lord wanted me to get 3 cycles and the Lord wanted me to stop.”

I said, “I realize this and am not trying to persuade you (even though I pretty much was), but I want to make sure that you understand the seriousness of your decision not to opt for any treatment. The choice is yours but I want you to carefully consider your options before deciding.”

“Yes,” she smiled, “I understand.”

So I decided to change tactics. Did she have a family?“Yes,” and her face lit up in a wide smile, “4 children, all grown up; 3 grandchildren, of all different ages.” They would all come to visit her that evening. They knew about her decision. Her daughter had objected initially, but had finally reconciled herself to her mother’s decision.

“Can we do anything to make your treatment experience better?” I pressed one last time.

“Well,” she sighed, “it is not about the treatment or the doctors or even the cancer.” This was about her. She had decided that she did not want to fight this thing anymore. No external factors had influenced her decision. She had decided 3 months ago that she did not want any more treatment. She had a few things to take care of, which she already had. She was at peace and ready to move on.

The conversation lasted about an hour. Just like all the other members of the medical team taking care of her, I had attempted to understand my patient’s reasons for refusing treatment. We had all tried, to different extents, either by questioning her repeatedly to ascertain her level of understanding or by talking about her family’s wishes or by subtly expressing our disapproval, to somehow persuade her to get more treatment. We had all failed.

That day, I came out of the room feeling disheartened, as if I had not done my duty. I did not understand her reasons; I had not been able to think of anything I could say that would make her change her mind.

On Her Own Terms

Months later I saw her daughter, who was visiting the hospital. She told me that her mother had died, at home, with her family at the bedside—probably a peaceful, quick, silent death. They had a big family dinner the night before. She had cooked for everybody and had been the ever-gracious hostess; there was music, love, and laughter in the household. And when the family woke up the next day, she was no more. That was how she had wanted it. She had died just as she had lived her life: on her own terms. As I reflect back, I think about the day I saw her in the hospital. The sunlight streaming through the window of her 11th-floor room overlooking Center City Philadelphia, the certainty and determination written all over her face as she smiled at me, the tragic beauty of it all.

And I wondered: How long a discussion was long enough? When do we cross the thin line between attempting to understand our patients and imposing our opinion or conveying our disapproval of their decision? And when they do not agree with our opinions, how do we refrain from judging them for it? Or how do we leave the room not feeling annoyed and defeated? How do we, as physicians, not give up on our patients, even when they do not agree with what we think would be the right thing for them? How and when do I stop being a medical professional with firm, confident medical opinions, stop being a medical oncologist bent on eradicating disease at any cost, and become a fellow human being? Sometimes I wonder if it is then that we are closest to conquering cancer.

It seems the older I get, the more frequently high school students, undergraduates, medical students, or residents drop by my office to talk about career choices, inquire about shadowing, or request an interview for a school project. “Tell me about your typical day,” they’ll ask. That is a challenging question to answer, because there is no such thing as a typical day. That response usually leaves my questioner a bit frustrated. I go on to explain, however, that my inability to answer is part of the beauty of this remarkable field. For example, as I write this article, I am on an Ethiopian Airlines flight to Addis Ababa to participate in a multicountry initiative to bring pediatric oncology care to the children of Ethiopia. Just 10 years ago, I never in my wildest dreams would have imagined that such a mission would be part of my pediatric hematology/ oncology duties. So, a typical day? I don’t believe that exists, because our days are punctuated by the unexpected and our field is so diverse that we often change what we do over the course of our careers. Time alters us and our field.

Expect the Unexpected

There is no typical day because we live in an ever-morphing world. We counsel our patients to expect the unexpected, but we would be wise to tell ourselves the very same thing. Many is the day I have looked forward to quiet time in the office so that I can catch up and clear my head, but then my pager will sound and the emergency room will call. “Dave, we have a 4 year old down here with headaches and vomiting, and the head CT scan does not look good. Help!” Or a worried parent will call to talk about her 10-yearold daughter, who just finished treatment for acute lymphoblastic leukemia and now has a little knot behind her left ear. Or there is a sad meeting with a bereaved parent who just needs to talk. Or, on a more cheerful note, a chance encounter with a bushy-haired, lanky teen—a 10-year survivor of Ewing sarcoma whom you would never in a million years recognize if he didn’t have his parents with him. So, seldom is the “quiet” day quiet.

A typical day does not exist because even when things go as planned, there is so much variety in the things we do. On Monday and Tuesday I might attend on the inpatient clinic service; Wednesday might find me devoted to administration and teaching; and on Thursday and Friday I may be focused on research. Even within each day there is further variability. One patient may be here for routine follow-up for sickle cell anemia, whereas the next is a 13-year-old boy with a white blood cell count of 100,000 and an enlarged spleen. A clinical research day may run the gamut from enrolling a child in a study to filling out endless Serious Adverse Event (SAE) Report forms to conference calls on how to conduct a particular clinical trial.

A typical day does not exist because as the years go by our careers flow in different, unexpected directions, and what was typical for us 10 years ago may bear little resemblance to what is typical for us now. In my own career, 20 years ago, my days were spent juggling test tubes in the lab with time in half-day clinics that morphed into 3/4-day clinics that morphed into full-day clinics—not to mention long stretches of wearying time in the inpatient trenches. Twenty years later, I am a very happy clinician who spends most of his clinical time caring for children with brain tumors, running a pediatric palliative care program, administering a fellowship, and delving into international pediatric hematology/ oncology.

Then and NowA typical day does not exist because not only do we change as we grow older (or shall I say, more mature ), but the times change as well. Twenty years ago, a desktop computer with Internet access was as far from standard issue as a landline is for a college student today. My typical day included very little time at the computer, because there just weren’t that many computers. Besides, there was not that much in the way of online medical information to click and scroll through, even when I had this novelty at my fingertips. So, a typical day 20 years ago in the Webless era included playing phone tag to reach referring physicians and experts in the field, calling labs for results, and reading through piles of hard-copy lab reports. Now that typical day includes many hours at the laptop, desperately trying to keep up with e-mails and trying to keep my cool in a vain attempt to decipher the bewildering electronic medical record system. Twenty years ago, a typical day might include an occasional tiff with an insurance company, whereas now our days are filled with skirmishes over prior authorizations and battles over covering the medications we know our patients need. Twenty years ago, we gave little thought to how much revenue our care and our notes would bring in. Now our typical days are filled with careful scrutiny of what we write, not just for the purposes of medical care but for the need to bill commensurate with what we document.

So, in a nutshell, there is no typical day. And I for one would not have it any other way. I love the stimulation that the unexpected brings. I love the different sorts of gratification I get from a day spent teaching, in clinic, or on service. And I love the fact that nothing is static—that we change and the times change.

That said, there can and should be constants in our careers and in this field from day to day and from year to year. Overall, my passion for the field and the privilege of being a part of it is unwavering. I believe that is a thread that connects each day and represents what is typical in the world of pediatric hematology/ oncology—not just from day to day and year to year, but from generation to generation. And perhaps the most important constant of all—at the core of all we do—is sitting at the bedside of the child with cancer and his/her family, stripped of time, technology, and the trappings of the modern era. May that relationship with child and family, and that perilous trip with them from diagnosis down whatever road it may take us, forever be a part of our typical or atypical day.

Quality Oncology Practice Initiative (QOPI) is an oncologist-created quality improvement program developed and maintained by ASCO. It is important to be able to objectively review the care that is given in your institution in order to improve the quality of care that is ultimately delivered. The QOPI program creates a uniform measurement of the quality of care delivered by an oncologist; this affords self-examination and directed improvement of practices. QOPI enables self-assessment through twice-yearly retrospective medical chart reviews that are designed to be used in the outpatient hematology/oncology setting. The collection of data from medical records applies identified universal quality measures that have been defined and developed by practicing medical oncologists based on established consensus guidelines. QOPI is designed to objectively measure parameters reflective of quality care that are managed by the medical oncologist. The results of each chart audit allow participants to compare their findings against other participating groups, enabling them to direct their efforts of quality improvement by identifying areas of deficiency.

Why should fellows be involved in QOPI?

There are many benefits to QOPI. At its most basic level, QOPI places an emphasis on documentation. In medicine, we have all been told, “If it is not documented, it didn’t happen.” QOPI also focuses our attention on specifically what is important to include in an oncology patient’s medical record, which is paramount in a fellow’s education. For example, we may know that a particular chemotherapy in a certain case is for palliative intent and we may have discussed it with the patient, but it should be explicitly documented. QOPI also exposes us to continual practice-based quality improvement, which is one of the ACGME core competencies for fellowship. Participation in QOPI satisfies the practice-based improvement component of the ACGME requirements.

What type of information do you obtain from the charts?

QOPI includes a variety of modules from which to choose. Some modules are universal (Core Measures, End-of-Life Care, and Symptom/ Toxicity Management), and others are disease specific (Breast Cancer, Colorectal Cancer, and NHL). Our fellowship program plans to participate in the Core Measures and Symptom/Toxicity Management modules for the spring 2012 audit. (There are 2 audits each year, in the spring and fall.) These 2 modules contain 34 total data points (25 Core Measures and 9 Symptom/ Toxicity Management measures) to be collected from patient charts. An example of the Core Measures data includes identifying chart documentation of pain assessment: Was the patient’s pain documented and quantified by the second visit? Was a plan documented for the treatment of moderate/ severe pain? If narcotics were prescribed, was the effectiveness documented at the next visit, and was constipation addressed? These questions address 5 of the 25 core measures.

How does the program work?

One or several modules are chosen, and charts are sequestered for audit. It takes approximately 30 to 45 minutes to audit each chart. After the data are collected, they are entered into a Web-based program that is maintained by ASCO. The data (expressed as percent compliance for each measure) can then be reported in a variety of ways. Percent compliance for each measure can be reported by overall practice or broken down to report each individual physician/fellow. The results can then be compared with the overall database results. This allows each program to compare its compliance with results from previous audits in order to gauge its overall improvement, as well as to judge overall performance in comparison with other programs.How does your program incorporate QOPI for the fellows?

The Allegheny General Hospital has been using QOPI on the attending level since 2006, and it is being initiated on the fellow level in spring 2012. To prepare for the addition of the program, we have been asked to keep track of at least 10 patients from our continuity clinic to submit for the spring 2012 audit. We were asked to choose our patients based on the following criteria, which are established by ASCO QOPI guidelines: patients must be diagnosed with an invasive malignancy in the past 2 years and must have had 2 office visits in a 6-month-period. Additionally, we were asked to choose patients whom we were involved with directly in development of the treatment plan and its documentation. In spring 2012, we plan to submit our 10 patients for review by another fellow in the program. Charts will not be self-analyzed in an attempt to prevent bias in regard to interpretation of the documentation.

In preparation of initiation of QOPI, the fellows were involved in auditing charts for the attending-level spring 2011 audit. At that time, each fellow was asked to review 2 charts that had been previously audited by a third party. We were instructed not to interpret the documentation and to record data based directly on what was documented. For quality control, our individual audits were compared with audits previously performed on the same charts by a third party to determine reproducibility of results. When compared, the results were within 2%, which indicated that we were auditing the charts appropriately.

How will we use the results of the audit?

We plan to meet after the spring 2012 audit to review our results and formulate a plan for improvement based on our discovered deficiencies. We are excited to participate in the spring 2012 audit, and we are interested to see how our fellowship compares with the practice as a whole and to other fellowships regarding these measures of quality. We were left wondering, however, if QOPI truly measures quality of care, or if it simply measures the quality of documentation. Either way, we believe it is a good tool to utilize in fellowship to help prepare us for our careers in hematology oncology.

Many of us training in the United States have encountered patients and their families from resource-limited regions of the world—families who have uprooted themselves for the chance to save the lives of their children diagnosed with cancer. This will not come as a surprise when you review the cancer survival rates worldwide. The United States’ current 5-year overall survival rate for childhood cancers is 80%. Compare this with 30% for childhood cancers in Colombia, 20% for acute lymphoblastic leukemia (ALL) in Malawi, and close to 0% for most childhood cancers in Ethiopia. An estimated 100,000 children worldwide who die without treatment do so without access to palliative care.

It is estimated that 70% of the children with cancer in developing nations with cancer receive substandard care, if any care at all. The incidence and mortality of cancer in the United States has declined dramatically over the past 50 years because of increased awareness, prevention, earlier detection, and increasingly effective treatment protocols. After reading numbers like these in developing countries, it behooves us as future pediatric hematologists/oncologists to help eliminate this disparity, especially since many childhood cancers are highly curable. So how can we make the biggest difference? Sharing our knowledge effectively with the rest of the world is a great start.

Bridging the Gap

Twinning programs, developed by the St. Jude’s Children Research Hospital, have become a successful model to help bridge this gap. Twinning partners high-income countries with resource-limited institutions to share information, organizational skills, and technology. One example is the Instituto Materno Infantil de Pernambuco, a St. Jude’s partner hospital in Recife, Brazil, which showed dramatic improvements after twinning with St. Jude’s by its markedly reduced rates of abandonment of treatment, relapse, and death due to toxic effects of treatment.

Another outstanding example of well-appointed funds exists in Egypt. Through a unique fund-raising strategy via the Association of Friends of (Egypt’s) National Cancer Institute, Egypt’s Children’s Cancer Hospital 57357 (http:// beta.57357.com) opened in 2007 in El-Saida Zenab. This very modern facility has been able to change Egypt’s cancer survival rates from less than 40% to 75% to 80%.

Other Resources

The Cure4Kids website is a tremendous resource for oncologists all over the world (www.cure4kids.org). Many other institutions have built international initiatives, including Baylor College of Medicine, Dana Farber Cancer Institute, Children’s Hospital Los Angeles, and Georgetown University, among others.

A well-established international organization is the International Network for Cancer Treatment and Research (INCTR; www.inctr.org), which is headquartered in Brussels, Belgium, and has branches in Brazil, Canada, Egypt, France, Nepal, Cameroon, India, Tanzania, the United Kingdom, and the United States. Among its many tasks, INCTR has successfully devised lower-cost protocols for ALL and lymphoma; provided education and training for cancer treatments; and supplied supportive care, psychosocial support, and palliative care.

The International Society of Paediatric Oncology (SIOP) holds annual conferences worldwide and is an excellent medium for sharing information. The International Confederation of Childhood Cancer Parent Organizations (ICCCPO) spans 5 continents and follows in this same vein, as does the World Child Cancer organization (www.worldchildcancer.org). Other outstanding organizations include the Asociación Hematología y Oncología Pediátrica Centro Americana (AHOPCA) and the Union for International Cancer Control (UICC).In June 2011, Princess Dina Mired, director general of the King Hussein Cancer Foundation, delivered a keynote speech at the United Nations intended to bring awareness to noncommunicable diseases that include cancer, heart disease, diabetes, and chronic respiratory illnesses. These 4 categories of illness account for more deaths worldwide than all other causes combined. This is an example of how cancers, including pediatric cancer, are gaining recognition and how the geographic inequalities in treatment are beginning to be addressed.

On the Ground in Malawi

A close friend of mine, Nader Kim El- Mallawany, MD, is a recent pediatric hematology/oncology graduate who has been working for the past 2 years in Malawi, a country in southeast Africa that has been hit hard by the AIDS epidemic. His work there has primarily centered on patients who are HIV-positive and have Kaposi sarcoma (KS)—specifically, trying to improve the diagnostic and therapeutic approaches for these patients.

“We have about 20 to 25 children diagnosed with KS per year in our clinic, and this is probably an underrepresentation of the true numbers of children with KS in the surrounding areas, because very few clinicians are aware of the nuances of presentation of KS in children,” said El-Mallawany.

He also supports the pediatric oncology ward in the central hospital. “The most common diagnosis is Burkitt lymphoma, but certainly children present with a wide array of different diseases, including leukemia, solid tumors, Hodgkin disease, and other non-Hodgkin lymphomas,” he said.

“Because there is a paucity of subspecialists in this setting, teaching is one of the most important tools we can provide,” El-Mallawany noted. “We can significantly improve outcomes for common diagnoses by providing fundamental tools and carefully constructed protocols that are sensitive to the available resources and practical limitations that clinicians encounter.”

He finds his work in Malawi “rewarding, more so than any other work I have ever done.” He said, “Small and simple interventions can have very positive effects for the patients and their families. Yet at the same time, the work can be frustrating when you consider the limitations imposed upon us by the severe shortage of resources. Therefore, with time, you come to figure out how to bridge the gap between these 2 extremes and try to provide the most effective therapeutic approach for the patients.”

El-Mallawany encourages international outreach because “there are very few subspecialists in the region bringing knowledge and teaching to local clinicians. Our colleagues throughout the world are trying their best to overcome the challenging situations that they struggle with on a daily basis, and empowering them with the sustainable tools to carry on treating pediatric cancers will be valuable for years to come.”

So how did he make this a reality? “Ultimately, it was simply a matter of deciding to make the move and finding the right opportunity,” he stated. He said that he made this decision “understanding that in a field like oncology, we cannot expect to go somewhere that is lacking so many resources and try to deliver the exact same approach as that which we are used to in the Western world.” El- Mallawany continued, “Yet nonetheless, we can try to effect systematic changes that aim to improve the outcomes and opportunities for individual children.”Fellows who travel to other countries to help should not expect to work only in their field. El-Mallawany noted that they will need to “be aware of the context in which healthcare programs are trying to deal with diseases like cancer. When millions of children around the world still die of easily curable illnesses like malaria, diarrhea, pneumonia, measles, tuberculosis, malnutrition, etc, we must understand that our approach as pediatricians and as hematologist/oncologists should be driven by a goal to improve child health overall.”

As hematology/oncology fellows, we work with colleagues from multiple specialties. However, the majority of our interactions are with the internal medicine service, so here we will help you to maximize the quality of your interactions with internal medicine residents. In the following paragraphs, you will find many ideas that if followed will not just help you to “do your time” during fellowship, but contribute to the internal medicine residency program. And who knows, you just might inspire a resident to pursue oncology as a career!

Generally, fellows work with internal medicine residents on the consultation service and on the inpatient oncology service. Thus, I will focus on these settings. At the end, there are also some general considerations that can be applied throughout your fellowship.

The Consultation Service

The consultation service is the bread and butter of the hematology/oncology fellowship. As a future consultant, you are expected to develop the skills necessary to become an effective and efficient team player. Remember, you have been consulted for clinical guidance in answering a question, no matter how simple it may seem to you. The following is a list of points to consider:

Do not belittle a consult. Residents are not born hematologists/ oncologists—there is a reason why they are consulting you. Belittling a consult only creates tension between the consultant and primary team. Treat every consult as a learning and teaching opportunity.

Understand the questions being asked. It is imperative to know what questions the consulting team are asking. This is best clarified by speaking to the primary team directly. Oncology patients frequently have multiple problems. You do not want to write a detailed note regarding management of lung cancer when help is requested to evaluate thrombocytopenia.

Establish the urgency of the consult. Once again, this is best established by speaking directly to the consulting team. As 7fellows, we receive many consults of varying urgencies. Triage is of utmost importance. A 5 pm consult for thrombotic thrombocytopenic purpura is very different from a 5 pm consult for a mild chronic anemia.

Gather all patient-related information yourself. For an effective consult, every piece of clinically relevant data must be known. If this requires calling different offices and physicians, it is far more efficient to do it yourself than to delegate it to the primary team. We are often searching for specific information from a hematology/ oncology perspective, which the primary resident may not yet be qualified to address. Not only is this a fellow’s responsibility, but it also expedites the consult, preventing the patient and primary team from waiting in limbo.

Communicate recommendations. When you’re finished writing your note, it is best to call the resident on the consulting team and verbally communicate your recommendations. Most training programs require that consultants not place orders on patients and instead allow the primary team to write all orders. This prevents multiple orders on the same patient and also serves as an opportunity for resident teaching. Speaking with the residents also results in quicker implementation of your recommendations. If you are unsure about the specifics of a recommendation, check with your attending before writing them down.Do not offer unsolicited advice. It is important to understand your role as a consulting fellow. It may seem natural to comment on issues like electrolyte disturbances, hypertension, and diabetes with recommendations on how to correct them. This is especially true for first-year fellows who are just coming out of residency and are used to managing every aspect of patient care. These comments are often not welcomed by the primary team or other consulting specialties. Thus, it is probably better to stick with making recommendations specific to your expertise, unless there is a glaring issue.

Provide educational material. Providing an article addressing the consulting topic improves patient care and resident education. Not only will this give credence to your recommendations, but it will serve as testament to your commitment to resident teaching. The extra effort to provide education today may even save you an extra consult on a busy day.

Provide appropriate follow-up. Your role as a consultant does not end with the initial consult. It is your professional responsibility to provide appropriate follow-up until the primary team is satisfied that their question has been answered. Consultation can conclude when the primary team feels comfortable managing the issue for which you were consulted.

The Inpatient Service

Many programs have inpatient oncology, hematology, or bone marrow transplant services with resident and fellow coverage. The fellow serves as the junior attending and is encouraged to make decisions regarding patient care, as well as to take an active teaching role. It is important to make these services worthwhile for residents so that instead of considering the rotation a burden, they see it as an exceptional educational experience.

Treat residents as your colleagues. Do not consider residents as simply “help.” They should be treated respectfully, and it is your responsibility to look after their well-being. The service runs far smoother if the residents feel they are part of the team and not just there to do grunt work.

Respect the residents’ time. Learn to run an efficient service from the get-go. As the liaison between the attending and the residents, you will be in the best position to coordinate a smooth service. This ensures that the resident’s time is not wasted waiting for rounds to finish, etc.

Teaching. Teach residents on a daily basis. Be it a 5-minute talk on common hematology/oncology topics or reviewing board questions, residents will appreciate your commitment to education. With education incorporated into resident interactions, the internal medicine program will see the value and continue to staff the inpatient oncology service with residents.

Minimize scut work. Try to help out the residents from time to time in areas where there is no educational value, such as appointment scheduling and gathering outside records. This goes a long way in establishing rapport with your residents.

General Considerations

Outside of the 2 major settings described, there are many other opportunities to contribute to the internal medicine program.

Attend morning reports as a subject expert. Hematology/ oncology patients are invariably presented at morning report. Since it is hard to be well versed in our specialty at a resident’s level, it is of great benefit to the program to attend these sessions. This develops a healthy relationship between yourself and the program and establishes your commitment to resident education.Help with board reviews. Another area where you can pitch in is at board review sessions. Many internal medicine programs will arrange these sessions for their third-year residents. You can provide guidance in how to approach hematology/ oncology questions and identify the key issues. This is an easy way to enhance the quality of the internal medicine program and cement resident-appropriate teaching points.

Help with research. In every program, there are residents aspiring to be fellows like yourself. They will invariably want to get involved in research projects. Attendings are often hard to get a hold of, so you can serve as a great resource. Include residents in your research or develop ideas with them that they can pursue on their own. This act of goodwill will help them advance their careers.

Following the above advice will not only help you train as an effective teacher and team player, but will add immense value to the internal medicine residency program. As future hospitalists and internists, today’s residents will look to your teachings in their care of patients with hematological or oncological problems. In the end, remember this twist on the famous quote by John F. Kennedy: “Ask not what your residency program can do for you, ask what you can do for your residency program.”

Cloud computing refers to Web-based programs that allow the user to store information in a central location, typically not the device being used to access the information (such as your laptop, desktop PC, or iPad). In this article I will describe 4 valuable programs that I have discovered during my fellowship: Evernote, Dropbox, GoodReader, and EndNote.

Evernote

Upon reflection, most senior fellows realize that they entered their fellowship with just a small fraction of the specialty knowledge that they have today. During the course of our training we acquire little gems of knowledge from our peers and attendings, and many times we write these down on little pieces of paper, on the back of patient lists, and on small steno notepads. The problem with this method is that there is no way to arrange, rearrange, or efficiently search the accumulated information.

Fortunately, I discovered the free program Evernote (www.evernote.com), a cloud-based note-taking program that is available for Mac OS X, Windows, BlackBerry, Apple iOS, and Android. The iOS program comes with an iPhone/ iPod Touch version as well as a version scaled natively for the iPad. Regardless of on which device a note is made or edited, it is automatically synchronized to the cloud.

Evernote has a Web-browser interface, so you can access and update without having to download the program to each computer. When an update is made with Evernote through any of your devices, the changes are synchronized when logging onto another device. Everything is updated all the time. Evernote can be a repository of information from books, but also more practical information learned in clinic and on wards. These small bits of information can be arranged however you like. But the icing on the cake is being able to search through your notes. Don’t remember the TKI resistance mutations? Search your Evernotes and they will come back to you.

Sharing is another nice feature of Evernote. If you feel your notes would be helpful to the incoming class of fellows, it is simple to designate a folder or folders to be shared with other Evernote users. This can be simple information, such as frequently called telephone numbers, or more complex material, like the initial workup of a particular disease. The sharing feature is helpful for rotating residents on the hematology or oncology service.

The word processor–like interface of Evernote is basic, with only simple formatting available, so it is not nearly as encompassing as a stand-alone word processor. This may be a limitation for some users. Another drawback for some may be the data limit. Each user has an upload limit of 60 MB per month with unlimited storage. There is also a cap on data transfers per month, but additional storage and data transfer can be purchased. (I’ve never even come close to the monthly data limit.)

Dropbox

Another issue that you undoubtedly deal with is the accumulation of journal articles that are printed and then end up in a huge stack on your desk. Why not use a cloudbased program for this as well? I found that Dropbox (www. dropbox.com) is a very useful program to store those PDF articles—and many other things, too. The articles can be saved to the Dropbox folder and accessed through the Dropbox app (on iPhone, iPod Touch, iPad, Android, and BlackBerry devices) or they can be downloaded to your Windows, Mac, or Linux computer. Dropbox is basically just a shared folder that is synchronized in the cloud.

GoodReaderAn even more powerful, robust app to use for articles is GoodReader (http://www.goodiware.com/goodreader.html), especially if you have an iPad. There is also GoodReader for iPhone and iPod Touch, but these are different apps than the iPad version. It is not free, but for $4.99 GoodReader is still a great deal as it allows you to annotate PDF articles directly on any of these devices. The articles are managed locally on the device rather than in a folder in the cloud, but the Dropbox folder can be integrated into GoodReader.

EndNote

You will probably also need to write research papers or protocols during training. Although it is neither free nor inexpensive (the full Windows and Mac versions are $249.95 for a download, and upgrades are $99.95 for a download), the EndNote (www.endnote.com) program, which makes your research and citation tasks much simpler, is used by many fellows. EndNote has also begun to utilize the cloud as well. Instead of having to carry a USB thumb drive with all the EndNote data files, you can access the EndNote website’s cloud system for online storage. This online library allows you to synchronize citations later, especially when you are working with multiple computers.

As we move forward in our oncology/hematology careers, there will be an ever-increasing amount of information to handle. The use of programs like Evernote, Dropbox, GoodReader, and EndNote can help us become efficient at managing and consolidating this information. As a note of caution, these programs should never be used for HIPAAprotected information such as sign-outs or patient notes.

Everybody is aware that career choices in oncology abound these days. But when you ask fellows what job they are interested in once they complete their fellowship, many just don’t know—even in their third year. This isn’t surprising, because we’re so busy with patient care and learning more about oncology and hematology that little time is left to contemplate our careers after fellowship. Instead, our time is spent adapting to our new fellowship training programs in our first year and then consolidating our knowledge in our second year. Then before we know it, it is time to apply for a job. Although we have waited for this opportunity for many years, now that it’s arrived most of us feel ill-equipped to make a decision. For this reason, organizing an oncology/hematology fellows’ career day is very important.

A fellows’ career day is best held in an informal setting— and ideally with the involvement of a few local hospitals’ fellowship programs. You should invite a diverse group of fellows so as to ensure that everyone is exposed to a number of career choices. In my opinion, the career day is best held between September and December, as the first-year fellows have by then adapted to their respective programs, secondyear fellows have not started looking for a job, and third-year fellows are gearing up to sign their employment contracts. There are a few key elements that should be covered in the career day, which I will discuss here.

Career Options

Clearly, career options will be the primary theme of your career-day program. Almost all careers in oncology can be categorized into 3 areas: academic practice, communitybased practice, and practice in industry or government. According to FREIDA Online, almost as many oncology fellows go into academia as community practice.1 So, it is important that both fields be equally represented. While the goal of academic practice is patient care, research, and teaching, community oncology is more focused on patient care. Most fellows already know about academic-based practice because most fellowship programs are based in academic institutions (of course), but it is still useful to get a faculty member’s perspective on the pros and cons of academia. Also, for the appropriate audience, discussing career choices in basic lab research will be helpful. On the whole, however, most fellows are less familiar with community oncology practice. It will be very helpful to have an open conversation among practitioners from these 2 disciplines to discuss the various aspects of these career tracks.

Whereas the majority of fellows go into either community or academic practice, careers in industry or pharmaceuticals are less common. And to be frank, oncology fellows rarely go into the pharmaceutical industry or the FDA; however, given the current scenario of a rapidly growing drug armamentarium, this is becoming a more attractive option. Having people from industry interact with the fellows will open your eyes to career options beyond the traditional choices.

Physician Recruitment Process

It’s not enough to merely learn about the nitty-gritty details of various career options; it is also important that fellows learn the basics of launching a career search. It is helpful to discuss the appropriate time to start a job search, resources to use during your search, tips on writing your CV, the qualities or accomplishments that each career choice requires, how to prepare for the interview day, and what questions to ask during the interview.Physician recruitment agencies are a great resource, so try to have at least 1 such representative at your career day. As you’re undoubtedly aware, most fellows receive job offers from the time they start their fellowships. But it is important to match your needs with the appropriate job description. The physician recruitment agencies can get basic information from you, determine what you’re looking for, and match it to the appropriate jobs. There’s no sense in going through hundreds of job advertisements when you have a certain job description in mind. If you have visa restrictions, for example, it is no use seeking a job at an employer that does not sponsor your particular visa.

Contract Negotiation

Contract negotiation is an important aspect of starting a job, yet no fellow is ever trained in it. Although most fellows hire a lawyer, that won’t help them learn about the various contract terms. Ultimately, it is you who will be up all night taking extra calls, even when you were told in the contract that calls would be “equitable.” (Yes, I learned that equitable doesn’t mean “equal”!) Also, many lawyers are not that familiar with contract negotiation in the health care fields, so you should retain a lawyer experienced in these matters who can highlight the important points in the contract.

Visa Processing

With nearly half of all fellows being international medical graduates, it goes without saying that visa concerns should not be ignored.1 With particular job restrictions and J-1 waiver/H1-B visa processing methods in the United States, most fellows are in the dark about how to go about finding the right job with their particular visa. A great addition to your career day, if it can be arranged, would be an immigration expert and/or lawyer or an agency that deals with visa applicants. Because this might be relatively useless for fellows who are not in the United States on a visa, it might be a good idea to present this information at the conclusion of the career day or at an after-hours meeting for interested people only.

Board Certification

Fellowship is all about learning and expanding your knowledge, but the ultimate test of your efforts will be the medical examining boards. Given that preparation for these boards and finding a job go hand in hand, it will be a good idea to teach attendees the best methods of preparation for their boards. Also appreciated will be advice on how to obtain state licensures and CME requirements.

Role of New Physicians

Life after fellowship is another important area to cover at your career day. This is most important for third-year fellows, because once you sign on the dotted line of your contract you’ll be on your way to your new career. It will be crucial for you to learn how to contribute profitably to your practice, how to make contacts, how to approach difficult cases, and whom to ask for help.

Oncology is a difficult field emotionally; most of us already have experienced this downside of our field. And it doesn’t make it easier when you become an attending physician to learn that you are the person who is solely responsible for making potentially life-altering decisions for your patients. For example, maybe you chose a particular chemotherapy regimen that your patient did not tolerate well, and she ended up having an adverse event or even dying. How do you deal with this situation? Or when do you decide you’ve tried enough and it’s time to let your patient go? As a new attending physician, how will you continue to maintain your inner peace and empathy? This would be a great philosophical discussion to have at the career day.Its drawbacks aside, oncology is an exciting field to be in. Most fellows (>99%) will be employed at the end of their training program.1 And with the anticipated shortage of 3800 oncologists by 2020, the demand far exceeds the supply.2 A fellows’ career day is an ideal opportunity for you to learn and explore your career possibilities. Its goal is to ensure that each fellow gets something out of it. By the end of the day, the first-year fellows should know their career options and best resources for boards preparation, the second-years should know how to embark on the process of job hunting, and the third-years should learn about contract negotiation and how to prepare for their roles as new independent physicians. With a bit of planning, your fellows’ career day will be a great learning experience for all attendees.

REFERENCES 1. American Medical Association. FREIDA Online. http://www.amaassn. org/ama/pub/education-careers/graduate-medical-education/ freida-online.page. Accessed February 2, 2012. 2. Hortobagyi GN. A shortage of oncologists? The American Society of Clinical Oncology workforce study [published online ahead of print March 14, 2007]. J Clin Oncol. 2007;25(12):1468- 1469. doi:10.1200/JCO.2007.10.9397.

This graphic depicts a state-by-state breakdown of the approximately 1.6 million new cases of cancer that will be diagnosed in the United States this year. (This figure does not include new cancer cases in Puerto Rico and the other US territories.) Not included in these 1.6 million new cases are basal and squamous cell skin carcinomas and noninvasive cancers (with the exception of urinary bladder cancer), because they do not have to be reported to cancer registries. In 2012, about 577,000 Americans will die of cancer—the second-leading cause of death following heart disease. Fortunately, 5-year relative survival rates for all cancers have improved to 67%, based on statistics gathered between 2001 and 2007, compared with the 5-year survival rate of 49% reported between 1975 and 1977. This increase in survival is largely due to earlier diagnosis of cancers combined with overall treatment improvements.  

 

We all have to balance competing demands on our time. But as an academic oncologist, I have to keep a foot in 2 worlds, research and clinical, while still keeping my balance. Working as a medical oncologist in an academic setting challenges doctors to have a foot in 2 worlds: the first world revolves around scientific advancement, and the second around patient care. Each realm has inherent opportunities, rewards, and difficulties that we encounter every day. In this brief snapshot of my experiences, I will try to describe a day that illustrates the balance between these worlds, which is essential to achieve a balanced career in academic oncology.

Of course, each academic medical center has its own culture, demands, and spectrum of job types. Some academic physicians have a much more lab-based research practice; others focus on a strictly clinical research practice. My description reflects my own experiences in what might be a typical workday for a clinical trial researcher in gastrointestinal oncology.

Each week, I spend 2 days with an entirely clinical schedule. On these days, I see patients in the clinic and administer chemotherapy. I also have at least 1 day each week for entirely academic work. On this academic day, I dedicate my time to research protocols; student, resident, and fellow mentorship; and administrative duties. On other days, I have a mixed schedule with both clinical and research responsibilities. In this article, I will describe a typical Tuesday, which is the best example of a mixed clinical and academic day on my schedule.

Tuesday 7–8 a.m.

Multidisciplinary colon conference

Our GI oncology group works closely with a variety of other disciplines, and we are lucky to have collaborators in surgery, radiation oncology, gastroenterology, and radiology who share a common vision for patient care and research. We meet weekly to review challenging cases at a colorectal surgical conference. Since this conference is run by our surgical colleagues, we have an early start (but coffee is readily available)! The surgeons review new patient consults and challenging cases. Representatives from each of the participating disciplines have an opportunity to weigh in with their expertise and feedback. This conference is not only a place to collect fascinating cases, it is also a chance to learn the styles and personalities of the other physicians from other departments. Outside of this in-person conference, I may only interact with them over the phone. During conference, we also discuss open research trials, update the group on how shared patients are doing, or vet ideas about possible proposals for new research studies. Getting a “buy-in” for study participation from the providers who have the first contact with patients (in GI, that is usually the gastroenterologists and surgeons) will lead to more fruitful studies and faster subject accrual.

8 am–1 p.m.

Hepatobiliary-pancreas clinic/conferenceAfter meeting with the colorectal surgeons, we share clinic space and time with our hepatobiliary surgical colleagues. Like the colorectal conference, this multidisciplinary clinic provides us with an opportunity to see patients as close to the time of diagnosis as possible. In this half-day clinic, we see up to 7 patients. Pancreaticobiliary malignancies often need neoadjuvant/adjuvant therapy, which requires delicate timing and effective collaboration between medical oncologists, radiation oncologists, and surgeons. This collaboration is both clinically and academically rewarding. Patients like to be able to have a “one-stop shop” to see multiple health care providers, and the close collaboration across specialties maximizes our patients’ potential for the best clinical outcome. In addition to the clinical benefits, this multispecialty coordination allows for direct research collaboration among 3 different sets of research disciplines, since each subspecialty has its own multi-institution research group. We are an Eastern Cooperative Oncology Group (ECOG), Radiation Therapy Oncology Group (RTOG), and American College of Surgeons Oncology Group (ACOSOG) site. Furthermore, having other clinical and research experts from other departments working closely together and reviewing common literature helps keep all of us at the top of our games. At the conclusion of clinic, the most complicated cases are often also reviewed with our colleagues from radiology and pathology, which allows them to offer their insights as well.

1–2 p.m.

GI Research Group meeting

In this meeting, the GI oncologists gather with the research program manager, our mid-level providers, and clinical research assistants to review the status of our study patients for the last week. We review all open study protocols in our disease group. In a systematic way, we also discuss the status of each patient in terms of duration of treatment, toxicity, response to treatment, and survival. Protocol deviations and serious adverse events are reviewed for attribution, and we brainstorm ways to avoid future problems. We review the progress of proposed future studies and evaluate where they are in the regulatory process and how we can speed these ideas through the necessary regulatory bodies. At this meeting, the 4 GI oncologists bring up clinical trial ideas, and we review one another’s proposals, protocols, and grants and provide constructive feedback.

2 p.m.–? (end of the workday)

Administrative time

After a busy first part of the day working with my partners and seeing patients, it is nice to have some time to catch up on clinical administrative work: dictating notes, following up on the results of lab work, scans, and biopsies, and making phone calls to patients. All of these tasks are vital for good patient care. It really takes a dedicated block of time to stay on top of clinical information, and, ideally, some time with the all-too-rare space of peace and quiet. Sometimes it feels as though there is no way to ever be caught up with the administrative work, but it is really essential to make a regular effort to stay on top of clinical documentation. I’m very thankful that I work with very good nurses and administrative assistants, who help to keep me organized and also do as much of the administrative work as possible. But as the doctor, there are some things that I have to do myself.

If I have patients in the hospital, I check in on them during my inpatient time. I’ll also coordinate with the inpatient team to see if guidance is needed.For my research work, I use some of my administrative time, in addition to my dedicated research hours scattered throughout the week, to review protocols, make study-related conference calls, and meet with study monitors and basic science collaborators. It is especially challenging to find time when more than 2 busy schedules can coordinate, but it is imperative that an academic investigator have regular meetings with mentors and collaborators to keep research heading in the right direction. This is true for both clinical or basic science research. My colleagues who perform basic science research use their administrative time to meet with students and techs in their lab, ensure that their experiments are progressing to the next step, and troubleshoot ahead of time.

Heading home

My workday really ends whenever the rest of those tasks in my administrative time are done. Before I head home, I stop by my department mailbox to see if there are any journals I can pick up and read at home. It is vitally important for any research or clinical physician to make time every day, whether at work or at home, to try to stay current with the literature. I must confess that I have not been able to carve out that reading time at work, so I do my reading after I put my little guy to sleep.

That’s a pretty full day.

As an oncology fellow, you are among the best educated individuals in the country. From basic science to applied clinical technique, what you didn’t learn in the classroom you will continue to learn, every day you spend in the office, the clinic, the lab, and the operating room, as long as you practice. Over the course of what you hope will be a long and illustrious career, you will likely be expected to share the benefits of your research, education, and experience with your colleagues, primarily by writing articles for publication in reputable peer-reviewed journals and trade publications. If you are among the vast majority of physicians, however, you may not be properly prepared for this leg of your career journey. Your medical school curriculum likely didn’t include a single course on clinical writing.

This reality notwithstanding, are physicians really expected to be effective writers? The answer to this question is both “yes” and “no.” You might ask, “Isn’t that what editors are for?” Certainly every medical publication has an editor (or a staff of editors) whose job it is to ensure that all accepted articles conform to the publication’s standards and read as clearly, concisely, and error-free as possible. But the responsibility for producing accurate and effective articles remains with the author(s). In fact, the “cleaner” and more publication-ready the manuscript is as written, the less editorial work it will need. Less extra editing reduces the chance that your intended meaning could be changed inadvertently or that your article will read as if it’s been written by the copy editor and not by you.

Because a complete medical writing primer is far beyond the scope of this brief article, the following tips are intended to help you recognize and avoid a few of the most common writing errors. These are the key pitfalls to avoid since they make copy editors cringe when they catch them and, if they should happen to miss them, reflect poorly on you when they appear in print. When you avoid these errors in your writing, you ensure that your articles will retain your voice and effectively reflect and communicate your expertise.

One-size-fits-all Writing

The content and tone of your article, the amount of detail and background information you provide, and the explanations of medical terminology you include will differ substantially depending upon your intended readers. After all, an article describing a technique used specifically by those in your subspecialty will be written differently if it is intended to provide an overview for primary care physicians than if it is detailing the specifics of how to perform the technique for an audience of medical oncologists, surgical oncologists, those in your subspecialty, etc. This is why knowing your readers should be the “first commandment” for any type of writing, including medical writing. If you don’t reach your audience appropriately, you run the risk of alienating, confusing, or even insulting at least some of your readers. If you’re not sure who reads the journal you want to submit your article to, visit the journal’s website for a description of the scope of the journal and its target audience. Many journals’ editorial information also identifies their readers.

Failure to Look Beyond the GuidelinesIt can be argued that knowing your journal is as important as knowing your readers. Every peer-reviewed publication has a clear set of author guidelines (or “information for authors”). This information is usually available on the journal’s or publisher’s website and may be periodically published in the journal itself. These guidelines list essential details about how to submit an article for publication and how to prepare it for review. These requirements often list everything from article length and types of articles accepted, to the specifics of preferred font size and acceptable table and figure formatting. Different journals may also have distinct specifications for clinical art or diagrams, rules for how to reference drugs and devices, and instructions on how to format references. To increase the chances of your article being accepted for publication, all of these requirements must be followed to the letter. In addition, read several different articles already published in the journal to get a sense of how the guidelines are applied, and to get a sense of valuable information that isn’t typically found in the guidelines, such as the tone and style (eg, formal versus informal) expected by the readers. Find 2 or more articles similar to the type of article you want to submit (case study, research-based, review, etc) and use those articles as guides through the writing process.

Trading Clear and Concise for Confusing and Wordy

Run-on sentences, unnecessary adjectives, and flowery descriptions have no place in a description of a minimally invasive technique for tumor resection. In fact, a rule of thumb for any type of writing is to communicate clearly and concisely, using only the words needed to convey the information. Anything more is distracting.

Poor Choice of Words

As the author of an article, your readers and colleagues must accept you as an authoritative expert on the topic at hand or, at the very least, as someone with knowledge and experience that might be useful to them. You will have a hard time keeping your credibility if you misuse medical or even lay terminology, or simply choose the wrong words to convey your message. For example, the word data is plural, not singular (“these data were analyzed” is correct; “this data was analyzed” is not) and patients don’t fail therapy; instead, they undergo a failed course of treatment. Also, remember to target your word choice to your intended audience. Avoid the use of subspecialty jargon in an article for a general physician audience.

Sloppy Work

There’s no need to raise your hand and ask; yes, spelling counts (as do grammar, punctuation, and sentence structure). A misplaced comma or sloppy sentence structure can change your intended meaning, and can easily slip past even the most careful copy editor or proofreader, since they can’t read your mind to know what you intended to say. Do not rely on “Spell Check,” which will accept anything that’s an actual word, even if that word was not the one you intended to use. A non-medical but real-life (and amusing) example from a classified lost and found ad makes the point quite effectively: “Found. Large white rabbi hopping down Route 80.” How can you avoid such snafus? Long before submitting your article, read it and reread it. It can often help to read it slowly, even reading it aloud. Perhaps most importantly, ask someone else to read it. The more familiar you become with your article, the easier it is to miss such errors, and a fresh pair of eyes is frequently the best safety net.

The Bottom LineWriting of any kind is about communicating. To ensure that you are, indeed, communicating effectively, share your manuscript with a colleague and invite (and be open to) constructive criticism. Your ability to clearly communicate your findings, experience, or ideas to an appropriate audience reflects on your credibility as a medical professional. In turn, your contributions to the published literature will help to advance cancer prevention and treatment by providing the clear and concise sharing of knowledge.

One of my mentors once told me that it was unrealistic to expect to excel in research and simultaneously excel in the clinic. Initially, I had a hard time believing this idea. In fact, I had evidence on my side. He is a leader in his field, and I saw him maintain a very busy clinic schedule, while he was also involved about some of the most interesting research. I thought that he was voicing his frustrations about his own experience of needing to be in 2 places at the same time. But now, at the end of my fellowship, I can far better appreciate his advice to me. Some of the skills that are essential for advancing in clinical education are similar to the skills needed for the successful practice of structured research. With careful attention to detail and conscientious efforts, those clinical skills are likely to be transferable from clinical education to meeting research goals. But in order to make this transition possible, you must be patient, constantly reading, willing to collaborate, open to suggestions, forward thinking about your goals, and not afraid to spend long nights in either the clinic or the lab (or both).

Aside from the overlapping skills needed to succeed in clinic and research, I believe that the key to being successful in a hybrid translational role is the use of effective time management skills. Translational medicine is becoming more popular as physicians get involved in hybrid roles. There are tremendous opportunities in designing clinical trials, contributing to early drug discovery, learning regulatory principles, and engaging in biomarker related work. There are variations on aspects of all of these opportunities in academia, industry, regulatory agencies, and the government.

I would like to share my thoughts on 5 time management skills that I have found to be fundamental elements for succeeding in clinical medicine and laboratory-based research.

5
Concentrate on 1 thing  

Acknowledge that you cannot bend the laws of physics to be in 2 places at the same time. You cannot attend 2 lectures simultaneously, and it is not feasible to be in the lab when you have a busy clinic waiting for you, or need to be with a patient who is not doing well. It is very important to prioritize your commitments, and the sooner you do this, the more efficient you may become in managing your time effectively. Many people have found the smart phone app Things useful in helping to manage daily tasks for small and mediumsized projects. This app can be particularly useful as a note-taking tool since it allows you to connect audio, image, and text notes with a certain task or project. Find the organizational tool that works for you and use it consistently.

4
Seize the moment  

Take every possible opportunity to learn. Utilize your down time to attend as many lectures as possible and make time to read clinical publications and the biographies of the speakers who will be presenting throughout the week. You might be surprised to find a rewarding educational experience that you did not expect. The smart phone app ReQall will allow you to take video or audio notes (when permitted) to replay at later times to reinforce oncology information recall.

3
Maintain balance and avoid burn-out  No matter how busy you are or how many competing clinical and research tasks you are juggling, it is very important to find a way to keep some balance in your life. This means that you have to make a determined effort to schedule time for exercise, to eat a healthy diet, and to spend time with your loved ones. Especially when it seems hardest to carve out time in your schedule for these things, this valuable time will allow you to recharge yourself. With this down time, you are better able to be your best with your patients. Be flexible and willing to consider alternate strategies when things do not go as planned. The ability to redirect and revise your plans when things are not going as anticipated will help you throughout your professional and personal lives. Keep your schedule on your computer and/or your smartphone so you can set electronic notifications, reminders, and alarms. These alerts can be critical to keeping you on target and on schedule. This way, you can optimize your time, which will also make it possible to schedule and keep your appointments for quality time for personal commitments.

2
Maintain effective communication  

Sometimes it’s hard to recognize how much time we can waste and how undermined our efforts can be because of miscommunication. As your schedule fills up and you take on increasingly demanding responsibilities, the skills of writing, presenting, and effective communication are more important than ever before. Speak to mentors in your field and ask for their advice on building strong communication skills. Study successful techniques until you find the tools that work best for you. Also, check into any available resources or education that might be available through a university professional development office that could help you in developing these skills to meet your goals.

1
Try hard not to procrastinate  

This is usually far easier said than done; and we all likely have some room to improve in this arena. Once you are making frequent use of your electronic calendar and reminders, take it to the next step and plan all of the necessary steps before the deadline or appointment. Plan to complete the initial tasks well in advance, and assign yourself a deadline for each step of the process. Make frequent lists, on paper or electronically, whichever will work most consistently for you. Divide large jobs and daunting projects into smaller pieces and keep them on your to-do list. Make use of your scheduling system to send you alerts and reminders of each step of the process. This way, you are not faced with 3 days’ worth of work to do, 1 day before a deadline. Force yourself to get into good habits of planning ahead and chipping away at your tasks each day. With good time management techniques, you will be able to increase your productivity, expand your skill sets, and be more successful in translational medicine. You will also greatly reduce your stress, since you will have a plan of how to manage larger tasks over time. We have more technology available now than ever before that can increase our efficiency. Utilizing these tools effectively in training provides a solid foundation (and good habits) that will help you to implement them throughout your career. With less stress and more productive hours, you will expand your horizons of successful growth in translational medicine.

Translating medical nomenclature into language that is easily understood by patients can be difficult: how do you explain the pathology of cancer or the benefits of myeloablative chemotherapy in patient-friendly terms? Your ability to do so, however, can impact treatment adherence, health outcomes, and the perception of physician empathy during a patient’s bleakest moment. The use of analogies, long recognized in medicine as a way to facilitate physician-patient communication, can help get your message across. I still vividly recall the elderly Vietnamese male patient in the busy emergency department of Harborview Medical Center. He seemed to be dazed at the frenetic pace of activity around him as he laid on a gurney in a room created by curtains, grimacing in pain. Family members spanning 4 generations surrounded him and looked up at me as I approached and gently bowed in respect. There I was, a busy hematology/oncology consult fellow, who had to announce his diagnosis of metastatic pancreatic cancer and answer a multitude of questions that would likely make no sense to anyone. I’m certain that many of my peers have been in a similar situation countless times, in which translating clinical information into “human” terms proves difficult. In my experience, the effective use of analogies when communicating with patients has been an invaluable tool that is often met with a sigh of relief and a nod of understanding. While I have improvised analogies to cater to the educational background of patients and family members, I prefer to use basic analogies, as rudimentary explanations are best for even the most educated of individuals when it pertains to issues of life and death. Most patients appreciate this sort of explanation, and more often than not, the analogies generate a smile during even bleakest situations.

Some of my most useful analogies have been as follows:

Chemotherapy: I often explain to new patients who are about to start the first of many chemotherapy regimens that they are embarking on a marathon; the physician is the coach and the health care team, composed of the nursing staff and pharmacists, are track coordinators monitoring their well-being. Many patients ask about nail changes with chemotherapy. I often tell them that just like the annual circles in the cores of trees that demonstrate their age and reflect the harsh times they have experienced, each hyperpigmented nail line indicates the chemotherapy insult that they have received, and that normal nail usually develops once they discontinue chemotherapy.

Blood counts: I communicate the importance of blood cell counts by telling patients that white blood cells, red blood cells, and platelets represent the Army, the Navy, and the Air Force. All 3 are needed to fight disease and stay in homeostasis; inadequate levels of any of them can put the patient’s health in major jeopardy.

Neutrophils: Mostly needed to prevent infection, they are like policemen that curtail offenders (ie, microbial pathogens). When there is unrest (ie, infection) there is always an increased number of troopers (ie, leucocytosis); neutropenic patients are therefore vulnerable to infection due to less policing.

Lymph nodes and metastasis: Lymph nodes are like security guards at multiple checkpoints or roadblocks in the body. When there is disorder and mayhem, the security guards radio for backup to swell their numbers. Similarly, lymph nodes enlarge when they become involved in an irregularity upstream, thus preventing it from dissipating downstream. If they are overwhelmed, metastases occurs.Myeloablative chemotherapy: This is like winter, in which the cold weather causes the grass to die and take on a pale hue. When new growth appears in small pockets during the spring, it is difficult to ascertain if it is fresh grass or tainted with weeds (ie, disease). Oftentimes in patients with leukemia who have undergone induction chemotherapy, a day 14 marrow aspiration is performed to identify the persistence of blasts (ie, weeds), and another marrow aspiration and biopsy is performed on day 28 to identify if the new growth is devoid of blasts (ie, weeds in the grass). Another similar analogy is the effect of a powerful weed killer on grass.

GI malignancies: Using the analogy of drilling though a timber frame wall is helpful to explain the stage of disease. If the cancer has penetrated most of the muscularis mucosa and serosa (ie, the insulation and sheathing of the home’s wall), its chance of metastasizing is high (ie, through the outside brick). The more the cancer has spread through its confining walls, the greater the chance that the cancer will disseminate.

Proper hydration: Although need for proper hydration in patients with cancer is essential, many do not consume enough fluids due to chemotherapy-associated nausea, anorexia, and changes in taste. Such patients often have darkcolored urine indicating high urinary concentration and poor oral fluid intake. I use the analogy of a few drops of a blue coloring agent changing the color of water in a small glass, but not of a tub of water. Volume does matter. After hearing this analogy, they often return to tell me that their urine is mostly clear now, which is very gratifying!

Non-malignant hematology patients: In patients who are mostly well, I cannot over-emphasize that the need for regular medical follow-ups is imperative for their well-being. Many patients do not keep their appointments or do so only when they need medication refills. I ask these patients how often they change the oil in their cars. It is like a light bulb turning on when patients see the connection between the maintenance of their vehicle and their body. Analogies are extremely useful when used in the proper way. If they are misused and misunderstood by the patient, it could lead to confusion and discontent. The central message is to use familiar concepts to help patients understand unfamiliar or complex issues to help ease their anxiety. One must always gauge the level of understanding of the patient and avoid overusing analogies. Always bear in mind the rule that analogies are like cars—if driven too far, they will inevitably break down!

One of my teachers in medical school was fond of saying, “Internal medicine isn’t sexy.” Hematology/ oncology is no exception to this rule. Certainly, it is not as glamorous as cardiology or as hands-on as gastroenterology. More often than not, practicing hematology/oncology lacks the instant gratification and immediate results associated with rapid intubations and acute resuscitation. Rare is the mad dash to the emergency department, and even rarer is a patient who thanks an oncologist an hour after receiving treatment. Regardless of these realities, there’s a reason I’ve chosen to work in hematology/oncology: it encompasses what I enjoy most about medicine. In this field, we face a wealth of diagnostic dilemmas, therapeutic challenges, and unique interpersonal relationships. While this is all true, my circuitous path to a Heme/Onc fellowship was drawn out. In medical school and in residency, I was fortunate (and unfortunate) enough to find every field intriguing. This made the decision of which subspecialty to pursue an especially difficult one. In the end, I narrowed it down to cardiology with an emphasis on congestive heart failure or hematology/oncology. To be fair, CHF is the oncology of cardiology, which makes the 2 fields more similar than one would think. By the time I finally decided on Heme/Onc, I was a third-year resident. This late choice all but guaranteed that I would spend at least 1 year in transition as the ubiquitous hospitalist. In fact, I spent 4 years as a hospitalist at a large academic institution on the East Coast while my wife finished her own residency.

As hospitalists around the nation can attest, the transition from resident on June 30 to a attending on July 1 was quite intimidating. I was suddenly working without the builtin safety nets of a training program and the sage advice of a supervising attending physician. I found myself carefully scrutinizing and second-guessing medical decisions that previously had been completely routine and mundane. Patient disposition was no longer my ultimate goal. Instead, I was focused on the supreme goal of avoiding an embarrassing “bounce-back.” My discharge summary became a surrogate performance evaluation that all other medical providers had access to and could pass judgment on. I was acutely aware of (and frightened by) the fact that I was solely responsible for the care a patient received. I quickly discovered what it truly meant to take responsibility for a patient’s care.

In time, I grew more comfortable with my new role as an attending and eventually found my own rhythm. Rounds went smoothly and efficiently because I no longer had to preround or present my patients to another physician. I had the freedom to determine treatment plans and adjust those plans as needed without double-checking with or getting approval from a supervisor. Consults were called and studies were ordered because I wanted them…and I actually understood the questions I was asking. I moved from clinical instructor, to physician unit director, to general medicine ward attending complete with my own entourage of eager medical students and hard-working house staff. It was profoundly gratifying to teach medical students the basic principles of medicine, work through complex medical issues with residents, and provide helpful recommendations to colleagues as a consultant. But, to be honest, it was the flexible work schedule and the generous financial incentives that are unique to a career in hospitalist medicine that I sometimes appreciated the most.Although at times it seemed like a dream job, there were obvious downsides to being on the front line at a busy tertiary care center in a large metropolitan city. “Continuity of care” could often be an unwanted experience, depending on the patient population in question. The perpetual sense of urgency and pressure from the hospital administration to evaluate and discharge a large number of patients quickly led a number of my colleagues to burn out. Our department alone averaged a yearly turnover of at least 30% in a group that grew from 14 to 24 full-time employees by the time I left. While I enjoyed a great number of things about being a hospitalist, I found myself continually drawn to cases that involved a hematologic disorder or a new diagnosis of malignancy. Once my wife’s training program was complete, I applied for and was accepted for a heme/onc fellowship in the Pacific Northwest.

Now, as I near the end of my first year of my heme/onc fellowship, I still field the same questions from future heme/ onc hopefuls as I did from interviewers during my fellowship application process. “Do you feel that your years as a hospitalist were beneficial or a detriment?” “Was the adjustment difficult?” In the interest of full disclosure, I usually start by answering the latter question and admit that leaving a 2-week on/off schedule and a 6-figure salary was disheartening. But that change was actually easily overcome. Most people who ask me these questions assume that the transition from attending to house staff is a difficult prospect, since it involves a loss of both stature and autonomy. In truth, the transition was quite effortless because I came into my heme/onc fellowship with the utter certainty that I knew absolutely nothing, and I relished the opportunity to unabashedly ask the “dumb questions.” While hematology/oncology is not without its own intrinsic frustrations and challenges, it has been an undeniably exciting and fulfilling experience to be able to address medical issues in which I am truly interested and invested.

Aside from the realization that medical students I have trained are now my co-fellows and that my former co-residents are now established attendings in their own subspecialties, I truly believe that my years as a hospitalist were well spent. The confidence to make decisions and act on them comes more easily to me now. Years of admitting multiple patients and rounding on a large panel of acutely ill people have helped me to streamline my approach. This allows me to be more efficient when triaging and evaluating consults on a busy service. Numerous interactions with difficult patients have taught me the importance of simply listening and have helped me to refine interpersonal skills. This is especially important in a field in which patient communication is absolutely essential. Dedicating time for medical student and house-staff teaching rounds has ingrained in me the importance of recognizing that a good consultant provides education as well as recommendations.

Having been on the other end of this interaction as a requesting provider, I have particularly come to appreciate the value of being a courteous and gracious consultant in an academic center where everyone is overworked and overwhelmed. Admittedly, I forget that last lesson at times, but as with all of the other lessons I continue to learn, it remains a work in progress.Perhaps this is the most important lesson I’ve learned throughout my training journey to date: I am still a work in progress. We all tell bright-eyed medical students, petrified interns, and weary residents that “physicians are lifelong learners.” That’s how we justify the many years of higher education, the long hours of residency and fellowship, and the endless pursuit of CME credits to maintain “board-eligible” status. That is why we challenge ourselves to stay abreast of recent advances, fastidiously address our knowledge deficits, and battle complacency in our careers and in the care of our patients. The truth of the matter is this…that 1 statement is simultaneously a cliché, a humble reminder, and a source of perpetual encouragement. Taking it 1 step further, I try to remind myself every day that, no matter where my career takes me, I will always be a trainee

This graph shows selected data from the Medscape Physician Compensation Report 2012. Using an online survey provider, Medscape collected the responses of 24,216 US physicians to a variety of questions, including personal income, time spent with patients, number of patients seen in a week, and time spent on administrative tasks. The responding physicians represented 25 different medical specialties. The bar graph shown below represents reported personal income, broken out by specialty. In these data, oncologists were reported to be the seventh-highest paid specialists, with an average reported income of $295,000. The highest paid specialties, radiology and orthopedics, reported an annual income of $315,000. The lowest income was reported by internal medicine ($165,000), family medicine ($158,000), and pediatrics ($156,000). Interestingly, while oncology compensation showed a 4% increase in reported income since Medscape’s 2010 report, radiology and orthopedics each showed a decrease of 10% and general surgery had a decrease of 12%.

Hepatitis C virus (HCV) has been referred to as a “stealth virus” because most people who develop chronic hepatitis C don’t know they are infected. Infected individuals can remain asymptomatic for decades until HCV’s typically slow progression causes destructive complications—cirrhosis, liver failure, or hepatocellular carcinoma (HCC).1 The spread of HCV has been termed a “silent epidemic,” and the World Health Organization describes the growing prevalence of this common, blood-borne infection as a “viral time bomb.” Silent no more, HCV now has the spotlight, for both positive and negative reasons.

 
On the negative side, the “viral time bomb” is expected to explode soon, very soon. Of the almost 4 million Americans infected with HCV, 50% to 75% are chronically infected but still unaware of their condition; they are just beginning to experience the most serious effects of the virus.1-4 In the United States, liver cancer has most often affected older adults (mean age 65), but that is changing. Currently, incidence is shifting to younger people, primarily affecting men aged 45 to 65.2 Prior to 1990, many were infected before blood banks knew how to screen for the virus, and others were infected during the 1960’s, 70’s, and 80’s as HCV infection paralleled a rise in illicit drug use and shared needles.


 
A study released in February 2012 reported that in 2007, for the first time, HCV-related deaths in the United States surpassed those caused by HIV.4 Another study showed that liver cancer has become the fastest growing cause of cancer-related death in the United States.5 Worldwide, chronic infection with hepatitis is the cause of up to 80% of liver cancers.4 In 2010, the American Cancer Society reported 24,120 cases of liver cancer, and in the same year, liver cancer caused 18,910 deaths.6


 
The positive news about HCV, however, is very good indeed. Dozens of new therapies for HCV are in the pipeline, and many are expected to come to market within the next two to five years. Better yet, the first two direct acting antivirals (DAAs) were approved in 2011. Boceprevir and telaprevir, the new agents, significantly increased the percentage of patients able to achieve a sustained viral response (SVR), which is the most reliable sign of a successful “cure.” The DAA agent was combined in a triple-therapy regimen with the existing standard of care (pegylated interferon and ribavirin). Thousands of HCV patients were treated in 2011 with one of the two new regimens, and outcomes continued to be positive.7
 
References
1. The “Secret” Epidemic: Disparities in Hepatitis C Incidence, Treatment and Outcomes. Joint Center for Political and Economic Studies. 2010.
2. Armstrong GL, et al. Ann Intern Med. 2006;144:705-714.
3.United Press International. Baby Boomers at Elevated Hepatitis C Risk. Available at: http://www.upi.com Health_News/2012/02/21/Baby-boomers-at-elevated-hepatitis-C-risk/UPI-45321329871972/.
4. Ly KN, et al. Ann Intern Med. 2012;156:271-278.
5. El-Serag, HB. N Engl J Med. 2011;365:1118-1127.
6.  American Cancer Society. Cancer Facts & Figures. Available at: http://www.cancer.org/Research/CancerFactsFigures/index.
7. Alter HJ, Liang TJ. Ann Intern Med. 2012;156:317-318.


In 2011, the medical community welcomed two new direct-acting antiviral (DAA) agents for HCV—telaprevir (Incivek, Vertex Pharmaceuticals Incorporated) and boceprevir (Victrelis, Merck & Co., Inc.)—with an excitement that hadn’t been seen since 1990.

Before 1990, HCV was generally considered incurable, and use of early interferons helped only 10% of chronic HCV patients. In 1990, when new pegylated interferons (peg-IFNs) were combined with an antiretroviral agent, ribavirin, cure rates rose to 50%. The treatment regimen was complicated, long, and difficult, but considerably more effective than any prior treatment.1 For the next two decades, peg-IFN and ribavirin regimens of 24 to 48 weeks became the standard of care (SOC) for patients with chronic hepatitis C. A cure was determined by the patient’s attainment of a sustained virological response (SVR) that lasted when the treatment finally ended. An SVR at 12 weeks post-therapy meant that replication of the virus had ceased; traces of HCV had dropped to “undetectable levels” in the patient’s RNA.3

Advent of DAA-based therapy

In May of 2011, both telaprevir and boceprevir were approved by the FDA, and clinicians and patients hoped for broad-based cures. These two new drugs, and dozens of more DAA drugs expected to launch in the next two to five years, were based on two decades of experimentation using models and in vitro studies to produce an understanding of the HCV lifecycle and genetic makeup. Such studies identified agents that might cure hepatitis C by targeting the viral RNA genome in ways that prevent its replication.3

Telaprevir and boceprevir are protease inhibitors engineered to block a key protein in the HCV RNA chain. Either agent is added to the existing SOC, creating a triple regimen with peg-IFN and ribavirin. Results are encouraging: Many more chronically ill patients can be cured, and cured in a shorter time. On average, 70% of patients with genotype 1 HCV (the virus genotype that is most difficult to treat) attain and retain SVR.4  Continuing trials have shown that many patients who had failed on SOC alone can succeed with the new triple therapy that includes a DAA agent. Because peg-IFN and ribavirin are so important in the new DAA-based therapies, it is particularly exciting that HCV patients who failed earlier treatment with the SOC regimen can be cured with triple therapy. Patients who at first responded to SOC but relapsed later are big winners when either DAA is added to the regimen. In trials, the new therapies worked for 70% to 88% of “relapsers.” Patients who try SOC treatment and have some response but don’t achieve an SVR also do better with the new drugs. From 40% to 61% of “partial responders” are able to attain an SVR when treated with DAA-based therapy.5



Not everyone is a good candidate for treatment

Despite the amazing success rates seen during trials and the excitement during widespread use of the drugs in 2011, some patients do fail therapy, and some patients are not able, or not recommended, to take these treatments.The primary reason patients are not treated or withdraw from treatment before it is finished is because side effects are significant, often serious, and sometimes intolerable. This was true of the peg-IFN and ribavirin SOC regimens and continues to be true with the addition of telaprevir and boceprevir, which add their own side effects to the regimens.1-7

Even prior to 2011, the healthiest HCV patients often opted to wait until their symptoms worsened before entering such a daunting therapy. After all, genotype 1 patients (the majority of HCV patients in the United States), had less than a 50% chance of a cure even after enduring a year of therapy. Often physicians did not even offer treatment to asymptomatic patients who had minimal liver damage.6

Response-guided therapy

With protease inhibitor-based regimens, patients and clinicians are more willing to try therapy and manage the side effects because the cure rates are so much higher. Ongoing trials have also proven that, within four weeks after they enter treatment, it’s possible to tell which patients are likely to be cured. Patients who clear the virus from their bloodstream that early in treatment are said to have a rapid virologic response (RVR), and trials have also shown that such patients have an 80% to 96% likelihood of achieving SVR. If the virus is still undetectable

at 12 weeks, these patients are candidates for shortened regimens of 12 to 24 weeks.6

References

1. Alter HJ, Liang TJ. Ann Intern Med. 2012;156:317-318.

2. Chevaliez S, Pawlotsky M-M. Int J Med Sci. 2006;3:35-40.

3. Sharma P, Lok AS. Gastroenterology. 2011;141:1963-1967.

4. Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

5. Zeuzem S et al. N Engl J Med. 2011;364:2417-2428.

6. Shiffman ML, Esteban R. Liver Int. 2012; 32(Suppl 1):54-60.

7. Ghany MG, et al. Hepatology. 2009;49:1335-1374.


It’s always hard to know how many new therapies will make it all the way through a drug development pipeline. At the time of this writing, there are 12 combination therapies in phase II trials, 19 individual agents in phase II, and five more in phase III. The adjective being used most consistently to describe the DAAs in development is “potent.”1

Besides potency, what will new combinations need?

New combinations have to address resistance issues shown by the emergence of resistance with telaprevir and boceprevir (similar to other DAA protease inhibitors) when used as monotherapy. In addition to viral mutations triggered through treatment, most HCV patients begin treatment with pre-existing drug resistance variants with one, two, three, and even four mutations. To overcome resistance variants with four-drug resistance, a combination of more than three DAAs is probably needed.

Each agent in the combination must have the potent antiviral activity mentioned above, and should have non-overlapping resistance profiles.

To treat HCV patients safely, combination treatments should present minimal or manageable drug-drug interactions, and add minimal adverse events to drug regimens.

Finally, and ideally, all the agents should be at similar stages of development of so that the drugs can be tested in combination together.2

DAA developers are stretching to meet all four goals, and also want to be able to meet the widespread need for therapy that can cure difficult-to-treat patients. To bring successful drugs to market, developers want to be able to treat patients who have failed previous therapy or have relapsed, as well as those who did not accept SOC therapy or who were not recommended for therapy because of their conditions:

HIV and HCV co-infection

Advanced level of cirrhosis

Transplant candidates and recipients

African Americans and Latinos

Beginning in 2012 and continuing over the next few years, results of phase II and phase III studies with experimental DAA drugs and reports from clinicians will supply much more information about resistance and about efficacy in difficult-to-cure patients than we have now.

Interferon-free combinations

In 2012 we also expect much more information about interferon-free regimens. The most compromised patients—those with a poor prognosis—will wait if they can for DAA combination therapies without peg-IFN. Some may enter drug-drug interaction studies. All are hungry for news of IFN-free treatment success.

Two early study reports of interferon-free treatments seem to support the strategy of more-is-better when DAAs take on HCV without peg-IFN:

A small study of 21 patients with chronic hepatitis C tested the possibility that patients who had failed treatment with peg-IFN and ribavirin might be helped by a combination of 2 DAA drugs.3 In this phase II study from Bristol-Myers Squibb, 11 patients received daclatasvir (a NS5A replication inhibitor) and asunaprevir (an NS3 protease inhibitor) as combination therapy without peg-IFN and ribavirin; while 10 patients received the two DAA drugs with peg-IFN and ribavirin.

This trial proved, for the first time, that some patients could be cured by DAA drugs alone, without using IFN. Four of the 11 patients treated with DAAs alone had SVR at 12 weeks and 24 weeks after treatment. Two of the four were genotype 1a, and two had genotype 1b. Six had viral breakthrough during treatment. Resistance mutations to both antivirals were found in all cases. All patients treated with the combination of two DAAs plus SOC had SVR at 12 weeks post-treatment; nine retained the SVR at 24 weeks post-treatment.In early 2012, Gilead Sciences released preliminary data for an interferon-free treatment using a nucleotide analogue polymerase inhibitor (known as GS-7977) plus ribavirin. The study was small with a very brief treatment period. For 12 weeks, 10 genotype 1 patients, who had failed to respond to SOC therapy, received the two-drug oral treatment. After an early SVR, eight of the responders relapsed within a month of completing the 12-week treatment period.

Can we afford to treat everyone who needs therapy?

In 2011, we learned that the pipeline is likely to become pricey. Standard of care treatment with peg-IFN costs close to $25,000 for a year, and ribavirin costs about $12,000 per course of therapy. Boceprevir adds $22,000 for 24 weeks or $48,000 for 24 to 48 weeks of therapy. Using telaprevir for 12 weeks costs $49,000. Insurance paid for most treatments, after patients and prescribers met pre-authorization requirements. The drug manufacturers offered subsidy programs for those who didn’t have insurance and qualified for help.

Can we afford not to treat?

However, questions of pipeline costs takes us back to the “viral time bomb” warning from the World Health Organization. Estimates in the United States are specific and clear about which population cohorts are most likely to have asymptomatic HCV now, and thus are most likely to develop cirrhosis, end-stage liver disease, or liver cancer.4  To meet the challenge, the Centers for Disease Control and Prevention (CDC) has proposed that primary care practices conduct HCV birth-cohort screening of everyone born between 1945 and 1965.5

The CDC funded a cost-effectiveness analysis of such an approach, which found that compared to current practices, birth-cohort screening would identify an additional 808,580 cases of chronic hepatitis C at a screening cost of $2874 per case. If the treatment that followed is the SOC (peg-IFN and ribavirin), screening would result in an incremental cost-effectiveness ratio of $15,700 per QALY (quality-adjusted life-years) gained. If judged by generally acceptable cost-effectiveness standards, this ratio is a very good result for both the health system and the patient.5  Payers and clinicians probably expect it to improve over time as sustained treatment efficacy improves with new therapies.6

Questions of cost for HCV therapy also must be considered in the context of its ability to cure. Unlike HIV and hepatitis B patients, those with HCV do not have to take medications for their lifetimes. The clinical advantage of being cured of a serious chronic disease is clear for the patient and for the health system. Moreover, every effectively treated patient diminishes the infectious pool and the risks of secondary transmission.

References

1. Ghany MG, et al. Hepatology. 2011;54:1433-1444.

2. Sharma P, Lok AS. Gastroenterology. 2011;141:1963-1967.

3. Lok AS, et al. N Engl J Med. 2012;366:216-224.

4. Mitchell AE, et al. Hepatology 2010;51:729-723.

5. Rein DB, et al. Ann Intern Med. 2012;156:263-270.

6. Alter HJ and Liang TJ. Ann Intern Med. 2012;156:317-318


Interferon is the therapeutic backbone of HCV treatment, as well as the major barrier to HCV treatment access, uptake, and completion. This summation of the key problem in treatment of HCV opens an HCV pipeline report from the HCV Treatment Action Group.1 As welcome as telaprevir and boceprevir are, they have not razed the interferon barrier.

The promise of drugs now in the treatment pipeline is to bring an interferon-free treatment to market. General estimates suggest that only 10% to 20% of those who know they are infected will undertake therapy that includes interferon and go on to complete the regimen.2 The launch of two successful therapies in 2011 raised the bar even higher: New agents in development are now challenged to be as effective as the protease inhibitors telaprevir and boceprevir, as well as more tolerable than interferon.

Challenges in drug development

There are many avenues of exploration just opening to trials with patients. Early studies identified multiple steps in the hepatitis C viral lifecycle that offer potential pharmacologic targets. In response, pharmaceutical developers have already created at least five distinct classes of agents to attack differing aspects of the viral RNA chain.3,4

Creating without a template: This is very new science. Although protease inhibitors have been used previously to treat HIV, the ones currently being used for HCV are very specific—targeted, direct acting. Telaprevir and bocepervir precisely inhibit the HCV nonstructural protein 3/4A (NS3/4A) serine protease.3 Other DAAs are being developed to interrupt viral replication at completely different targets. Among agents in development, those closest to launch include:

• Nucleoside/tide polymerase inhibitors

• NS5A protease inhibitors

• NS3/4A protease inhibitors

• Non-nucleoside/tide reverse transcriptase inhibitors

Resistance: Viruses regularly mutate, and HCV has shown itself to be exceedingly agile in this respect. When telaprevir and boceprevir were used without interferon, both rapidly selected for resistance variants, leading to virologic failure. Combining either agent with peg-IFN and ribavirin, however, protects against the selection of resistant variants, and the antiviral response strengthens.3

We know that HCV patients have differing responses to hepatitis C antivirals depending on which viral genotype the patient (host) is carrying. The sidebar on page 2 lists the six genotypes that Racing Toward an Interferon-Free Treatment have been identified so far, and they seem linked to hereditary ethnic origin.

If six variants were the only problem, the issue would probably have been solved already. However, there are over 50 subtypes within those six genotypes. These different “strains” of hepatitis C virus have resulted from the uncommonly high chance of mutation in its genetic code when the virus replicates—resulting in the development

of very similar but technically different types of hepatitis C virus.4 In the United States, 57% of people with HCV have genotype 1a; 17% have genotype 1b. Genotypes 2 and 3 are the next most common.5

New therapies have also been able to raise cure rates in some populations that had high incidences of chronic hepatitis C but persistently low success rates when treated with the original SOC regimen. For example, the addition of DAAs did improve cure rates in African American and Hispanic patients, but not as much as they improved outcomes in Caucasian patients.3 It is possible that these longrecognized disparities may represent a clinical subtype difference that could be addressed by new targeted therapies without interferon,3 but at this point, there are no trial data to support that hope.6Meeting global needs: As long as interferon remains as the base of HCV therapy, it is unlikely that the millions of people with HCV across the world will benefit from advances in treatment. The need for a cure is most acute in underdeveloped parts of the world, where it is impossible to administer a parenteral therapy on a daily basis and just as impossible to monitor patients for the serious side effects that would emerge.

Thus, the hope is to see combination therapies emerge from the HCV drug pipeline in oral formulations. Researchers are seeking potent combinations of three or more DAA agents, each targeting different aspects of the virus, with the goal of inhibiting HCV replication and suppressing drug resistance. Nucleosides/nucleotides and protease inhibitors could be the preferred backbone in a combination regimen because they have different modes of action, complementary resistance profiles,

and broad genotypic activity. Potent NS5A inhibitors and non-nucleosides could be the third or fourth component of a DAA combination treatment.7 It is possible, according to early stage outcomes, that such treatments may approach 90% cure rates for broad categories of patient types.8 Two to five years—that’s the hope.

References

1. Treatment Action Group. The Hepatitis C Treatment Pipeline Report. Available at: http://www.treatmentactiongroup.org/ hcv/publications/2011/hcvpipeline2011.

2. Mitchell AE, et al. Hepatology. 2010;51:729-723.

3. Ghany MG, et al. Hepatology. 2011;54:1433-1444.

4. Pawlotsky JM. Hepatology. 2011;53:1742-1751.

5. New York Times. About.Com: Hepatitis. Available at: http://hepatitis.about.com/od/questions/f/genotype_HCV.htm.

6. HCV Advocate Newsletter. Available at: hcvadvocate.org/ news/newsletter/2012.

7. Idenix Hepatitis C Pipeline Fact Sheet. Available at: http://www.idenix.com/antiviral/product.html.

8. Alter HJ, Liang TJ. Ann Intern Med. 2012;156:317-318.

Lung cancer, one of the most molecularly complex cancers, is rapidly yielding its secrets. Inside of 10 years, a one-size-fits-all disease and treatment model has been overtaken by a concept of lung cancer as a group of heterogeneous diseases with different molecular origins. Research, drug development, and guidelines are beginning to reflect and amplify a new lung cancer paradigm, in which testing for a “driver” mutation is factored into the selection of therapy, along with the cancer histology.

The history of the epidermal growth factor receptor (EGFR)-targeted therapy erlotinib (Tarceva, OSI Pharmaceuticals)1 was an important factor that helped foster the idea of identifying and directing a therapy to its most likely responders, according to D. Ross Camidge, MD, PhD, from the University of Colorado Comprehensive Cancer Center, who spoke on the subject recently with H. Jack West, MD, Swedish Cancer Institute in Seattle, Washington, and president and CEO of the Global Resource for
Advancing Cancer Education (GRACE).2


Erlotinib was licensed in 2004 for the treatment of patients with locally advanced or metastatic nonsmall cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen. In April 2010, the FDA approved erlotinib for maintenance treatment of patients with locally advanced or metastatic NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.1

Retrospectively, Camidge said, it was evident that 10% to 15% of the treated population seemed to have the most dramatic responses. It took another five years from the time the drug was licensed to show prospectively that if selecting only for people with EGFR mutation-positive NSCLC, erlotinib or another EGFR-targeted therapy, gefitinib (Iressa, AstraZeneca), “was…actually better than chemotherapy in the first-line setting.”2


A 2011 publication of results from the SATURN trial (Sequential Tarceva in UnResectable NSCLC) underscored the power of prognostic testing to optimize outcomes
when target and target drug are in alignment. In this phase III randomized, controlled trial of 889 subjects with advanced NSCLC, subjects with EGFR mutations had a 90% reduction in the risk of death or disease progression when treated with erlotinib versus placebo (hazard ratio [HR], 0.10; P < .001).3


Compared with the years-long process resulting in matching erlotinib with its likely responders, the march from clinical research to approval of crizotinib (Xalkori, Pfizer) was lightening fast. The FDA approved the kinase inhibitor in 2011 on an accelerated basis for treatment of anaplastic lymphoma kinase (ALK)-positive patients with locally advanced or metastatic NSCLC.4 Within two years of its discovery, “dramatic responses” were being seen in the subset of lung cancer patients with a gene translocation resulting in the EML4-ALK oncogene.2 And, for the first time ever, concurrent with approval of crizotinib was approval of a companion genetic test, the Vysis ALK Break Apart FISH Probe Kit.5


Evidence that targeted therapy is most effective when it is given to the right patient continues to mount. In one recent phase II trial (CALGB 30406) of erlotinib alone or in combination with carboplatin/ paclitaxel in never or light former smokers, patients with EGFR mutations had a significantly better response rate at 67% (P <.0001) and progression-free survival (PFS) than patients without the mutation.6 Fast-forwarding the bench-to-bedside journey of molecularly targeted agents is the Lung Cancer
Mutation Consortium (LCMC), a National Cancer Institute (NCI)-sponsored initiative made up of 14 leading cancer centers across the country. Goals of the new  consortium, introduced at the 2011 American Society of Clinical Oncology (ASCO) meeting, are to identify frequencies, characteristics, and therapeutic options for genetic mutations in lung cancer. One of the LCMC’s current initiatives involves a prospective


 
study in which lung cancer tissue is assessed using a multiplex assay to identify and assess the 10 known driver mutations: EGFR, ALK, KRAS, HER2, BRAF, PIK3CA, AKTI, MEKI, NRAS, and MET. Early reported results (which are updated as they are acquired) showed that of the more than 800 patients on whom full mutation testing was
carried out from tumor samples, over half (54%) had single-driver mutations.7

Guidelines also reflect the changing paradigm in advanced lung cancer. In a 2011 update, the National Comprehensive Cancer Network (NCCN) guidelines called for a determination of histological subtype before conducting EGFR testing on patients with recurrent or metastatic NSCLC. EGFR testing, the authors added “…is a category 1 recommendation for adenocarcinoma, large cell, and NSCLC not otherwise specified.”8

EGFR-tested patients should also undergo testing for KRAS mutations, according to the NCCN update, as both mutations are associated with intrinsic tyrosine kinase inhibitor (TKI) resistance, and thus will confer resistance to (“Launching” continued) (“Crizotinib” continued) gefitinib and erlotinib. Testing for the presence of KRAS mutations is useful in another way: Persons who are positive for KRAS mutations are unlikely to have ALK rearrangements and are thus identified as poor candidates for newly approved crizotinib, a targeted therapy for ALK-positive patients with advanced-stage NSCLC.8

References

1. Tarceva [package insert]. Farmingdale, NY: OSI Pharmaceuticals, Inc; 2011.

2. Global Resource for Advancing Cancer Education (GRACE). Dr. D. Ross Camidge on One Size Doesn’t Fit All: ALK Gene Rearrangements, ALK Inhibitors, and the Future of Lung Cancer. February 2010. Available at: http://cancergrace.org/lung/files/2010/02/dr-camidge-on-alk-inhibitors-andmolecular-oncology-transcript.pdf. Accessed March 29, 2012.

3. Brugger W, Triller N, Blasinska-Morawiec M, et al. Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib
maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol. 2011;(31):4113-4120.

4. Xalkori [package insert]. New York, NY: Pfizer; 2011.

5. Vysis ALK Break Apart FISH Probe Kit. Available at: http://www.abbottmolecular.com/us/products/oncology/fish/lungcancer/vysis-lsi-alk-dual-color-break-apart-rearrangementprobe. html. Accessed March 29, 2012.

6. Janne PA, Wang XF, Socinski MA, et al. Randomized phase II trials of erlotinib (E) alone or in combination with carboplatin/ paclitaxel (CP) in never or light former
smokers with advanced lung adenocarcinoma: CALGB 30406. ASCO 2010. Abstract 7503.

7. Lung Cancer Mutation Consortium (LCMC). Available at: http://www.golcmc.com. Accessed March 29, 2012.

8. National Comprehensive Cancer Network (NCCN). Updated Guidelines for Non-Small Cell Lung Cancer. Available at: http://www.nccn.org/network/business_insights/flash_updates/flash_update_information.asp?FlashID=32. Accessed March 29, 2012.


Lung cancers with mutations in the epidermal growth factor receptor (EGFR) respond well to EGFR tyrosine kinase inhibitors (TKIs), but drug resistance invariably emerges, typically after a median of 10 to 14 months of treatment.

Several mechanisms of acquired resistance were discussed in a landmark paper by Zhou et al1, who noted that in more than 50% of cases, T790M is responsible for TKI resistance. T790M is a gatekeeper mutation that restores ATP binding and permits tyrosine kinase activity, even in the presence of inhibitors. Another major

mechanism of acquired resistance is compensatory amplification of the MET gene, which has been suggested to occur in more than 20% of cases of resistance.

Sequist et al2 elaborated on the subject of the evolution of drug resistance with a recent series of genetic and histological analyses of tumor biopsies from 37 patients with drug-resistant nonsmall cell lung cancer (NSCLC) carrying EGFR mutations. In addition to retaining all original activating EGFR mutations, some of the tumors

acquired the commonly occurring EGFR T790M mutation or MET gene amplification.2

Some tumors displayed unexpected genetic changes, however, including EGFR amplification, mutations in the PIK3CA gene, and a pronounced epithelial-to-mesenchymal transition. Five (14%) of the resistant cancers transformed from NSCLC to small cell lung cancer (SCLC).

Resistance was lost in three patients without the continued selective pressure of EGFR inhibitor treatment, meaning that responsiveness to a second round of EGFR inhibitor treatment was restored.2

One surprising finding from research on the molecular mechanisms of resistance is that while some mutations in the EGFR gene are activating and drive tumor formation, others could actually be governing intrinsic resistance against EGFR inhibitors. Intrinsic resistance is also reportedly conferred by the presence of mutations in the KRAS gene

Other theories posited as explanations for acquired resistance to EGFR inhibitors include ubiquitination, which targets EGFR for destruction in the cell; the epithelial-to-mesenchymal transition, in recognition of the fact that mesenchymal cells are more resistant; oncogenic shift, involving increased expression of alternative ErbB receptors; and activation of alternative signaling pathways, including the Akt/mTOR cascade. As a result, EGFR inhibitors are also being tested in combination with

other agents, including vascular endothelial growth factor receptor and MET TKIs.



Acquired Resistance to Crizotinib

Acquired resistance to crizotinib has been reported in patients with ALK gene-rearranged NSCLC who had previously shown robust responses to the drug. In a study to gain insight into the mechanisms of intrinsic and acquired crizotinib resistance in ALK-positive NSCLC patients who showed radiologic progression while on crizotinib,

Doebele et al3 identified three responsible processes: somatic domain mutations, ALK

gene fusion copy number gain (CNG), and the emergence of separate and new oncogenic drivers. Based upon molecular analyses of tissue from 11 patients, the investigators found the following:

• Four patients (36%) developed secondary mutations in the tyrosine kinase domain of ALK. In two of the four patients, the cause was a novel mutation in the ALK domain.

• Two patients (one with a resistance mutation), had evidence of new-onset ALK CNG.

• One patient had evidence of outgrowth of EGFR-mutant NSCLC without evidence of an ongoing ALK gene rearrangement.

• Two patients each had a KRAS mutation, one of which appeared to be lacking evidence of an ALK gene rearrangement.

• In one patient’s tumor, there was evidence of the emergence of an ALK gene fusion-negative tumor, compared with baseline, but without an identifiable alternative driver.• Two patients retained ALK-positive status, but with no identifiable resistance mechanism.

Writing in his blog (cancergrace.org) about these findings by the researchers from the University of Colorado, H. Jack West, MD, suggests two potential mechanisms for acquired resistance appear to be operating. The first is development of a second cancer driver coexisting with the original one in the cancer cell. “Under evolutionary pressure of a treatment with an EGFR tyrosine kinase inhibitor (TKI), …the cancer cells still have the driver mutation (EGFR, in this example) but develop a competing and overriding feature that confers resistance.”4

In the second mechanism scenario, “selection pressure” of effective treatment may lead to a new oncogenic driver mutation. “The idea here is that  there are different subsets of cancer cells.” And, prior to treatment with a targeted therapy “… the cancer may be comprised of primarily ALK rearrangement positive cancer cells, while a small minority has a KRAS mutation.” After ALK inhibitor therapy, ALK-positive cells die, yielding a cancer that is now growing and comprised predominantly

of KRAS mutation positive cancer.4

There is significant clinical relevance to this work, West says, even if the implications remain unproven at this time. “We’ve seen examples of situations in which the cancer, or at least some areas of the cancer, have morphed into a new version, sometimesa different subtype of lung cancer entirely. Even looking at the small number of cases here, we can see a complex array of possibilities. Our knowledge of what’s possible is growing on a case by case basis, but it is helping direct us to literally individualized recommendations for patterns that are becoming cancer and patient-specific.”4

West points to the potentially significant value to doing repeat biopsies, since these results may help shape subsequent treatment decisions.

References

1. Zhou W, Ercan D, Chen L, et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature. 2009;462(7276):1070-1074.

2. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26.

3. Doebele RC, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012;18(5):1472-1482.

4. West J. New Insights on mechanisms of resistance to XALKORI (crizotinib): implications for molecular oncology. January 13, 2012. Available at http://cancergrace.org/

lung/2012/01/13/mechanisms-of-criz-resistance/ Accessed March 29, 2012.

Four recent studies have given physicians a more realistic picture of patient adherence to disease-modifying drug (DMD) treatments for multiple sclerosis (MS). Although study designs differed, all reported a disturbingly high level of nonadherence. The earliest study reported here is a survey of almost 800 MS patients from 17 neurology clinics in the US. Published in 2009, that survey found that 37% of patients admitted they had missed one or more injections of their DMD agent during the previous four weeks.

Looking at adherence from a different perspective, two studies published in 2011 analyzed prescription claims data to identify gaps in DMD treatment. Nonadherence was defined as a patient’s failure to obtain prescribed DMD drugs on a regular basis. Both analyses collected data over a two- to five-year period. Despite the differences in approach, number of patients, and timeframes, both database analyses were consistent with the earlier, patient-reported survey data:

• Halpern et al tracked DMD use by 6680 patients, finding that over time, adherence ranged from 52% to 62% in MS patients.

• Tan et al studied prescription data of 2446 patients, finding that 60% were adherent to DMD therapy.



Considering the importance of adherence in controlling progression of MS, another group of investigators returned to the survey approach in the hope of finding “why” and “how” so many patients are nonadherent. Researchersdesigned the MS Choices Survey, which surveyed prescribing physicians as well as patients. Results from this study, therefore, report two distinct points of view regarding adherence to DMD therapy. Supplying qualitative rather than quantitative results, the study sought information

that could be used by clinicians to improve patient adherence.

However, from the first question to the last, the answers from physicians indicated a much  more positive, perhaps misguided, view of patient behavior. The patient responses did not support an assumption of early treatment initiation, or of adherence to DMDs. Almost all physicians (86%) reported that their patients initiated DMD therapy with 6 months of diagnosis. Among the patients who were surveyed, only half (51%) began DMD therapy within six months, and more than a third

(36%) waited for longer than a year. (Patients were not matched to a particular physician practice.)



Neurologists who were recruited for the survey had to have been in practice for three years or longer and had to see no fewer than 15 MS patients in an average month. It is possible that their patients were more closely followed than the group of patients answering the parallel survey. Still, the breadth of divergence between the group

responses to matched questions raises concerns.

For example, responding physicians underestimated the number of MS patients who “decide to take a break” from their DMD therapy, as well as the number who discontinue therapy entirely. Across all countries, physicians estimated

that roughly 17% of MS patients take a break from treatment, and an average 14% discontinue therapy entirely. However, 31% of responding patients reported taking deliberate breaks from therapy, and 19% reported that they had stopped taking their MS treatment completely. And why? Eighty percent of physicians believe that the mainreason patients stop therapy is because of side effects. While 42% of patients agreed, checking “side effects” as a reason, that left more than half of the patient respondents viewing other factors as more personally difficult. The next largest group of patients reported that they took a break or discontinued using their DMD agent because they were “emotionally or mentally drained” or “fed up with therapy.” Others reported that they had “practical reasons to stop taking the therapy” or

the treatment “wasn’t working.”

The MS Choices Survey was fielded in seven countries: Australia, Canada, and five European countries. Although the breadth of divergence between physician and patient perceptions varied from country to country and also by question, the central conclusion is that physicians may underestimate the scale of poor adherence to DMDs as well as the reasons for it. If that is so, the physicians’ assessment of treatment efficacy might also be underestimated, and clinical decisionmaking about duration and escalation of therapies could be impacted. It also shows that some prescribing neurologists may be missing important opportunities to improve patient outcomes through a more direct, supportive dialogue with patients about adherence.

Sources

• Treadaway K, Cutter G, Salter A, et al. Factors that influence adherence with disease-modifying therapy in MS. J Neurol. 2009;256:568-576.

• Halpern R, Agarwal S, Dembek C, Borton L, Lopez-Bresnahan M. Comparison of adherence and persistenceamong multiple sclerosis patients treated with diseasemodifying therapies: a retrospective administrative claims analysis. Patient Prefer Adherence. 2011;5:73-84.

• Tan H, Cai Q, Agarwal S, Stephenson JJ, Kamat S. Impact of adherence to disease-modifying therapies on clinical and economic outcomes among patients with multiple sclerosis. Adv Ther. 2011;28:51-61.

• Riñon A, Buch M, Holley D, Verdun E. The MS Choices Survey: findings of a study assessing physician and patient perspectives on living with and managing multiple

sclerosis. Patient Prefer Adherence. 2011;5:629-643.

FDA approval of crizotinib (Xalkori, Pfizer) in late August 2011 to treat anaplastic lymphoma kinase (ALK)-positive patients with late-stage non-small cell lung cancer  (NSCLC) represented a three-way milestone. It was only the second time a drug was aimed at a specific subset of lung cancer patients. Crizotinib is the first targeted agent to be approved along with a diagnostic test to identify patients with an abnormal ALK gene. And the path from discovery to development to availability of crizotinib for patient care was extraordinarily rapid and efficient. It took only four years from the discovery of ALK-rearranged NSCLC for its developer, Pfizer Inc, to obtain FDA approval.1,2

A small proportion, about 3% to 5%, of lung cancers are driven by the ALK oncogene, which is characterized by a break in chromosome 2 and a re-fusion of the two genes in the opposite direction. In a review of crizotinib from discovery through development by Sai-Hong Ignatius Ou,1 the author said that anaplastic lymphoma kinase was known to be a player in cancer from an initial discovery in the 1980s of translocation in anaplastic large cell lymphoma. However, its role in a solid tumor had only just been characterized at the time the phase I clinical development program with crizotinib was launched in 2007.1

The FDA approval of crizotinib was based on results from two single-arm trials. The primary endpoint of both trials was objective response rate (ORR). Two-hundred-fifty-five patients with latestage ALK-positive NSCLC, median age 52 years, received 500 mg/day of crizotinib. Ninety-six percent of subjects in the trials had adenocarcinoma; 95% had metastatic disease; and 94% had received systemic treatment for NSCLC prior to the study. The ORR was 50% (95% confidence interval [CI],

42%-59%) in the first trial and 61% (95% CI, 52%-70%) in the second. Median duration of response was 41.9 weeks and 48.1 weeks, respectively.2

The most common adverse events were vision problems, nausea, diarrhea, vomiting, edema, and constipation. The FDA issued warnings and precautions for pneumonitis, liver enzyme abnormalities, and QT interval prolongation.2

FDA approval of crizotinib occurred under the agency’s accelerated approval program because of the drug’s ability to treat a serious disease, based on clinical data showing that crizotinib is likely to create a clinical benefit for patients.3

In a study presented at the 14th World Conference on Lung Cancer in Amsterdam in July 2011, and at American Society of Clinical Oncology (ASCO) annual meeting in 2011, investigators presented early phase II results from the single-arm, open-label PROFILE 1005 trial. In it, 51% of 133 patients who had undergone prior chemotherapy who were treated with crizotinib exhibited an overall response, including one patient who experienced a complete response. At 12 weeks into the trial, the disease control rate was 74%, meaning that a proportion of participants achieved stable disease, or partial or complete responses.4

Two phase III trials comparing crizotinib and chemotherapy are ongoing. PROFILE 1014 compares crizotinib with standard chemotherapy pemetrexed plus cisplatin or carboplatin in previously untreated patients with ALK-positive NSCLC. The primary endpoint is progressionfree survival, and patients who are randomized to chemotherapy are permitted to cross over to crizotinib upon disease progression. PROFILE 1007 is comparing crizotinib with pemetrexed or docetaxel second-line in patients with ALKpositive NSCLC. The primary endpoint of this trial is also progression-free survival.1

Research also continues with the goal of elaborating on other therapeutic extensions of crizotinib in NSCLC. Investigations are under way to assess the properties of crizotinib as a multi-targeted receptor tyrosine kinase inhibitor, particularly a potential therapeutic role arising from activity of the MET (mesenchymal-epithelial transition) gene.1At the same time, work is under way to combat the development of crizotinib resistance in NSCLC patients, which typically develops after one year.

References

1. Ou SH. Crizotinib: a drug that crystallizes a unique molecular subset of non-small-cell lung cancer. Expert Rev Anticancer Ther. 2012;12(2):151-162.

2. Xalkori [package insert]. New York, NY: Pfizer; 2011.

3. U.S. Food and Drug Administration (FDA). FDA approves Xalkori with companion diagnostic test for a type of late-stage lung cancer. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm269856. htm Accessed March 29, 2012.

4. Crinò L, Kim D, Riely GJ, et al. Initial phase II results with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): PROFILE 1005. American Society of Clinical Oncology 2011 Annual Meeting. J Clin Oncol. 2011;29(suppl; abstr 7514).

Cancers can be smart or dumb, and the smart ones are more difficult to deal with. Such is the case with lung cancer, which has a complex molecular heterogeneity. However, clearer insights into the molecular underpinnings of lung cancer and advances in diagnostics are enabling researchers to define the molecular subtypes of this cancer, aiding in the development of new therapeutic approaches.

In a paper published in the open-access journal PLoS ONE in February 2012, a multi-institutional and industry group defined “molecular subtypes” of lung cancer based on specific actionable genetic aberrations.1 The group had previously developed a formal process for classifying melanoma into molecular subtypes. The researchers defined a subtype as actionable if the mutation/aberration is associated with an approved assay and at least one FDA-approved or experimental targeted therapy with the potential for efficacy. For example, one subtype would be lung tumors with the EGFR exon 19 mutation, for which both commercial assays and targeted agents are available (the latest version of this model is available at http://bigmac.collabrx.com/lc_edit/index.php/File:Lung_SubtypeTable_1final.jpg).

Five oncogenes defining the subtypes with the current highest “strength of evidence” may be closest to arriving at the pharmacy as approved agents (Table).



EGFR mutations are found in about 10% of Western populations and about 50% of Asians with lung adenocarcinoma. Data from several clinical trials show that progression-free survival is improved in patients treated with the EGFR inhibitors erlotinib or gefitinib over standard-of-care chemotherapy. In its 2011 updated guidelines for management of non-small cell lung cancer (NSCLC), the National Comprehensive Cancer Network (NCCN) called for EGFR testing in lung adenocarcinoma and large cell lung cancers upon recurrence of metastasis. In-progress or planned trials in recurrent or advanced NSCLC will determine the efficacy of approved and second-generation EGFR inhibitors in combination with agents such as MET/VEGFR2 inhibitors.

The T790 mutation is responsible for about 50% of cases of acquired resistance to erlotinib or gefinitib. Second-generation EGFR inhibitors such as afatinib (BIBW2992, SelleckBio), which irreversibly inhibits human EGFR2 (HER2) and EGFR kinases, are among potential therapeutic approaches to EGFR T790 mutations. MET inhibitors address the approximately 5% to 20% of patients with acquired resistance to EGFR inhibitors due to cMET amplification. These include adding crizotinib, foretinib, ARQ

197, and MetMAb to first-generation (eg, erlotinib) or second-generation EGFR tyrosine kinase inhibitors (TKIs). Heat shock protein 90 (Hsp90) inhibitors

(AUY922, ganetespib), which may block multiple signaling pathways that are not functioning properly in cancer cells, represent another approach to EGFR resistance mutations. Combination therapies such as a dual MET/VEGFR2 inhibitor, and others, are also under investigation.

The VeriStrat proteomic signature is a diagnostic tool for NSCLC patients who have tested negative for EGFR mutation. This lung cancer molecular subtype indicates likely responsiveness to EGFR inhibitor therapies such as erlotinib in the absence of EGFR mutations. Several studies have demonstrated that VeriStrat classification has significant predictive power. In one study, 73% of EGFR wild-type NSCLC patients who had previously received erlotinib and who had VeriStrat “good” status had improved survival after erlotinib treatment versus patients with VeriStrat “poor” status.K-ras mutations have been reported in 15% to 20% of patients with NSCLC, and in about 30% to 50% of adenocarcinomas. Almost all patients with this mutation are smokers. This molecular subtype is associated with decreased response to EGFR TKIs. Potential therapeutic approaches to NSCLC patients within this group include MEK and mTOR inhibitors, Hsp90 inhibitors, and REOLYSIN (Reovirus Serotype 3-Dearing Strain, a proprietary formulation of human reovirus that lyses cancer cells, in particular those that have upregulated RAS signaling). REOLYSIN is currently in phase I, II, and III trials in NSCLC and other forms of cancer.

The EML4-ALK subtype is named for the EML4-ALK fusion oncogene, which produces a transforming tyrosine kinase with as many as nine different variants. Several isoforms are known to play a role in lung cancer. EML4-ALK is a novel target in a small subset of NSCLC patients who are typically younger women who are never to

light smokers. Therapeutic targets for this subtype of NSCLC include ALK inhibitors, such as the recently approved crizotinib (Xalkori, Pfizer) and LDK378 (Novartis). An Hsp90 inhibitor, IPI-504 (Infinity Pharmaceuticals), is in phase I and II trials. Ganetespib (Synta Pharmaceuticals) is also being studied as an ALK-targeted therapy.

In addition to these lung cancer molecular subtypes, which are accompanied by high strength of evidence, a number of secondary subtypes suggest that the landscape of future treatment options in NSCLC is promising.

Hoping to accelerate the process of translational research and to provide a conduit for open communication between basic research scientists, clinical trialists, and treating physicians, the authors of the PLoS ONE article designed an online lung cancer therapy finder, which can be found at www.collabrx.com/lung. Physicians who enter detailed information about a patient’s tumor can retrieve detailed current information about disease subtype, molecular testing options, suggestions for management of the tumor, and a list of current trials.

Reference

1. West L, Vidwans SJ, Campbell NP, et al. A novel classification of lung cancer into molecular subtypes. PLoS ONE. 2012;7(2):e31906.

Over the past decade, it has become clear that MS is a predominantly T cell-mediated disease: dendritic cells that direct T cell activity have a critical role in the initiation and progression of disease. Potential autoimmune disease therapies that target dendritic cells aim either to inhibit their immunogenic functions or support their potential to engender T cell tolerance, inhibiting an autoreactive immune response. In patients with MS, both of these outcomes hold promise. So far, none of the approved agents for MS specifically targets dendritic cells, but natalizumab (Tysabri, Biogen Idec), a monoclonal antibody, has a mechanism of action that seems to affect the presence of those cells in cerebral spaces. Also, a number of agents already in phase III trials for treatment of MS have been used to treat other autoimmune diseases. Only one, abatacept (Orencia, Bristol-Myers Squibb), targets T cell activity. Abatacept is currently used to treat rheumatoid arthritis. Other monoclonal antibody agents being tested as MS therapy target B cells.

Researchers continue to pursue dendritic cell-targeted therapies in the belief that they may be able to halt or

retard MS progression. Analyses of infiltratingcells from the brains and cerebrospinal fluid of patients with MS have consistently shown that T cells are associated with  inflammatory MS lesions. Furthermore, individual T cell clones have been identified in the blood of patients with MS over long periods of time, and their presence indicates a strong persistent response and ongoing antigen exposure. Dendritic cells are “professional” antigen-presenting cells that can modulate adaptive immune responses. The dendritic cells process antigens, dropping peptide fragments on molecules of naïve T cells. A mature dendritic cell can use this process to direct a naïve T cell to become one or another type of T-helper (TH) cell. For example, one type of TH cell takes on a crucial  role in initiating an immune response by guiding immune T cells to locations where such a response is most needed. Dendritic cells can also direct a T cell to become a regulatory agent that is able to inhibit an autoreactive immune response. That particular ability is both valued and known to be present during the steady-state periods of an autoimmune disease. While a steady state is maintained, infection and inflammation are absent, and inappropriate autoimmune responses are quieted.

An understanding of how these cells regulate adaptive immune responses is driving development of a

new generation of immunotherapies. Many of the existing agents now being tested for MS are monoclonal

antibodies, which target molecules that have been selectively expressed by dendritic cells. Earlystage

research may present a targeted approach to modulate the activity of the versatile dendritic cells

themselves.

Sources

• Comabella M, Montalban X, Münz C, Lünemann JD. Targeting dendritic cells to treat multiple sclerosis. Nat Rev Neurol.

2010;9:499-507.

• National Institutes of Health. ClinicalTrials.gov. Available at http://clinicaltrials.gov. Accessed March 13, 2012.

• National Multiple Sclerosis Society. Clinical Trials. Available at: http://www.nationalmssociety.org/research/clinical-trials/index.

aspx. Accessed March 13, 2012.

• Tam S, Lopez A, Shek A, Yeh J. Multiple sclerosis: a paradigm change with oral agents? Formulary. 2011;46:228-240.

A study published in March 2012 in the Journal of Virology suggests that components of a virus called HERV-Fc1 are present at higher levels in plasma and immune cells of

people with active multiple sclerosis (MS). HERVFc1 is a type of a human endogenous retrovirus, which is derived from genes that are normally found in the DNA of all humans. Laska et al, the authors of the article, direct attention to a specific aspect of this virus that they suggest may either cause or result from immune attacks in MS. It has long been believed that a combination of environmental factors (such as viruses) and genetic factors are associated with increased risk of MS.

HERV-Fc1 had previously been shown to have a genetic association with MS, when components of the virus were found in blood and brains of MS patients. It is not uncommon for DNA to have genes that contain parts of retroviruses, but normally, these genes remain mostly silent, and few viral components are found circulating in the body. This particular study looked at whether components of HERV-Fc1 are found in higher quantities in the circulating immune cells of people with active MS compared to healthy Searching for the Causes of MS: Human Endogenous Retrovirus—HERV-Fc1 controls and people with inactive MS.

Within a group of 61 patients, researchers obtained blood samples from three groups: 30 healthy volunteers, 19 people with inactive MS (no relapses for an average of 36 months), and 22 people with active MS (relapses within an average of 3.2 months). Although all three groups had the same number of HERV copies in their DNA, the number of copies in RNA differed between groups. (RNA is the first step in making virus from the gene.) HERV levels were four times higher in plasma samples from people with active MS compared to healthy people and people with inactive MS.

The team then looked at a protein related to HERV, examining white blood cells that are known to be important in MS immune attacks. Again in white blood cells, more HERV-related protein was found in samples from people with active MS. The team also explored whether disease-modifying therapies made a difference in HERV levels in the active MS group, and found no difference between those on therapy versus those who were not on therapy. The findings suggest that HERV-related gene components are “switched on” at a higher level in immune cells of people with active MS. How and why that happens is not answered by this study. The association of their presence with cellular immune attacks could provide important information for the development of targeted therapies or even preventive vaccines.

Do HERV components play a role in launching or worsening the immune attacks on the central nervous system in people with MS? Those are questions that must be answered before practical application of the research findings is possible. The authors summarized their results, explaining that they had been the first “to quantify extracellular HERV-Fc1 RNA viral loads in plasma from MS patients and healthy controls.” They found a fourfold increase in extracellular HERV-Fc1 RNA titers in

patients with active MS compared with healthy controls (P < .001), findings that strengthen the link between HERV-Fc1 and the pathology of MS.

Source

• Laska MJ, Brudek T, Nissen KK, et al. Expression of HERVFc1, a human endogenous retrovirus, is increased in patients with active multiple sclerosis. J Virol. 2012;86:3713-3722.

A  

t the same time that the incidence of melanoma is rising globally,1 this most aggressive skin cancer is being unwound at a molecular level. Evidence has converged around the concept of driver mutations acting within molecular pathways known to play key roles in the onset, progression, and prognosis of the disease. Melanoma is coming to be understood as a highly variable form of cancer, with many subtypes that differ from patient to patient, and therapeutic outcomes dependent on matching precise subtypes to medical interventions. Reasoning that knowledge of the genetic basis of melanoma has advanced enough to permit a classification of tumors into molecular subtypes, and that a burgeoning biotech industry is bringing the world of personalized medicine into view, a group of industry and academic experts collaborated to create a Melanoma Molecular Disease Model.2 Published in 2011, the model links melanoma molecular pathways with key genes and biomarkers, available diagnostic technologies, and potentially effective therapies.

The concept behind the Melanoma Molecular Disease Model was demonstrated in the summer of 2011, with the approval of vemurafenib (Zelboraf, Genentech) to treat patients with metastatic melanoma tumors that express the BRAFV600E mutation. The drug was licensed on the basis of phase III trial evidence showing an improvement in overall survival,3 and was approved together with the Cobas 4800 BRAF V600 Mutation Test to identify the BRAF mutation.4 (See “New Therapies Emerge for Metastatic Melanoma.”)

Developing the Model

Early in the process of developing the Melanoma Molecular Disease Model, Vidwans and colleagues assembled a panel of recognized melanoma experts whose consensus judgment resulted in the initial map of melanoma subtypes. Each subtype comprising the initial list is defined by an association with a key oncogene/tumor suppressor (eg, BRAF, cKIT), that either acts alone or in combination with other oncogenes that play supportive roles.2

The model’s principal molecular subtypes were then ranked in rough order of importance based on prevalence among patients, as well as the current potential for targeted therapeutic intervention. Variations under major subtypes (eg, 1.1, 1.2) reflect a recognition that a melanoma may contain aberrations in more than one pathway (Table, page 2).2

Figure: Key Pathways in Melanoma

Rollover to enlarge. Pathways
The MAPK Pathway

The mitogen-activated protein kinase (MAPK) pathway is especially important to melanoma tumorigenesis and regulation of cell growth, proliferation, and differentiation. Genetic aberrations in the MAPK pathway are reportedly found in over 80% of cutaneous melanomas, with abnormalities in RAS, RAF, MEK and ERK.2,5 Melanoma molecular subtype 1 is defined overall by aberrations in the MAPK pathway, either alone or in combination with other pathways (eg, AKT/PI3K, CDK).2Melanoma Subtype 1.1

The most common mutation in the MAPK pathway (melanoma subtype 1.1) is in the BRAF gene.2 This mutation occurs in 40% to 70% of melanoma cases.6 In addition to the recently approved vemurafenib, another BRAF inhibitor, sorafenib, has been investigated in phase I, II, and III clinical trials.2,7 Results to date suggest that sorafenib as monotherapy or in combination with chemotherapy may be of limited use,7 or the subpopulation of patients with advanced melanoma that will receive benefit from sorafenib awaits identification of the right biomarker.2,7

Melanoma Subtypes 1.2 & 1.3

Mounting evidence suggests that melanoma development and metastasis may require multiple pathways. Accordingly, melanoma subtypes 1.2 and 1.3 define cases that possess abnormalities in both the MAPK and AKT/PI3K pathways. Some drug development initiatives for these subtypes call for combination therapy, with inhibitors of both pathways.2

Melanoma Subtype 1.4

Subtype 1.4 is associated with mutations in both the MAPK and CDK pathways, resulting in activation of BRAF and overexpression of CCND1/Cyclin D. (The CDK pathway has been proposed as a contributor to metastasis in melanoma with BRAF mutations.)2

The rational approach to therapy for the melanoma subtype 1.4, according to the authors of the Melanoma Molecular Disease Model, is a combination of CDK and BRAF inhibitors.2

Melanoma Subtype 2 Overview

Subtype 2 is characterized by mutations in the c-KIT pathway, a receptor tyrosine kinase (RTK) involved in intracellular processes such as cell growth, cell division, and migration in response to Stem Cell Factor (SCF) activity.2 Several approved drugs target c-KIT, including imatinib, sunitinib, nilotinib, and dasatanib.2

Melanoma Subtype 2.1

As of the publication of the Melanoma Molecular Disease Model in 2011, c-KIT is the only subtype in this category. It is characterized by genetic aberrations in c-KIT, which generally include mutations and/or copy number increases. One study reported the occurrence of these mutations in 39% of mucosal, 36% of acral, and 28% of melanomas on chronically sun-damaged skin (but not in melanomas on skin without chronic sun damage).2

c-KIT inhibitors represent the rational treatment strategy for this subtype of melanoma, and clinical evidence has provided support for the efficacy of therapies such as imatinib, sorafenib, temozolamide, and dasatinib.2

One example of the potential of a precise matchup of mutation to target drug was demonstrated in a study by a group at MD Anderson Cancer Center. The group had previously succeeded in identifying the first human melanoma cell line with L576P, the most common KIT mutation in melanoma.8

After determining that the mutation was not responsive to KIT inhibitors imatinib, nilotinib, or sorafenib, but was responsive to dasatinib in the laboratory, the researchers treated two patients with metastatic melanoma with dasatinib. Both patients tested positive for the L576P KIT mutation, and one of the patients had previously received treatment with imatinib. Following dasatinib treatment, both patients experienced a more than 50% reduction of their tumors.8

The c-KIT inhibitor imatinib also was associated with significant activity in patients with metastatic melanoma and c-KIT mutations. In a phase II open-label, single-arm trial of 43 patients, the overall response rate was 23.3%.9

Melanoma Subtype 3, 3.1Subtype 3 is characterized by mutations in the G proteins, GNAQ and GNA11. In subtype 3.1, a mutation in the GNAQ gene affects codon 9, which may drive constitutive activity in the MAPK pathway.2

Melanoma Subtype 3.2 Overview

Subtype 3.2 is characterized by a mutation in the GNA11 gene that affects codon 209. This mutation may drive constitutive activity of the MAPK pathway. 2 Several MEK inhibitors in development could be useful to treatment of this subtype.

Table: Primary Melanoma Molecular Subtypes

Rollover to enlarge. Subtypes
Melanoma Subtype 4

Subtype 4 is characterized by abnormalities in the RAS gene. RAS-regulated signal pathways are involved in control of proliferation, differentiation, cell adhesion, apoptosis, and cell migration via MAPK and AKT/PI3K pathways.2

Melanoma Subtype 4.1

Subtype 4.1 is characterized by mutations in NRAS, found in about 20% of melanomas.2 (Clinical testing of an approach of concurrently targeting MAPK and AKT/PI3K pathways is planned by two pharmaceutical companies.)

Melanoma Subtype 5, 5.1

Subtype 5 is characterized by abnormalities in the melanoma development and survival pathway. In this pathway, melanocyte transcription factor (MITF—microphthalmia-associated transcription factor) is a regulator of the development, differentiation, and maintenance of melanocytes.2

Subtype 5.1 features aberrations in MITF; MITF may be an amplified locus in melanoma, and MITF amplification has been correlated with decreased survival and increased resistance to chemotherapy.2

MITF expression has been reduced by histone deacetylase (HDAC) inhibitor drugs. A study to evaluate the efficacy of panobinostat (LBH589) in patients with metastatic melanoma is under way.

The Melanoma Molecular Disease Model is a living document. Its authors expect that with time and expanding basic science knowledge, the model will acquire increasing specificity and more links to targeted therapies and diagnostics. As new information is gathered, the model is to be updated online at http://mmdm.cancercommons.org/smw/index.php/A_Melanoma_Molecular_Disease_ Model.


References:

1. MacKie RM, Hauschild A, Eggermont AM. Epidemiology of invasive cutaneous melanoma. Ann Oncol. 2009;20(suppl 6):vi1-7.

2. Vidwans SJ, Flaherty KT, Fisher DE, et al. A melanoma molecular disease model. PLoS One. 2011;6:1-10.

3. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516.

4. Zelboraf [package insert]. San Francisco, CA: Genentech USA, Inc; 2011.

5. Lemech C, Arkenau H-T. Novel treatments for metastatic cutaneous melanoma and the management of emergent toxicities. Clin Med Insight Oncol. 2012;6:53-66.6. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949-954.

7. Mangana J, Levesque MP, Karpova MB, Dummer R. Sorafenib in melanoma. Expert Opin Invest Drugs. 2012;21:557-568.

8. Woodman SE, Trent JC, Stemke-Hale K, et al. Activity of dasatinib against L576P KIT mutant melanoma: molecular, cellular, and clinical correlates. Mol Cancer Ther. 2009;8:2079- 2085.

9. Guo J, Si L, Kong Y, et al. Phase II open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-KIT mutation or amplification. J Clin Oncol. 2011;29:2904-2908.

W  

ith the emergence of new therapies targeted to specific drivers of melanoma and the approval of two new agents that demonstrate improvements in overall survival,1,2 there appears to be fresh hope for improving outcomes in a cancer that, after metastasis, formerly left patients with very little hope. Today, the median survival of melanoma patients with distant metastases, according to the American Joint Committee on Cancer (AJCC) stage IV statistics, is less than one year.3 In March 2011, the FDA approved ipilimumab (Yervoy, Bristol-Myers Squibb), a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 (CTLA-4), for patients with metastatic melanoma.4 CTLA-4 is thought to play a role in preventing the immune system from fighting off cancer cells, and ipilimumab may allow the immune system to recognize, target, and attack melanoma cells.4

In August 2011, the BRAF inhibitor vemurafenib (Zelboraf, Genentech) was FDA-approved to treat patients with metastatic melanoma whose tumors express the BRAFV600E mutation; the approval was granted on the basis of phase III trial evidence showing an improvement in overall survival. The drug was licensed along with a test, the Cobas 4800 BRAF V600 Mutation Test, to specifically identify the mutation that the drug targets.2,5,6

Developments from ASCO 2012

This year’s annual meeting of the American Society of Clinical Oncology (ASCO) saw several important developments in the treatment of melanoma.

Results from the phase III METRIC trial of the oral investigational agent trametinib showed that the drug delayed tumor growth and extended survival in patients with advanced melanoma with BRAF mutations. Trametinib inhibits the protein MEK, which is part of the MAP kinase signaling pathway, of which BRAF is a component.7

Patients who had received up to one prior chemotherapy regimen were randomly assigned to treatment with trametinib (n=214) or standard chemotherapy (n=108; either dacarbazine or paclitaxel). Median progression- free survival (PFS) was 4.8 months in patients treated with trametinib versus 1.5 months in the chemotherapy group, a 55% reduction in the risk of progression. A total of 81% of patients in the trametinib group were alive after six months of follow-up compared with 67% of patients in the chemotherapy group. Side effects of trametinib were generally manageable; severe side effects included skin rash (7% of patients), eye problems (less than 1%), high blood pressure (12%), and reduced heart function (7%).7

Interim results of phase III BREAK-3 study presented at ASCO found that dabrafenib, an investigational oral drug that targets BRAF, reduced the risk of disease progression by 70% versus standard dacarbazine chemotherapy in patients with previously untreated, advanced melanoma with BRAF mutations. Estimated median PFS was significantly longer in the dabrafenib group compared with chemotherapy: 5.1 months versus 2.7 months. Overall survival data were not yet mature. The study authors noted that there appeared to be fewer cases of serious skin toxicities associated with dabrafenib treatment, including squamous cell carcinomas, than have been previously reported in trials of the approved BRAF inhibitor, vemurafenib.8Two abstracts featured promising results from phase I studies. BMS-936558 is a fully human monoclonal antibody that blocks Programmed Death 1 (PD-1) protein, overcoming immune resistance and mediating tumor regression. Topalian and colleagues (abstract CRA2509) successfully demonstrated the clinical activity and safety of this agent in melanoma, renal cell carcinoma, and non-small cell lung cancer, and verified the importance of the PD-1 ligand (PDL1) as a potential predictive biomarker.9

A related phase I study (abstract 2510) established the safety and clinical activity of an anti-PD-L1 antibody, BMS-936559, in patients with solid tumors including melanoma, as well as the importance of the PD-1/PDL1 pathway as a target for cancer immunotherapy.10

The safety, activity, and immune correlates of anti- PD-1 antibody in cancer were detailed in the June 2 issue of The New England Journal of Medicine.11 In the report, a total of 296 patients with advanced melanoma, nonsmall cell lung cancer, castrate-resistant prostate cancer, or renal cell or colorectal cancer received varying doses of anti-PD-1 antibody every two weeks in eight-week cycles for up to 12 cycles, until disease progression or complete response. Of 236 patients in whom response could be assessed, cumulative response rates at all doses were 28% among patients with melanoma, 18% in non-small cell lung cancer, and 27% in patients with renal cell cancer. Stable disease (≥24 weeks) was observed in six patients (6%) with melanoma as well as the other cancers under study. Twenty of 31 patients had responses that lasted more than one year.11

These data, together with similarly impressive results for the anti-PD-L1 antibody, also reported in the June 2 issue of The New England Journal of Medicine,12 demonstrate that immunotherapy agents with “wide applicability” “…have broken the ceiling of durable tumor response rates of 10 to 15% (the highest rate of antitumor activity of the many immunotherapy approaches tested in the clinic for the treatment of cancer during the past 30 years..” according to a concurrent Journal editorial.13

Other immunotherapeutic approaches in late-stage development include T-VEC, formerly OncoVEXGMCSF, an oncolytic herpes simplex virus type 1 encoding granulocyte macrophage colony-stimulating factor (GMCSF). This agent is formulated for direct injection into accessible melanoma lesions. According to an abstract presented at ASCO, results from a randomized phase III clinical trial in patients with unresectable Stage IIIb, IIIc, and IV melanoma are expected in 2012.14,15

Systemic immunotherapy Allovectin7 (veligene alloplasmid, Vical) is undergoing a phase III clinical trial comparing Allovectin-7 alone vs chemotherapy alone in patients with stage III or stage IV melanoma (active). The estimated completion date for the trial is June 2012.16


References:

1. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.

2. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516.

3. Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Cin Oncol. 2009;27:6199-6206.

4. Yervoy [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2011.

5. Zelboraf [package insert]. San Francisco, CA: Genentech USA, Inc; 2011.

6. U.S. Food & Drug Administration. FDA approves Zelboraf and companion diagnostic test for late-stage skin cancer. August 17, 2011. Available at: http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm268241.htm7. Robert C, Flaherty KT, Hersey P, et al. METRIC Phase 3 study: Efficacy of trametinib (T), a potent and selective MEK inhibitor (MEKi), in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy (C) in patients (pts) with BRAF V600E/K mutant advanced or metastatic melanoma (MM). J Clin Oncol. 2012;30(suppl: abstr LBA8509).

8. Hauschild A, Grob JJ, Demidov LV. Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma. J Clin Oncol. 2012;30(suppl; abstr LBA8500).

9. Topalian SL, Brahmer JR, Hodi, FS, et al. Anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced solid tumors: clinical activity, safety, and a potential biomarker for response. J Clin Oncol. 2012;30(suppl; abstr CRA2509).

10. Tykodi SS, Brahmer JR, Hwu W-J, et al. PD-1/PD-L1 pathway as a target for cancer immunotherapy: Safety and clinical activity of BMS-936559, and anti-PD-L1 antibody, in patients with solid tumors. J Clin Oncol. 2012;30(suppl; abstr 2510).

11. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012. Published online June 2, 2012. DOI: 10.1056/NEJMoa1200690.

12. Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti–PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012. Published online June 2, 2012. DOI: 10.1056/NEJMoa1200694.

13. Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med. 2012. Published online June 2, 2012. DOI:10.1056/NEJMe1205943.

14. Kaufman H, Wagner VJ, Goldsweig H, Yao B, Coffin R. OPTiM: A randomized phase III trial to evaluate the efficacy and safety of talimogene laherparepvec (T-VEC) compared with subcutaneously (sc) administered GM-CSF for the treatment (tx) of unresectable stage IIIb, IIIc, and IV melanoma. J Clin Oncol. 2012;(suppl; abstr 95193).

15. ClinicalTrials.gov. Efficacy and safety study of OncoVEXGM-CSF compared to GM-CSF in melanoma. Available at: http://clinicaltrials. gov/ct2/show/NCT00769704?term=OncoVEX+GM-csf&rank=4. Accessed May 28, 2012.

16. ClinicalTrials.gov. A phase 3 pivotal trial comparing Allovectin-7® alone vs chemotherapy alone in patients with stage 3 or stage 4 melanoma. Available at: http://clinicaltrials.gov/ct2/show/ NCT00395070. Accessed May 28, 2012.

I  

mproved outcomes and options for overcoming resistance to targeted therapies are still needed in metastatic melanoma. Researchers are exploring the use of combination therapies to reach these goals. gp100 peptide vaccine and interleukin-2. The authors of this 2011 randomized phase III trial hypothesized that the effectiveness of melanoma vaccine gp100 could be boosted by adding a cytokine to drive the immune response. In 185 patients with locally advanced stage III or stage IV melanoma, patients receiving gp100 plus interleukin-2 had higher response rates and progression-free survival (PFS) than did patients taking interleukin-2 alone. Combination therapy patients were more than twice as likely to experience a clinical response—the primary endpoint— than were interleukin-2-treated patients (16% vs 6%, P=.03) Patients receiving the combination also had increased average survival (by 7 months) over the single agent—from 11.1 months to 17.8 months. Incidences of sinus tachycardia and supraventricular arrhythmia resulted from the addition of the vaccine, but these were transient and reversible.1

Ipilimumab plus dacarbazine. In this phase III trial, 502 patients with previously untreated metastatic melanoma were randomized to receive either ipilimumab plus dacarbazine, or dacarbazine plus placebo. Overall survival (OS) was significantly longer in the combination therapy group. After 3 years, 20.8% of ipilimumab-plus-dacarbazine patients were alive, compared with 12.2% of patients receiving dacarbazine plus placebo (P <.001). Adverse events were consistent with other ipilimumab studies, except that rates of elevated liver function values were higher and gastrointestinal events were lower.2

Vemurafenib plus ipilimumab. A phase I/II study of vemurafenib plus ipilimumab in patients with BRAFV600 mutation-positive metastatic melanoma is currently under way. The rationale for this study is that inhibition of the MAPK pathway in BRAF-driven tumor cells can decrease production of immune- suppressive factors such as IL-10, and enhance expression of antigens that could be recognized by the immune system, making melanoma cells more susceptible to immune attack.3

Dabrafenib plus trametinib. A combination of BRAF inhibitor, dabrafenib, and MEK inhibitor, trametinib, has shown promise in patients with advanced melanoma, including fewer serious side effects than the current standard single-agent BRAF-targeted therapy, vemurafenib. Results of a phase I/II study exploring the combination of these two investigational targeted therapies were presented in a press briefing at the 2012 American Society of Clinical Oncology (ASCO) meeting.4

A study of 125 melanoma patients who received varying doses of dabrafenib/ trametinib included a subgroup analysis of 77 patients who had not been treated with any BRAF inhibitors, and therefore had no prior resistance to BRAF-targeted therapy. Among the 77 patients who received the combination therapy, the overall response rate (ORR) was 56% (95% CI, 44.1%-67.2%). Six patients achieved a complete response (CR), 38 patients achieved partial response (PR), and 29 patients had stable disease (SD).4The median overall PFS was 7.4 months (95% CI, 5.5-9.2), which was comparable to results with single-agent vemurafenib. The highest PFS was achieved in 24 patients who received 150 mg of dabrafenib twice daily and 2 mg of trametinib once daily. (Dabrafenib/trametinib was given at 4 dose levels.) In this group, median PFS was 10.8 months. Fifteen of 24 patients (63%) achieved either CR or PR (95% CI, 40.6%-81.2%). The 150 mg/2 mg dose will be evaluated further in a phase III clinical trial.4

The phase III COMBI-d trial will evaluate the combination of the two investigational agents versus dabrafenib alone in stopping or slowing the progression of metastatic melanoma, with a primary endpoint of PFS.

The phase III COMBI-v trial will compare the two investigational agents against the FDA-approved BRAF inhibitor, vemurafenib, in improving OS in patients with metastatic melanoma.5


References:

1. Schwartzentruber DJ, Lawson DH, Richards JM, et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011;364:2119-2127.

2. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-2526.

3. Chapman PB. Vemurafenib and ipilimumab to be tried together. Available at: http://www.medscape.com/viewarticle/752983. Accessed May 28, 2012.

4. Weber JS, Flaherty KT, Infante JR, et al. Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAF-naïve metastatic melanoma. J Clin Oncol 2012;30(suppl; abstr 8510).

5. GlaxoSmithKline. GSK announces start of Phase III programme for combination of dabrafenib (GSK2118436) and trametinib (GSK1120212) in BRAF V600 mutation-positive metastatic cutaneous melanoma. Available at: http://www.gsk.com/media/ pressreleases/2012/2012-pressrelease-1110046.htm. Accessed May 31, 2012.

I  

mmune-regulating cytotoxic T-lymphocyteassociated antigen-4 (CTLA-4) puts the brakes on activated immune cells as an “immune checkpoint molecule” that downregulates pathways of T-cell activation. Ipilimumab enhances the body’s immune response against tumors by blocking CTLA-4-mediated T-cell suppression. In this process, as clinical studies have consistently shown, an unusual spectrum of side effects and pattern of clinical response often emerges.1-3 Consistent with its proposed mechanism of action, the majority of adverse events with ipilimumab are immune-related. In the pivotal trial showing improved survival with ipilimumab in patients with metastatic melanoma, immune-related adverse events (irAEs) most often affected the skin, liver, bowel, and endocrine system:3

  • Rash/vitiligo/pruritus, 43.5% any grade and 1.5% grades 3-4
  • Hepatitis/rise in liver enzymes, 3.8% any grade, 0% grades 3-4
  • Diarrhea/colitis, 29.0% any grade, 7.6% grades 3-4
  • Hypophysitis, thyroiditis, adrenal insufficiency, 7.6% any grade, 3.8% grades 3-4


Less commonly, ipilimumab-treated patients have experienced uveitis, conjunctivitis, neuropathy, myopathy, and nephritis.3 Although a preventive strategy for these adverse effects has not been identified, the irAEs have been responsive to interruption or discontinuation of the CTLA-4 blockade plus immunosuppressive drugs such as steroids or tumor necrosis factor-blocking antibodies.2

Ipilimumab was approved with a boxed warning in recognition that its use has the potential to result in severe or fatal immune-mediated adverse reactions related to T-cell activation.4 A Risk Evaluation and Mitigation Strategy (REMS) was developed by the drug’s maker in collaboration with the FDA, advising clinicians to:

  • Permanently discontinue ipilimumab and initiate systemic high-dose corticosteroid therapy for identified severe immune-mediated reactions.
  • Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy, and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose of ipilimumab.


Another unusual feature of ipilimumab relates to novel patterns of clinical response. In some instances after starting ipilimumab, there is an early period of disease progression before patients experience a disease response. In others cases, there is regression of initial tumors but development of additional smaller lesions.2

Interestingly, patients who experience irAEs may gain more benefit from ipilimumab therapy. However, serious adverse events are not required for a response to occur. Nor is the occurrence of irAEs a guarantee of clinical benefit from ipilimumab.2,3

These unusual response patterns call for a new way to evaluate the benefits of ipilimumab and other immunotherapeutic agents. Accordingly, Wolchok et al5 proposed immune-related response criteria (irRC) that consider a patient’s “total tumor burden” and require confirmation of any suspected disease program by radiographic testing approximately four weeks after treatment. IrRC are currently being employed along with traditional response criteria (such as Response Evaluation Criteria In Solid Tumors [RECIST]) in clinical protocols for prospective validation of immunotherapeutic agents.2,5

References:

1. Melero I, Hervas-Stubbs S, Glennie M, Pardoll DM, Chen L. Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer. 2007;7:95-106.2. Postow MA, Wolchok JD. Ipilimumab: developmental history, clinical considerations, and future perspectives. The Melanoma Letter. 2012;30:1.

3. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.

4. Yervoy [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2011.

5. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009; 15:7412-7420.

A  

s basic research on new targets for rheumatoid arthritis (RA) treatment continues, novel therapies move through phase II trials. Multiple approaches to therapy continue to be needed because RA and other related inflammatory diseases continue to progress in most patients despite additions to and switching of therapies. New drugs with different mechanisms of action can halt erosive effects for a time, thereby delaying disease progression. Recent insights into the processes driving the autoimmune attack underlying RA have led to promising new treatments, many of which were presented at the 2012 European League Against Rheumatism (EULAR) Annual Congress in June.

EULAR Many of the “new” targets being tested are only new to these arthritis diseases and have been used in other therapeutic areas, most often in cancer patients. These include granulocyte-macrophage colonystimulating factor (GM-CSF) and transforming growth factor-beta agents, both familiar in the cancer world.

A summary of abstracts presented at the 2012 EULAR Annual Congress are presented here. Selections were chosen because they shed light on several emerging changes in treatment with targeted therapies.

IL-20: A Target for RA Therapy?

Interleukin-20 appears to be a valid drug target in rheumatoid arthritis (RA), according to placebo-controlled trial results with a monoclonal antibody designed to inactivate the protein. However, the trial was small (67 patients), and results were affected by presence of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA).

In this phase II trial, across all 67 patients, the monoclonal antibody NNC0109-0012 reduced Disease Activity Scale- (DAS) 28 scores including C-reactive protein measurements (DAS28-CRP) by 0.88 points relative to placebo in 12 weeks of treatment. (P = .020).

When the analysis was restricted to the approximately two-thirds of patients in both treatment groups who were positive for RF and ACPA, the mean DAS28-CRP scores declined by about 0.7 points in the placebo group versus 2.4 points with the study drug (P = .0004).

Interleukin-20 (IL-20) is secreted from synovial tissues, which also contain receptors for the cytokine. Studies in animal models of RA indicate that anti-IL-20 monoclonal antibodies relieve pain and inflammation and prevent joint erosion.

In the current trial, treatment was stopped at week 12 (except for methotrexate), but patients were followed and evaluated for an additional 13 weeks. During that time, the difference in responses in sero-positive patients was maintained, with only slight increases in DAS28-CRP scores in both groups from weeks 12 to 25.

Source:

Šenolt L, Göthberg M, Valencia X, et al. Efficacy and safety of NNC0109-0012 (anti-IL-20 Mab) in patients with rheumatoid arthritis: results from a phase 2A trial. Ann Rheum Dis. 2012;71(suppl 3):152. Abstract LB0004.

Stelara Investigated for Use in Psoriatic Arthritis

Study results presented at the 2012 EULAR Annual Congress indicated that ustekinumab (Stelara), an agent already used in psoriasis, may help ease swollen joints in patients with active psoriatic arthritis.

In the phase III PSUMMIT I study, treatment with the interleukin (IL)-12 and IL-23 inhibitor ustekinumab led to 20% improvements in the ACR20 criteria in 42.4% of patients receiving 45 mg and in 49.5% of patients receiving 90 mg, compared with 22.8% of patients treated with a placebo (P < .001).Psoriatic arthritis—a deforming and debilitating arthritis characterized by inflammation of the synovium, enthesis, and periosteum—develops in approximately 10% to 15% of patients with psoriasis. Current treatment options include conventional disease-modifying drugs such as methotrexate and sulfasalazine, nonsteroidal anti-inflammatory drugs, and biologic TNF inhibitors; however, many patients have inadequate responses to these approaches.

Good results on skin involvement were expected because ustekinumab is already licensed and in clinical use for psoriasis. Researchers said that the real test in this trial was whether the treatment also worked in the joints, and the answer, at least in comparison with placebo, was that it did.

A 75% improvement in skin involvement was observed in 57.2% of patients receiving the 45-mg dosage and in 62.4% of patients receiving the 90-mg dosage, compared with 11% of those receiving placebo.

Source:

McInnes I, Kavanaugh A, Gottlieb AB, et al. Ustekinumab in patients with active psoriatic arthritis: results of the phase 3, multicenter, double-blind, placebo-controlled PSUMMIT 1 study. Ann Rheum Dis. 2012;71(suppl 3):107.

Head-to-Head Drug Trials in RA

Results of the first two head-to-head trials of biologic agents for RA were reported at the EULAR Congress in Berlin, Germany. According to news reports of the congress proceedings, these trials caused significant discussion both on and off the floor of the presentations.

Driven by regulatory requirements in Europe, drugs for RA and related conditions are increasingly being tested against other active agents in clinical trials, but the relevance of the results for clinical practice is a matter of debate, according to EULAR president Maxime Dougados, MD, of René Descartes University in Paris, who is also an active researcher in the field.

With the caveat suggested by Dougados, the two head-to-head trials that follow offer new information that may or may not help in making prescribing decisions concerning choice of biologic agents for RA.

Tocilizumab (Actemra, Genentech) vs Adalimumab (Humira, Abbott) as Monotherapy for RA

Tocilizumab is an infused agent, currently indicated for the treatment of adult patients with moderatelyto- severely-active rheumatoid arthritis who have had an inadequate response to one or more TNF inhibitors. It can be given with or without methotrexate.

Classified as a non-TNF biologic, tocilizumab is an interleukin 6 (IL-6) receptor monoclonal antibody. IL-6 is a pro-inflammatory cytokine produced by a variety of cell types, including T and B cells, lymphocytes, monocytes, and fibroblasts.

In this randomized, double-blind trial, tocilizumab was significantly more effective than adalimumab as monotherapy for patients with RA who were unresponsive to or unable to take methotrexate. Adverse events were similar between the two agents. In all efficacy measures, tocilizumab was higher than adalimumab.

Table 1. Secondary Efficacy Endpoints

Rollover to enlarge. Endpoints
Under current guidelines, most biologic drugs are not recommended as monotherapy in the US or Europe. Instead, a combination regimen with methotrexate or other conventional DMARDs is usually preferred. Nevertheless, in practice, a significant number of patients do receive biologics as single agents. Reasons vary: Some patients do not tolerate methotrexate well, or a copay issue might cause some to use a single agent only, or a patient’s preference may favor taking a single drug.The 24-week trial randomized 326 patients to either 8 mg/kg of tocilizumab by IV infusion every 4 weeks, or 40 mg of adalimumab, by subcutaneous injection every 2 weeks.

On the study’s primary outcome measure, change in Disease Activity Scale-28 (DAS28) score from baseline, tocilizumab was clearly superior, with a decline in mean scores of 3.3 points versus 1.8 with adalimumab (P < .0001). The secondary efficacy endpoints of response rates in each study arm also favored tocilizumab (see Table 1).

Source

Gabay C, Emery P, van Vollenhoven R, et al. Tocilizumab monotherapy is superior to adalimumab monotherapy in reducing disease activity in patients with rheumatoid arthritis: 24-week data from the phase 4 ADACTA trial. Ann Rheum Dis. 2012;71(suppl 3):152. Abstract LB0003.

Abatacept (Orencia, Bristol-Myers Squibb) vs Adalimumab (Humira, Abbott)

The head-to-head trial of these two biologic therapies for RA resulted in a draw, according to many reports from the 2012 EULAR Annual Congress, where the data were presented. Multiple measures of clinical response in patients with early rheumatoid arthritis showed that the two biologic drugs were equally effective.

Abatacept is an anti-CD28 peptide that blocks T-cell activation, and adalimumab is the leading TNF inhibitor. The study’s primary endpoint was efficacy after 1 year, the results of which were reported at the EULAR meeting. The study will continue for another 12 months. Study participants had had an inadequate response or relapse after treatment with methotrexate alone and had not yet received biologic therapy.

Both drugs were given with methotrexate, according to their currently approved labels. Abatacept was given by subcutaneous injection at 125 mg weekly; the adalimumab dosage was 40 mg every other week.

The study’s primary endpoint was 20% reduction in symptoms by American College of Rheumatology criteria (ACR20) at 1 year. Response rates for for abatacept were 64.8%, and 63.4% for adalimumab, meeting the prespecified definition for abatacept noninferiority.

Rates of low disease activity (DAS28 score ≤ 3.2) and remission (DAS28 <2.6) at 1 year were also virtually equal, according to Michael Schiff, MD, the researcher from the University of Colorado in Denver who served as the trial’s lead investigator.

Compared with TNF inhibitors, abatacept has a reputation for relatively slow onset of action, but in the trial, responses over time tracked closely in the two study arms. At week 2, there was a statistically insignificant advantage for adalimumab in ACR20 response rates and DAS28 scores.

Eighty-five percent of patients on abatacept were rated as radiographic nonprogressors versus 89% of the adalimumab group. Rates of severe adverse events and serious infections were similar

Source:

Schiff M, Fleischmann R, Weinblatt M, et al. Abatacept SC versus adalimumab on background methotrexate in RA: one year results from the AMPLE study. Ann Rheum Dis. 2012;71(suppl 3):60. Abstract OP0022.

T  

he Janus kinase ( JAK) molecule is an immunomodulating signal transduction agent, which has emerged as a new target for rheumatoid arthritis (RA) research. Four JAK enzymes have been identified: JAK1, 2, 3, and TYK2. All four enzymes are critical components of signaling mechanisms utilized by a number of cytokines and growth factors, including those that are elevated in patients with RA. Cytokines such as interleukin-6, 12, and 23 signal through the JAK pathway; these particular cytokines have already been clinically validated as therapeutic targets in inflammatory diseases.

Several agents for RA that target the JAK enzymes are now in development, including:

  • Tofacitinib: inhibits JAK1, JAK2, and JAK 3
  • Baricitinib: inhibits JAK1 and JAK2, and its manufacturer describes it as “JAK3-sparing”


Tofacitinib (Pfizer) Inhibits JAK1, JAK2, and JAK3: Phase III data

Tofacitinib is likely to be the first oral biologic agent to be approved in the US for treatment of patients with RA. Tofacitinib is an oral JAK inhibitor, now with phase III data under review. In the pivotal trials, both the 5-mg twice-daily dose and the 10- mg twice-daily dose of tofacitinib were superior to placebo on three primary efficacy endpoints.

However, while the FDA Advisory Board in May 2012 moved the drug forward with a highly positive 10 to 0 vote on its efficacy data, the vote on safety data was somewhat troubling at 7 positive votes, 2 negatives, and 1 abstention. The negative reviews were most affected by a perceived increased risk of malignancy in the higher-dosage arm of the trial, with one reviewer saying that it was not regarded as a class effect, but rather as a drug-related risk. Further discussion during FDA review will probably rest on whether the increased efficacy benefit between the lower and higher doses justifies the increased safety risk. The manufacturer is seeking an indication for treatment of patients with moderate-to-severe RA.

The efficacy bar was higher for secondary endpoints, with an endpoint of ACR50, a 50% improvement in symptoms. Results were fairly similar between active treatment arms, with 33.8% of patients on the 5-mg dosage and 36.6% of those on the 10-mg dosage reaching that level of recovery compared with 12.7% of patients on placebo.

Efficacy endpoints at 6 months were: Clinical improvement (ACR20): 52.7% on the 5-mg dosage; 58.3% on the 10-mg dosage. Remission: 11% on the 5-mg dosage and 14.8% on the 10-mg dosage.

Efficacy endpoints at 3 months were: Change from baseline in HAQ-DI (Health Assessment Questionnaire Disability Index): 0.46 decline in disability on the 5-mg dosage; 0.56 decline in disability on the 10-mg dosage.

In this 12-month study, patients with RA who were treated with background, nonbiologic, disease-modifying antirheumatic drugs (DMARDs) such as methotrexate were randomized to one of the tofacitinib arms for the next 6 months. At 3 months, nonresponding patients on placebo were reassigned to one of the tofacitinib arms. At 6 months, the remaining patients on placebo were put on one of the two dosages of tofacitinib.

Proximal signaling pathways upon stimulation of immune receptors in T cells

Rollover to enlarge. Pathways
Once all patients were put on tofacitinib, the placebo patients achieved treatment responses similar to other tofacitinib patients, and all were able to maintain improvements through 12 months.Source:

Kremer J, Li Z-G, Hall S, et al. Tofacitinib (CP-690,550), an oral JAK inhibitor, in combination with traditional DMARDS: phase 3 study in patients with active rheumatoid arthritis with inadequate response to DMARDS. Ann Rheum Dis. 2011;70(suppl 3):170.

Baricitinib (Lilly and Company/Incyte) Inhibits JAK1 and JAK2: Phase IIb Data

A second oral JAK inhibitor for RA is not far behind tofacitinib. Researchers announced promising results for baricitinib from a phase IIb study at the European League Against Rheumatism (EULAR) Congress in June 2012, only a month after tofacitinib was moved forward by the FDA Advisory Committee. Trial results showed significant efficacy in patients with active RA. Baricitinab was administered in a combination regimen with methotrexate.

A placebo-controlled, dose-ranging study showed statistically significant differences in achieving the ACR20 score between placebo (41%) and the two highest-dose baricitinib groups (76%) at 12 weeks. A significant difference was also observed at the earliest assessment point, after 2 weeks of treatment, and was sustained to 12 weeks.

This was a small study of 301 patients with active RA who were on stable doses of methotrexate. Patients were randomized to receive placebo or one of four once-daily doses of baricitinib (1 mg, 2 mg, 4 mg, or 8 mg). Baricitinib is also being tested in phase II trials in patients with psoriasis.

Source:

Keystone E, Taylor P, Genovese M, et al. 12-week results of a phase 2B dose-ranging study of LY3009103 (INCB028050), an oral JAK1/JAK2 inhibitor, in combination with traditional DMARDs in patients with rheumatoid arthritis. Ann Rheum Dis. 2012;71(suppl 3):152.

D  

uring the past decade, changes in the treatment of rheumatoid arthritis (RA) have been accumulating faster than treatment experience can be evaluated. Consequently, the 2012 guideline revisions from the American College of Rheumatology (ACR) follow just four years after the previous version in 2008. The update is welcomed by clinicians, who must manage patients taking a range of different agents, choose treatment regimens based on tolerability and efficacy in each individual patient, and fit treatments to particular points in the progression of the disease. Most of the changes in the 2012 revision reflect treatment lessons learned as biologic response modifier therapies have become better known (Table 1). A total of eight biologic agents were reviewed for the 2012 revision. In 2008, only five biologics were available for review: two nontumor necrosis factor (non-TNF) drugs, abatacept (a selective co-stimulation modulator) and rituximab (a B-cell inhibitor), as well as three anti-TNF drugs, adalimumab, etanercept, and infliximab.

The 2012 guidelines added another non- TNF biologic, tocilizumab (which blocks the IL-6 messenger cytokine), and two additional anti-TNFs, certolizumab pegol and golimumab. The particular nomenclature separating these biologics—anti-TNFs and non-TNFs—is that used by the ACR, but both mechanisms of action are effective in halting RA disease progression. Clinicians are able to select one or another of the drugs based on tolerability and effectiveness in individual patients.

Table 1. Biologic Agents Included in ACR Guidelines for RA

Rollover to enlarge. Agents
Anti-TNFs and Non-TNFs

Tumor necrosis factor is a proinflammatory cytokine produced by the immune system. Excess levels of TNF are associated with inflammatory diseases such as rheumatoid arthritis, plaque psoriasis, psoriatic arthritis, juvenile idiopathic arthritis, and ankylosing spondylitis. The anti- TNFs reduce TNF to control inflammation. Non- TNFs use other mechanisms to interrupt the inflammatory autoimmune response. Because both anti-TNF and non-TNF agents affect the immune response, they raise the risk of infection for patients taking them.

The anti-TNFs are the most familiar of the biologics, and the class has been used for more than 10 years to treat inflammatory conditions. Given by injection or infusion, these drugs are able to stop disease progression. Often, anti-TNFs as well as non-TNFs are used in combination with earlier disease-modifying antirheumatic drugs (DMARDs) to increase their potency, most often with methotrexate.The 2012 guidelines focus on use of both DMARDs and biologics, making recommendations regarding selection of and switches between these agents. New recommendations favor early initiation of treatment (within the first 6 months following diagnosis) using triple-combination DMARD regimens or a biologic, with or without methotrexate, for patients who show high disease activity with poor prognosis. Biologics are not recommended for early RA in patients with lowto- moderate-disease activity and without poor prognosis.

Use of biologics as first-line therapy (in some patients) and beginning such treatment in early RA constitute two changes from the 2008 guidelines and probably better reflect existing practice patterns that changed as biologics became better understood.

An important addition in the 2012 revision is an update focused on safety issues that have become more apparent over time. The ACR makes new recommendations for use of biologic agents in high-risk patients, including patients who have hepatitis, congestive heart failure, or a history of malignancy, and are thus considered most at risk for infection. Table 2 shows recommended biologic agents for treatment of patients at risk.

In addition, screening for tuberculosis is recommended for all patients who are beginning or currently receiving biologic agents. Vaccinations are recommended for all patients taking DMARDs or biologic agents: pneumococcal, influenza, hepatitis B, human papillomavirus (HPV), and herpes zoster.

Table 2. ACR Recommendations for Use of Biologics in Patients With Hepatitis, Malignancy, or Congestive Heart Failure

Rollover to enlarge. Recommendations
Other New Practice Resources from ACR

Osteoarthritis

In April 2012, the ACR released updated osteoarthritis (OA) guidelines. These were published in the April issue of Arthritis Care & Research and are on the website (www. rheumatology.org) for easy downloading. The OA guidelines address pharmaceutical as well as nonpharmaceutical treatments for the hand, hip, and knee.

Lupus

In June 2012, the ACR released updated guidelines for treatment of lupus nephritis. These guidelines were published in the June issue of Arthritis Care & Research and are available on the ACR website.

Registry

The ACR maintains the ACR Rheumatology Clinical Registry. The registry is a free, easyto- use, Web-based tool developed to assist members in practice. It is also available as an application for handheld devices. The registry delivers information based on local population management; it is integrated with national qualitycare programs and contains quality measures aimed at improving care and drug safety for patients with rheumatoid arthritis, osteoarthritis, osteoporosis, gout, and juvenile idiopathic arthritis.

In 2011, the registry enabled electronic submission and retrieval capabilities to support exchange of information with the Centers for Medicare & Medicaid Services (CMS) Physician Quality Reporting System (PQRS) and the Electronic Prescribing Incentive Program (eRx). More details about the registry are available on the ACR website.

Source:

Singh JA, Furst DE, Bharat A, et al. 2012 Update of the 2008 American College of Rheumatology Recommendations for the Use of Disease-Modifying Antirheumatic Drugs and Biologic Agents in the Treatment of Rheumatoid Arthritis. Arthritis Care & Research. 2012;64(5):625-639.American College of Rheumatology website. Available at http://www.rheumatology.org. Accessed June 21, 2012.

D  

espite decades of investigation, the causes of rheumatoid arthritis (RA) have remained elusive. In fact, research has indicated that there is unlikely to be a single root cause. Different paths of investigation have provided sometimes contradictory lines of evidence leading to multiple biologic triggers setting off the autoimmune response that causes RA. Recently, animal studies have produced findings that argue for a broader causal theory that supports a targeted “cure.” Researchers who developed a mouse model for RA found that it took multiple regulatory T cells, rather than any specific one, to prevent the immune system from generating the tissue-specific inflammation that is the hallmark of RA. The cumulative effect of an array of diverse T cells introduced into the mouse was more effective in mediating the RA response than the single T cell that investigators expected to activate the receptor and trigger an inflammatory response. It was the diversity of the array that protected against RA. If the diversity is not present, the researchers reported, the immune system attacks the joints.

“Our results, surprisingly, show that suppressing the immune response against a single target will not shut down the inflammatory response that causes rheumatoid arthritis.”
The Wistar Institute announced the results of this research in the May 2012 issue of The Journal of Immunology. Andrew Caton, PhD, the senior author, said, “Our results, surprisingly, show that suppressing the immune response against a single target will not shut down the inflammatory response that causes rheumatoid arthritis. Instead, an array of inflammation-stimulating antigens may be involved in causing the disease.” An array of regulatory T cells is required to temper it.

The mouse model investigations also pointed to a possible reason that RA affects membranes that line the joints. Regulating T cells also influenced receptor T cells to produce interleukin-17 (IL-17), which travels through the body’s lymphatic system. The lymphatic system drains into the joints. Caton suggests that, “…the joint inflammation is a side effect of the natural tendency of these cells [IL-17] to accumulate in these areas of the body.”

Source:

The Wistar Institute. Regulatory immune cell diversity tempers autoimmunity in rheumatoid arthritis [press release]. Philadephia, PA: Science Daily; May 8, 2012. Available at: http:// www.sciencedaily.com/releases/2012/05/120508142626.htm. Accessed May 21, 2012.

Oh S, Aitken M, Simons DM, et al. Requirement for diverse TCR specificities determines regulatory T cell activity in a mouse model of autoimmune arthritis [published online ahead of print March 26, 2012]. J Immunol. doi:10.4049/ jimmunol.1103598.

A recent phase II study found that advanced non-small cell lung cancer (NSCLC) patients who received dacomitinib experienced longer periods of progression-free survival than patients who received erlotinib. The study was published in the Journal of Clinical Oncology.

Dacomitinib is an irreversible pan-human epidermal growth factor receptor (HER) inhibitor. Other approved targeted therapies for NSCLC, such as erlotinib and gefitinib, target a single member of the HER family of receptors, epidermal growth factor receptor (EGFR). Dacomitinib, on the other hand, is designed to bind to three separate kinase-active members of the HER family: EGFR/HER1, HER2, and HER4. This trial is the first to directly compare an irreversible pan-HER tyrosine kinase inhibitor (TKI) with a reversible EGFR selective TKI.

The phase II trial enrolled patients with NSCLC with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 who had one or two prior chemotherapy regimens and no prior HER-directed therapy. Patients were randomized to receive either dacomitinib 45 mg once daily or erlotinib 150 mg once daily. Of the 241 patients assessed for eligibility, 188 patients were evenly assigned to each arm.

The median PFS among patients who received dacomitinib was 2.86 months compared with 1.91 months in patients who received erlotinib (hazard ratio [HR] = 0.66; 95% CI, 0.47–0.91; P = .012). In a subanalysis, patients who had KRAS wild-type tumors had a median PFS of 3.71 months in the dacomitinib group compared with 1.91 months in patients in the erlotinib group (HR = 0.55; 95% CI, 0.35–0.85; P = .006). Patients who had KRAS wild-type/EGFR wild-type tumors had a median PFS of 2.21 months in the dacomitinib group compared with 1.84 months in patients treated with erlotinib (HR = 0.61; 95% CI, 0.37–0.99; P = .043).

The median OS among patients who received dacomitinib was 9.53 months compared with 7.44 months in the erlotinib arm of the study, although the result was not statistically significant (HR = 0.80; 95% CI, 0.56–1.13; P = .205).

The most frequent treatment-related adverse events included diarrhea, acneiform dermatitis, stomatitis, and decreased appetite. Most of these toxicities were either grade 1 or 2. There were more treatment-related dose reductions in the dacomitinib arm (n = 38) compared with the erlotnib arm (n = 16). There were four treatment-related deaths during the study, with two tied to each of the two study arms.

“The results documented here for dacomitinib suggest that irreversible pan-HER inhibition may offer a new treatment option for patients with advanced NSCLC, potentially representing an effective alternative to reversible inhibition of EGFR,” the authors wrote.

A phase III clinical trial, ARCHER 1009, is currently underway to determine the efficacy of dacomitinib in a second- or third-line setting in patients with NSCLC.


Ramalingham SS, Blackhall F, Krzakowski M, et al. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2012;30(27):3337-3344.

Researchers have found that a pathway involving the genes RHOJ and PAK1 is implicated in resistance to chemotherapy in melanoma cells, suggesting a new therapeutic target for the skin cancer.

The research was published online on September 12 by the journal Cancer Research.

Researchers at the University of