Christina T. Logudice

According to the Skin Cancer Foundation, more than 3.5 million cases of nonmelanoma skin cancers (NMSCs) are treated in the United States annually, making it the most commonly encountered malignancy.

Historically, treatment has involved surgical excision, radiation, and/or topical chemotherapy, which can require many treatments and can sometimes be disfiguring. A new portable electronic brachytherapy (EBT) device is now providing patients with a noninvasive, outpatient treatment option that has been associated with fewer treatments and excellent response and cosmesis.

&ldquo;The primary treatment option for basal cell carcinoma and squamous cell carcinoma is surgery, however, there are segments of the NMSC population for whom EBT is a good alternative,&rdquo; said Ajay Bhatnagar, MD, MBA, medical director, 21st Century Oncology of Arizona, to

. &ldquo;Specifically, it is a good alternative for patients with lesions in anatomically challenging locations, such as the ears, nose, scalp, and neck; patients who are on blood thinning medications; and patients who may have conditions that can cause difficulties in wound healing,&rdquo; he added.

The EBT device, known as the Xoft Electronic Brachytherapy (eBx) System, enables the clinician to administer surface brachytherapy without using radioactive isotopes or requiring a megavoltage linear accelerator; thus, it can be used in any clinical setting under the supervision of a radiation oncologist, and it can be easily transported within a facility or between multiple locations, including rooms without a vault. Unlike traditional radiation therapy, which can require daily treatments for up to 6 weeks, eBx requires only two visits a week for 4 weeks, and patients can resume normal activities immediately after treatment.

The system improves tumor targeting using a lightweight (>150 g) direct contact surface applicator and a flexible clamp, enabling the applicator to be oriented to the desired location on the target lesion. Use of a low-energy miniaturized X-ray source minimizes exposure to healthy adjacent tissues, and reduced shielding requirements enable healthcare providers to remain near the patient during treatment. Furthermore, the faster fall-off rate spares patients&rsquo; healthy tissue and organs.

&ldquo;The Xoft System is the only FDA-cleared electronic brachytherapy system that has been used to treat more than 10,000 NMSC patients and is supported by positive 4-year clinical data,&rdquo; said Bhatnagar, who recently presented data on Xoft&rsquo;s eBx System at the American Academy of Dermatology Annual Meeting.

Dr. Bhatnagar&rsquo;s study included 200 patients (mean age, 77 years; range, 52 to 102 years) with 297 NMSCs who were treated with eBx between July 2009 and June 2014. Treatment involved placing a thermoplastic mask around the lesions to protect adjacent healthy tissue and then holding the eBx&rsquo;s surface applicator above the lesion to deliver radiation. Healthcare providers could select between 10-, 20-, 35-, and 50-mm surface applicators, enabling use of an applicator that would allow for complete coverage of the target lesion while providing an acceptable margin. All patients received same-dose fractionation (ie, 40.0 Gy at 2 fractions per week) at a prescription depth of 3-mm for most lesions; if a thick lesion was identified, computed tomography scanning was used to determine prescription depth.

After a mean follow-up of 16.5 months (range, 1-63 months), all 297 lesions showed a complete response, with only one recurrence. Cosmesis was also excellent for more than 90% of lesions, and no patients experienced poor cosmesis. The most commonly reported acute toxicities at 1 month included rash dermatitis (82%), pruritus (27%), and hyperpigmentation (2%), all of which resolved within 1 year. The only late toxicity, occurring at or after 12 months, was hyperpigmentation (2%), with no grade 3 or higher toxicities observed.

The eBx system is also being used to treat breast and gynecologic cancers. More information on using EBT to treat these cancers and NMSCs can be found at the

Skin Cancer Foundation. Nonmelanoma skin cancer incidence jumps by approximately 300 percent http://www.skincancer.org/skin-cancer-information/skin-cancer-facts/nonmelanoma-skin-cancer-incidence-jumps-by-approximately-300-percent. Accessed April 6, 2015.

Bhatnagar A. Electronic brachytherapy for the treatment of non-melanoma skin cancer: results up to 4 years. Poster presented at: 73rd Annual Meeting of the American Academy of Dermatology; March 20-24, 2015; San Francisco, CA. E-poster 2005.

Articles

New Device Treats Nonmelanoma Skin Cancer Noninvasively

Building on an earlier 12-month study, Shabbir M.H. Alibhai, MD, et al from the University Health Network in Toronto, Canada, found that impact from androgen deprivation therapy (ADT) on physical function persisted over 36 months,

indicating ADT has lasting effects, which need to be addressed.

&ldquo;Most men [with prostate cancer] starting ADT remain on it for at least 2 to 3 years, so it is important to determine whether the observed 12-month declines in physical function with ADT persist, worsen, or resolve over time,&rdquo; the researchers wrote.

included 87 men with nonmetastatic prostate cancer who were starting continuous ADT, 86 men with prostate cancer who did not receive ADT, and 86 healthy men, with the latter two groups serving as controls. All three groups were recruited from two tertiary care academic cancer centers in Toronto, Canada, between May 2004 and September 2007, and were frequency-matched by age, education, and walking independence at baseline.

Throughout the study, participants&rsquo; physical function was assessed using the 6-minute walk test (6MWT), grip strength on a Jamar dynamometer, and the Timed Up and Go (TUG) test, and quality of life (QoL) was measured using the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). All physical function and QoL measures were assessed at baseline and at 3, 6, 12, 18, 24, 30, and 36 months.

Using mixed effects regression models from baseline to 36 months, Alibhai et al found statistically significant differences between the ADT group and controls for all 3 measures of physical function. ADT users performed more poorly than both controls on the 6MWT, with controls showing initial improvements in this measure over the first 6 months of the study followed by stabilization (

= .003; all reported comparisons are with healthy controls). At 3 months, grip strength declined in ADT users and then stabilized over time, whereas both controls did not exhibit significant declines in grip strength over time (

= .004). Finally, ADT users demonstrated gradual worsening of their TUG scores, whereas these scores remained stable or improved slightly in both control groups (

With regard to QoL, all 3 cohorts had similar baseline scores on the physical component summary of the SF-36 (analysis of variance [ANOVA],

>.20), but they declined in ADT users and remained stable for both control groups (

<.001). Scores on the mental component summary of the SF-36 remained stable in all groups (

= .08, for ADT users vs controls). There was also no difference between groups in baseline scores in either the Barthel index or the Lawton-Brody index (ANOVA,

>.20), and these scores remained stable over time in all 3 cohorts.

Alibhai et al assessed whether or not age had an impact on the observed changes in physical function over time. They found that although baseline levels of physical performance were lower in older participants across all cohorts, the effects of ADT were not statistically different by age group for any of the objective physical performance measures or self-reported measures.

The authors&rsquo; study shows that ADT use is associated with persistent, clinically relevant declines in physical function that is independent of age. Although most declines stabilized, they did not improve beyond the first 6 months of use, and lower extremity function continued to worsen over time, as shown by patients&rsquo; TUG scores.

&ldquo;[Our] results will help clinicians and patients to better understand the risks of ADT. Moreover, they reinforce the need for greater adoption of exercise programs among ADT users, regardless of whether they are new or established users, to reverse or prevent these declines,&rdquo; the authors conclude.

Alibhai SMH, Breunis H, Timilshina N, et al. Impact of androgen-deprivation therapy on physical function and quality of life in men with non-metastatic prostate cancer. J Clin Oncol. 2010;28:5038-5045.

Alibhai SM, Breunis H, Timilshina N, et al. Long-term impact of androgen-deprivation therapy on physical function and quality of life. Cancer. http://www.ncbi.nlm.nih.gov/pubmed/25809861. Accessed April 2, 2015.

Shabbir M.H. Alibhai, MD, et al from the University Health Network in Toronto, Canada, found that impact from ADT on physical function persisted over 36 months, indicating ADT has lasting effects, which need to be addressed.

ADT May Impact Physical Function, Highlighting Need for Exercise

Solid tumors often have an abnormal web of blood vessels, creating areas of hypoxia that protect the tumor from the toxic effects of chemotherapy drugs and radiation, which are designed to seek out well-oxygenated tissue. Because exercise has been shown to improve blood vessel growth and perfusion of normal tissues, investigators at Duke Cancer Institute (DCI) sought to determine whether or not it might have the same effect in solid tumors. Their

The investigators assessed the effect of exercise on breast cancer tumor growth and response to treatment in mice with orthotopically implanted estrogen receptor (ER)-negative and ER-positive tumor cells and randomly assigned the mice to exercise (running on a wheel) or sedentary control. The investigators found that the mice that exercised had significantly reduced tumor growth and a 1.4-fold increase in apoptosis. Microvessel density was also approximately 60% higher in exercised mice compared with the sedentary mice, and oxygen transport to the tumors was improved, with a tumor vasculature that appeared and behaved more normally.

Based on these findings, the researchers tested whether or not exercise would also improve the efficacy of chemotherapy. They randomly assigned the mice to one of four groups: sedentary, exercise alone, cyclophosphamide alone, or exercise plus cyclophosphamide. They found that the rate of tumor growth was significantly slower in mice treated with exercise plus cyclophosphamide compared with all other groups. Although tumor growth was also delayed in the exercise alone and cyclophosphamide alone groups, there was no difference in tumor growth rate between those two groups, suggesting exercise had similar effects as chemotherapy in their experiment.

&ldquo;We were truly amazed by these findings,&rdquo; said co-senior author Mark W. Dewhirst, DVM, PhD, the Gustavo S. Montana Professor of Radiation Oncology, and vice director for Basic Science at DCI, in a DCI press release. &ldquo;I have spent the better part of the last 30 years trying to figure out how to eliminate hypoxia in tumors, and have looked at a lot of different approachesdrugs, hyperthermia, and metabolic manipulations. None has worked very well, and in some cases, made things worse. So these findings with exercise are quite encouraging.&rdquo;

had the opportunity to discuss the study and its findings in greater detail with Dewhirst.

What is the most important finding of your study?

That exercise simultaneously increases blood flow and oxygen delivery to tumors. The increase in blood flow will increase drug delivery to cancers, thereby increasing the likelihood that cancer cells will be exposed to enough drug to kill them. The increase in oxygen also increases sensitivity of tumor cells to chemotherapy and radiation therapy.

What do you think is the mechanism behind exercise reducing oxygen starvation of tumors?

Exercise seems to stimulate tumor blood vessel growth, in addition to opening existing blood vessels. We do not know the mechanism for certain. This is a subject of ongoing research.

Your study used mouse models that performed exercise by running on a wheel. Do you think the effects you observed would only be seen with high-impact aerobic exercises, or do you think other exercises (eg, yoga, weight-bearing exercises) might also show benefit?

The benefit comes from performing aerobic exercise. We do not have any evidence that weight-bearing exercise has the same benefit, and I cannot make any predictions about yoga. If there were an effect with yoga, it would be through a different mechanism than what is achieved with aerobic exercise.

You also examined how exercise worked in combination with a chemotherapeutic agent. Do you think exercise has the potential to increase the efficacy of other treatments as well, including some of the more targeted therapies?

I do believe that it will improve the efficacy of many drugs, including targeted therapies. One of the major limits to achieving better efficacy of any drug is achieving sufficient concentrations of drug in the tumor. Tumor blood vessel function is very abnormal and this abnormality limits efficiency in drug delivery. We happened to look at cyclophosphamide, but the improvement in perfusion would be expected to increase the delivery of any drug to tumors.

What should healthcare providers keep in mind as they learn about your study?

We know from this study and others that exercise can reduce tumor growth rate. What we do not know yet is how much exercise is sufficient to see a benefit. That is the subject of ongoing research.

Patients with cancer reading about your findings may be inclined to start exercising. What would you tell such patients?

It would be best for them to focus on aerobic training. It is difficult at this time to give them a precise prescription of exercise; however, the

guidelines set by the American Cancer Society

Solid tumors often have an abnormal web of blood vessels, creating areas of hypoxia that protect the tumor from the toxic effects of chemotherapy drugs and radiation, which are designed to seek out well-oxygenated tissue.

Preclinical Trial Shows Exercise Increases Efficacy of Chemotherapy

Two recently published studies have reported discoveries that could eventually lead to improved outcomes in patients with pancreatic cancer. The first study, by researchers from Indiana University, has identified a new angiogenic gene signature that can be targeted to thwart tumor growth.

The second study, by researchers from Taiwan, found a particular secreted immune protein and its receptors to be prevalent in pancreatic cancer.

When this protein and its receptors were targeted with a newly derived monoclonal antibody, metastasis was prevented and survival increased.

The Indiana University researchers assessed data from the Cancer Genome Atlas and found overexpression of pro-angiogenic factors in some pancreatic ductal adenocarcinomas (PDACs). These factors facilitated tumor growth by enabling abnormal blood vessels to form in PDACs. The researchers also found, for the first time, that endothelial cells can produce molecules that directly stimulate the growth of pancreatic cancer cells. According to a press release announcing these discoveries, the researchers&rsquo; findings have the potential to benefit approximately 15% of people with pancreatic cancer by enabling them to receive therapies targeting this newly identified gene signature.

&ldquo;We showed that endothelial cells can stimulate the growth of pancreatic cancer cells and that by silencing or inhibiting certain pathways  JAK1&ndash;2 and STAT3 &ndash; we can alter that effect,&rdquo; said Murray Korc, MD, the Myles Brand Professor of Cancer Research at the Indiana University School of Medicine and a researcher at the Indiana University Melvin & Bren Simon Cancer Center.

&ldquo;We demonstrated that it is possible to target these pathways and prolong the survival of genetically modified mice whose pancreatic cancers also have a strong pro-angiogenic gene signature.&rdquo;

Target: Overexpression of Interleukin-17B Receptors

Another important feature of Korc et al study was that it demonstrated the feasibility of generating human tumors in mice by implanting them with small biopsy samples obtained from patients undergoing endoscopic procedures. The researchers found that when the original human tumor exhibited evidence for angiogenesis, the implanted tumor in the mouse also exhibited angiogenesis. This approach to studying tumors could potentially guide the design of precision medicine using targeted therapies, but confirmatory studies are necessary, noted Korc.

The secreted immune protein interleukin (IL)-17 has been associated with cancer progression, and receptors for IL-17 are expressed in the pancreas. Now, researchers from the Academia Sinica in Taiwan have shown that overexpression of the IL-17B receptor (IL-17RB) strongly correlates with postoperative metastasis and inversely correlates with progression-free survival in patients with pancreatic cancer.

The researchers&rsquo; ex vivo experiments consistently validated that IL-17RB and its ligand, IL-17B play an essential role in pancreatic cancer metastasis and malignancy. Signals from IL-17B and IL-17RB activated CCL20/CXCL1/IL-8/TFF1 chemokine expressions via the ERK1/2 pathway, promoting cancer cell invasion, macrophage and endothelial cell recruitment at primary sites, and cancer cell survival at distant organs. When mouse xenograft models were treated with a newly derived monoclonal antibody against IL-17RB, tumor metastasis was blocked and survival improved.

The researchers conclude that their findings &ldquo;not only illustrate a key mechanism underlying the highly aggressive characteristics of pancreatic cancer, but also provide a practical approach to tackle this disease.&rdquo;

Gore J, Craven KE, Wilson JL, et al. TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis. http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=3233. Published February 25, 2015. Accessed March 2, 2015.

Wu HH, Hwang-Verslues WW, Lee WH, et al. Targeting IL-17BIL-17RB signaling with an anti&ndash;IL-17RB antibody blocks pancreatic cancer metastasis by silencing multiple chemokines. http://jem.rupress.org/content/early/2015/02/24/jem.20141702.abstract. Published March 2, 2015. Accessed March 2, 2015.

Pancreatic cancer patients with particular gene signature may benefit from personalized treatment [press release]. http://www.newswise.com/articles/view/630309/?sc=dwhr&xy=10013055. Indianapolis, IN: Indiana University; February 26, 2015. Accessed March 2, 2015

Two recently published studies have reported discoveries that could eventually lead to improved outcomes in patients with pancreatic cancer.

Studies Identify New Targets to Improve Survival in Pancreatic Cancer

Unlike many solid tumors, which are identified through diagnostic imaging, prostate cancer screening relies on prostate-specific antigen (PSA) testing and a digital rectal examination. When a PSA test shows elevated PSA levels (typically >4.0 ng/mL) and a digital rectal examination indicates an abnormality, patients often undergo a standard extended-sextant biopsy (ie, standard biopsy) for suspected prostate cancer.

Standard biopsy involves taking between 6 and 14 random samples from the prostate.

Without the use of imaging to guide sampling, this process has been called &ldquo;a shot in the dark.&rdquo;

Up to 20% of prostate cancers are missed using this technique, and another 20% are more aggressive than initially detected.

A new study published in JAMA, however, showed that prostate cancer detection can be significantly improved when biopsies are guided with imaging that fuses magnetic resonance imaging (MRI) with ultrasonography (ie, targeted biopsies).

The study investigators, led by Mohummad Minhaj Siddiqui, MD, assistant professor of surgery at the University of Maryland School of Medicine and director of urologic robotic surgery at the University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, reported that targeted biopsies identified 30% more high-risk prostate cancers and 17% fewer low-grade prostate cancers compared with standard biopsy.

"With fusion technology, we now have a tool to help us differentiate high-risk cancers from low-risk ones that may require minimal or no treatment," said Siddiqui in a University of Maryland Medical Center press release.

&ldquo;There is a concern that we over-diagnose and over-treat low-risk cancers that are unlikely to be terminal, and this technology enables us to make a more reliable diagnosis than the current standard practice,&rdquo; he added.

MRI/ultrasound fusion electronically superimposes images from multiparametric MRI onto transrectal ultrasound images in real time, enabling urologists to progress from blind biopsies to those that are mapped, targeted, and tracked.6 Previous studies have shown that targeted biopsies in combination with standard biopsies is a superior approach to standard biopsy alone, but these studies have also led to questions about the necessity of also performing the standard biopsy when a targeted biopsy was already being undertaken.

Siddiqui and colleagues&rsquo; prospective cohort study sought to shed light on these questions by comparing targeted biopsies with standard biopsies in identifying intermediate- to high-risk prostate cancers in 1003 men undergoing concurrent targeted and standard biopsies over a 7-year period (2007-2014) at the National Cancer Institute. All patients had elevated PSA levels, an abnormal digital rectal examination, or both, with most patients having previously received negative biopsy results.

In the study, targeted biopsies diagnosed 461 cases of prostate cancer and standard biopsy diagnosed 469 cases, with exact agreement between the two modalities occurring in 690 cases (69%). Targeted biopsy identified 30% more high-risk cancers compared with standard biopsy (173 vs 122 cases;

<.001) and 17% fewer low-risk cancers (213 vs 258 cases;

<.001). Adding standard biopsy cores to the targeted approach identified another 103 cases of prostate cancer (22%), most of which where low risk (83% low risk, 12% intermediate risk, and 5% high risk).

In addition, the predictive ability of targeted biopsy to differentiate between low-, intermediate-, and high-risk disease in 170 men with whole-gland pathology after prostatectomy was greater than that of standard biopsy or of the 2 approaches combined (area under the curve, 0.73, 0.59, and 0.67, respectively;

&ldquo;While these findings could translate into substantial benefit to patients, this study is preliminary with regard to clinical endpoints such as recurrence of disease and prostate cancer-specific mortality," said Siddiqui, noting that randomized clinical trials are needed to determine the impact of targeted biopsies on clinical outcomes.

Siddiqui is taking steps to undertake such a clinical trial. He plans to assess the ability of MRI/ultrasound fusion to identify and biopsy suspicious areas within the prostate and use the findings to guide treatment.

In low-risk cases, he will use this technology to perform more reliable active surveillance, enabling fewer biopsies to be taken. In intermediate-risk disease (ie, disease that requires treatment but is not widespread), he will use focal brachytherapy to irradiate only the tumor and protect the surrounding tissue, sparing these patients from experiencing the side effects associated with prostatectomy or whole prostate gland irradiation. In high-risk cases, he plans to use MRI/ultrasound fusion to guide more aggressive options, such as robotic surgery. No announcement has yet been made as to when Siddiqui&rsquo;s trial will start enrolling patients.

American Cancer Society. What are the key statistics about prostate cancer? http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics. Last Revised January 5, 2015. Accessed January 25, 2015.

Prostate mapping. Prostate biopsy. http://www.prostatemapping.com/prostate-biopsy.aspx. Accessed January 25, 2015.

McCallum J. Chapter 16...in which the author ponders the lessons of prostate cancer, offers tentative advice, and breaks bread with his prostatectomy pal.

The Prostate Monologues: What Every Man Can Learn From My Humble, Confusing, and Sometimes Comical Battle With Prostate Cancer

. New York, NY: Rodale Books; 2013:181-198.

Siddiqui MM, Rais-Bahrami S, Turkbey B, et al. Comparison of MR/Ultrasound Fusion-Guided Biopsy With Ultrasound-Guided Biopsy for the Diagnosis of Prostate Cancer.

New research in JAMA: targeted MRI/ultrasound fusion technique more effective than standard biopsy to detect high-risk prostate cancer [news release]. Baltimore, MD: University of Maryland Medical Center; January 27, 2015. http://umm.edu/news-and-events/news-releases/2015/mri-ultrasound-fusion-technique-more-effective. Accessed January 29, 2015.

Marks L, Young S, Natarajan S. MRI-ultrasound fusion for guidance of targeted prostate biopsy.

In many cases, prostate cancer grows slowly and causes few symptoms; thus, many men remain unaware that they have the disease.

Christina T. Logudice | Authors

Articles

New Device Treats Nonmelanoma Skin Cancer Noninvasively

ADT May Impact Physical Function, Highlighting Need for Exercise

Preclinical Trial Shows Exercise Increases Efficacy of Chemotherapy

Studies Identify New Targets to Improve Survival in Pancreatic Cancer

Targeted Biopsies Detect More High-Risk Prostate Cancers Than Standard Biopsies