Patients with lymphoma who are treated with brentuximab vedotin (BV; Adcetris) often experience peripheral neuropathy (PN) as an adverse event (AE) and potentially dose-limiting toxicity. A novel study has shown that, despite the prevalence of this toxicity, these patients report that the better outcomes yielded from treatment with BV outweigh the risk of neuropathy.

Of 89 eligible patients in the study, 93% received single-agent BV. The median number of BV doses was 5. Forty-three patients (48%) developed peripheral neuropathy. At a median follow-up of 12 months, the AE was resolved completely in 14 patients (33%). The median time to resolution was 13 weeks.

Sarah Nagle, MD, of the Lymphoma Program at the Abramson Cancer Center at the University of Pennsylvania, reported the findings at the 2017 Cancer Survivorship Symposium held January 27 to 28 in San Diego. Nagle and her research team sought to identify predictors of BVinduced peripheral neuropathy (BIPN), whether it affected disease outcomes, and explore any psychosocial impacts of BIPN.

&ldquo;Therapy was altered in 58% of patients due to BIPN,&rdquo; the researchers noted, &ldquo;but this did not affect overall survival [OS] or progression-free survival [PFS].&rdquo;

Although not statistically significant, there was a numerical difference in both of the survival outcomes: the median PFS for patients whose therapy was altered due to BIPN was 6.2 versus 12.4 months for those whose therapy was not altered (

= .09), and the median OS was 25.8 months versus not reached, respectively (

Of 18 patients surveyed on their symptoms, 14 (78%) reported BIPN. At a median follow-up of 24 months, 10 patients (71%) reported ongoing symptoms. For 50% of patients, quality of life was affected by BIPN.

However, despite these significant symptoms related to BIPN, all patients were reportedly satisfied with their decision to receive BV.

The researchers also investigated the effects of other factorsincluding age, sex, prior neurotoxic agent, underlying neuropathy, diabetes mellitus, or body mass index&mdash;on the risk of developing BIPN. None of these factors were found to increase the risk for developing the AE. However, 3 additional factors were identified as being associated with BIPN: the number of BV doses, the cumulative dose, and treatment response.

These findings are based on a retrospective chart review, open-ended survey, and self-reported symptom assessment involving 89 lymphoma patients who received treatment at the cancer center between January 2010 and May 2016; of the total, 54% had Hodgkin lymphoma and 23% cutaneous T-cell lymphoma. Eligible patients were aged 18 years or older (median age, 48 years) and had 1 or more cycles of BV therapy (median, 5 doses); 71% of participants were treated with prior neurotoxic therapy.

Nearly half of the patients studied (n = 43) developed neuropathy; of these, 3 individuals had their BV held, 9 discontinued therapy, and 14 had their BV dose modified, Nagle reported in a poster presentation at the symposium. Forty-two percent of patients with BIPN used analgesics, and 6 were referred to a pain specialist.

The researchers also looked at more subjective commentary with respect to the psychosocial burden of neuropathy and elicited a range of responses, including difficulty with balance, pain after periods of long sitting or when getting up in the morning, a reliance on family members for tasks they can no longer perform, and finding the condition harder to deal with in the winter months than during the summer.

Some patients, however, said the condition was not limiting, whereas others acknowledged the symptom but said they had no regrets. &ldquo;Despite significant symptoms from BIPN, all patients were satisfied with the decision to receive BV regardless of disease response,&rdquo; the researchers reported.

&ldquo;BIPN is a significant adverse effect in patients who receive BV, and it may fail to resolve in a large subset of patients,&rdquo; they continued. Nonetheless, patients surveyed, &ldquo;universally reported that the benefits of this therapy outweigh the risks. Clinicians should be aware of the risk for BIPN and educate patients accordingly,&rdquo; concluded the researchers.

Nagle S, Strelec LE, Loren AW, et al. Brentuximab-induced peripheral neuropathy: risk factors and patient experiences.

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Clinical Articles

Patients with lymphoma who are treated with brentuximab vedotin often experience peripheral neuropathy as an adverse event and potentially dose-limiting toxicity. A novel study has shown that, despite the prevalence of this toxicity, these patients report that the better outcomes yielded from treatment with brentuximab vedotin outweigh the risk of neuropathy.&nbsp;

Brentuximab Vedotin Benefits Offset Risk of Peripheral Neuropathy, Patients Say

The impact of the recent findings regarding tumor sidedness in patients with metastatic colorectal cancer (mCRC) are potentially practice-changing, with data demonstrating that patients with right-sided tumors have a poorer prognosis than those with left-sided tumors. In addition, sidedness could be clinically relevant as a predictive biomarker of response to standard frontline treatments.

Yet these findings are still immature. Further studies are required to confirm and to explore the molecular and biological reasons behind the differences between left- and right-sided tumors, before the findings can be integrated into clinical practice.

CALGB/SWOG 80405 JUMPSTARTS FOCUS ON SIDEDNESS

Although the importance of tumor sidedness in colorectal cancer has been referenced since 2001, the importance of this issue was pushed to the forefront in June during the 2016 ASCO Annual Meeting.

During the ASCO meeting, Alan P. Venook, MD, presented a retrospective subgroup analysis from the CALGB/SWOG 80405 trial that showed that patients with left-sided tumors had significantly longer median overall survival (OS) rates than patients with right-sided tumors.

Patients with right-sided tumors, consisting of tumors in the appendix, cecum, ascending colon, and hepatix flexure, had a median OS of 19.4 months (95% CI, 16.7-23.6) versus 33.3 months (95% CI, 31.4-35.7) in patients with left-sided tumors, consisting of tumors in the splenic exure, descending colon, sigmoid colon, and rectum (HR, 1.60; 95% CI, 1.37-1.86; P <.001). The results were similar when the transverse colon was allotted to the right side, as in other similar studies, and in patients with KRAS-mutant tumors.

In the study, 1137 treatment-naïve patients with KRAS wild-type (codons 12 and 13) mCRC were treated with FOLFIRI (irinotecan/5- fluorouracil [5-FU]/leucovorin) or mFOLFOX6 (oxaliplatin/5-FU/ leucovorin) with either bevacizumab (Avastin) or cetuximab (Erbitux). Patients with right-sided tumors treated with cetuximab had a median OS of 16.7 months (95% CI, 13.1-19.4) versus 36 months (95% CI, 32.6-40.3) in the left-sided tumors (HR, 1.98; 95% CI, 1.60- 2.46; P <.001). With bevacizumab therapy, patients with right-sided tumors had a median OS of 24.2 months (95% CI, 17.9-30.3) versus 31.4 months (95% CI, 28.3-33.6) for those with left-sided tumors (HR, 1.32; 95% CI, 1.05-1.65).

The analysis suggested that treatment with the anti-EGFR monoclonal antibody cetuximab was more beneficial for patients with left-sided tumors and bevacizumab improved outcomes for patients with right-sided tumors, which could potentially affect the frontline standard of care for patients with mCRC.

&ldquo;What we saw, and what others have now replicated, is that patients with tumors on the right side of the colon had no benefit from cetuximab,&rdquo; said Venook, the Shorenstein associate director for program development at the Helen Diller Family Comprehensive Cancer Center, and professor of medicine at the University of California, San Francisco, in an interview with

However, Venook, noted that this was a retrospective, unplanned analysis, so it cannot yet be confirmed that either drug is superior in the frontline based on tumor sidedness. However, similar results were seen in the FIRE-3 and CRYSTAL studies.

In the FIRE-3 trial, patients with KRAS (exon 2) codon 12 or 13 wild-type mCRC were treated with FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab. The median OS for patients receiving FOLFIRI plus cetuximab was 33 versus 25 months in the bevaci- zumab arm.

When analyzed by primary tumor location, those with left-sided tumors (n = 306) showed a median OS of 38.3 versus 18.3 months in patients with right-sided tumors (n = 88) when treated with cetuximab (P <.0001). Patients with left-sided tumors treated with bevacizumab had a median OS of 28.0 versus 23.0 months in patients with right-sided tumors (P = .038).

A recent retrospective analysis of FIRE-3 and CRYSTALanother study of anti-EGFR therapy for patients with mCRC&mdash;explored the predictive and prognostic nature of primary tumor location in patients with RAS wild-type tumors. The analysis demonstrated that patients with left-sided tumors had superior OS rates (TABLE) as well as superior progression-free survival and objective response rates compared with patients with right-sided tumors across both studies.

In addition, patients with left-sided tumors gained more of a benefit from treatment with cetuximab than patients with right-sided tumors did; meanwhile, patients with right-sided tumors did not benefit as much from treatment with standard therapy.

Consequently, sidedness could be both predictive of response to treatment with anti-EGFR therapy or standard therapy, and prog- nostic of patients' improved survival rates when harboring tumors in the left side of the colon. Venook similarly suggested the predic- tive and prognostic value of tumor sidedness in his analysis of the CALGB/SWOG 80405 trial.

Sabine Tejpar, MD, and her co-authors also noted a significant interaction in multivariable models between tumor sidedness and treatment with regard to OS rates in both studies when also stratifying for sex, prior adjuvant therapy, and BRAF mutational status.

Tejpar et al recommended that primary tumor location be included as a stratification parameter in future trials of patients with mCRC, especially for trials including anti-EGFR therapies.

The prognostic nature of tumor sidedness may depend on the stage of the disease. A study of patients with CRC from the Surveillance Epidemiology and End Results Program database, which was presented at the 2016 ASCO Annual Meeting by Deborah Schrag, MD, MPH, survival rates favoring left-sided tumors were confirmed in patients with stage III or IV disease. In stage III, patients with left-sided tumors had a 71% rate of survival at 3 years versus 62% for those with right-sided tumors (unadjusted HR, 1.39; 95% CI, 1.32-1.46). In stage IV, the 3-year survival probability was 27% with left-sided tumors and 16% for those with right-sided tumors (unadjusted HR, 1.40; 95% CI, 1.35-1.46). However, the association between primary tumor location and prognosis was weaker or nonexistent in patients with stage I or II disease.

POTENTIAL MOLECULAR AND BIOLOGICAL CAUSES

Further study is required to identify the molecular and biological causes that account for the differences in prognosis between left- and right-sided tumors.

&ldquo;Hopefully, we will soon have the data to explain what is going on. It is not a function of right versus left side; it&rsquo;s molecular features that appear to be nonrandomly distributed across the colon,&rdquo; Venook commented. &ldquo;I am hoping that we will have the opportunity to explain not only why patients do better on the left versus right with certain drugs, but also to prospectively understand why that is and how we should be treating patients.&rdquo;

In the analysis of the CALGB/SWOG 80405 trial, Venook suggested that BRAF mutation status, microsatellite instability (MSI), and/or methylation could provide potential explanations.

During the 2016 ASCO meeting, Schrag also suggested that there could be an association between sidedness and recently defined consensus molecular subtypes of CRC from an international consortium of experts.

The consortium differentiated the biological underpinnings of 4 subtypes: CMS1, tumors that are MSI-immune, CMS2 are canonical tumors, CMS3 are metabolic tumors, and CMS4 are mesenchymal tumors.

Schrag noted that patients with right-sided tumors were more common in the CMS1 and CMS3 subtypes, which are associated with BRAF and KRAS mutations, respectively. Both subtypes were associated with worse prognoses.

&ldquo;What we are hoping we will see is that there are molecular subtypes of CRC. We think there are 4, and some of them are overrepre- sented on the right or left side. We think that could explain much of the biological difference between right and left,&rdquo; Venook said.

A prospective analysis of common mutations in patients with CRC noted that BRAF V600E and PIK3CA mutations were more prevalent in patients with RAS wild-type CRC tumors in the right side of the colon (P = .0001).6 BRAF V600E mutations occurred in 31.7% of right-sided tumors compared with BRAF non-V600E mutations in 8.1%, and PIK3CA occurred in 19.2% of right-sided tumors. &ldquo;The existence of these mutations may affect anti-EGFR efficacy between right- and left-sided colorectal cancers,&rdquo; the authors concluded in their report.

Disparities based on gender could also affect differences based on tumor location. Women over 65 years who develop CRC typically have a lower 5-year OS rate than men. This could be due to the fact that women have a higher risk of developing tumors in the right side of the colon. A study investigated this role further to illuminate other differences associated with gender and tumor location.

Kim et al found that a number of hormonal and molecular factors may explain the larger percentage of right-sided tumors in women than in men (

). The lack of estrogen in older women could potentially relate to the increased risk of developing MSI-high CRC, which is more common in women and in right-sided tumors. Chromosomal instability, on the other hand, was more likely to be associated with left-sided tumors. Right-sided tumors show a link as well with the CpG island methylator phenotype and BRAF mu- tations. Hereditary non-polyposis colorectal cancer was also more likely to lead to right-sided tumors, while familial adenomatous pol- yposis led to left-sided tumors.

Perhaps including these and other features in future analyses of the effect of sidedness on treatment, or as a strati cation component in randomized clinical trials, could allow researchers to confirm the true underpinnings of tumor sidedness&rsquo; effect on outcomes.

Further molecular profiling will be essential to de ne the associations that primary tumor location has with gender, mutations, and other risk parameters. Defining these features will help to clarify tumor sidedness as a biomarker, as well as to personalize the treat- ment of patients with mCRC based on their characteristics.

Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1o) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analy- sis of CALGB/SWOG 80405 (Alliance). J Clin Oncol. 2016;34(suppl; abstr 3504).

Heinemann V, Fischer von Weikersthal L, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as rst-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase III trial. Lancet Oncol. 2014;15(10):1065-1075. doi: 10.1016/S1470-2045(14)70330-4.

Tejpar S, Stintzing S, Ciardiello F, et al. Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials. JAMA Oncol. 2017;3(2):194-201. doi: 10.1001/jamaoncol.2016.3797.

Schrag D, Weng S, Brooks G, et al. The relationship between primary tumor sidedness and prognosis in colorectal cancer. J Clin Oncol. 2016;34(suppl; abstr 3505).

Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350-1356. doi: 10.1038/nm.3967.

Taniguchi H, Uehara K, Nakayama H, et al. The location of colorectal cancer (right- vs. left-sided colon and rectum) a ects the prevalence of BRAF V600E, non-V600E and PIK3CA mutations: a prospective registration study in the Aichi Cancer Network. Ann Oncol. 2016;27(suppl 6): 569P. doi: 10.1093/annonc/mdw370.117.

Kim S-E, Paik HY, Yoon H, Lee JE, Kim N, Sung MK. Sex- and gender-speci c disparities in colorectal cancer risk. World J Gastroenterol. 2015;71(17):5167-5175. doi: 10.3748/wjg.v21.i17.5167.

The impact of the recent findings regarding tumor sidedness in patients with metastatic colorectal cancer are potentially practice-changing, with data demonstrating that patients with right-sided tumors have a poorer prognosis than those with left-sided tumors. In addition, sidedness could be clinically relevant as a predictive biomarker of response to standard frontline treatments.

Tumor Sidedness Findings Could Change Trials and Treatments in Colorectal Cancer

What are the challenges that clinical practices will face as they implement the Medicare Oncology Care Model (OCM)? What are some of the strategies that have worked for practices using similar payment models? How does the Center for Medicare & Medicaid Innovation (CMMI), also known as the Innovation Center, hope to work with oncologists for the success of the OCM? These were some of the questions that were discussed at the Payer Exchange Summit V sponsored by the Community Oncology Alliance (COA).

Experts on the panel included Jeffrey Patton, MD, chief executive officer, Tennessee Oncology; Barbara McAneny, MD, chief ex- ecutive officer, New Mexico Hematology Oncology Consultants; and Ron Kline, MD, medical officer, CMMI.

Patton provided the perspective of a practice that has 3 months&rsquo; experience with OCM. &ldquo;It&rsquo;s been good with respect to investing the dollars,&rdquo; he said. &ldquo;We used Via Oncology [clinical] pathways; nurse triage is important, and we built it on a Salesforce platform. We have also developed a relationship with a palliative care company. Additionally, care coordination is the last thing with respect to the OCM that we had to include as part of our practice transformation.&rdquo;

Patton told the audience that at their cancer clinics, the focus is on the top 10% of patients that may need hospitalization. These patients are expected to have a significant impact on care costs. He added that with 85 doctors and 32 sites of care delivery, &ldquo;We try to take care of patients where they are.&rdquo;

COME HOME is an oncology medical home model that McAneny pioneered at New Mexico Hematology Oncology Consultants. &ldquo;With COME HOME, our first year was spent on ramping up practices,&rdquo; McAneny said. &ldquo;So, with the OCM, practices that might already have a similar model in place might need about 6 months to gear up. We don&rsquo;t yet know what the &lsquo;targets&rsquo; will be; it&rsquo;s still a blur.&rdquo;

McAneny firmly believes that clinical pathways are critical to adequately implement cost-saving reimbursement models. &ldquo;With COME HOME, we created pathways in a collaborative waythey are a very important decision support tool. Triage pathways are important, too,&rdquo; she said.

Kline said he was delighted to see that oncology practices have started developing innovative ways to implement the OCM, which, he added, is the objective of this pilot phase. &ldquo;We have 95 practices with $6 billion in oncology spending, 3200 physicians, and 5000 providers under the OCM,&rdquo; Kline told the audience, adding that he hoped that through their work, &ldquo;We are changing oncology care in the country.&rdquo;

Speaking to the significant impact of drugs on the cost of care, he said that there are 2 categories of drugs. The first are game- changing drugs that are essential, but most of those are expensive. The second category are drugs that can be replaced by strategies that are equally effective but cheaper. &ldquo;It comes down to making nancially stable choices on treatments,&rdquo; Kline said.

The OCM requires physicians to include data on staging and molecular characterization of patient tumors in the electronic health record (EHR). &ldquo;We want to identify EHRs that will minimize physician burden and include them in the OCM system,&rdquo; Kline said.

So, what are some of the challenges with meeting OCM requirements, and what specific changes do clinics need to adopt to? Kline said that staging and mutations data are not a part of the claims system. &ldquo;For a better model, we need to include this information in the system.&rdquo; He added that the first year of quality reporting is &ldquo;pay- for-improvement, not pay-for-performance. So, the [requirement] is that you have to do this...submit the data.&rdquo;

Patton expressed concern with quicker access to outcomes data. &ldquo;Technology platforms, like [those developed by] Flatiron Health, can help us understand where we are lagging,&rdquo; he said.

Speaking about the importance of care coordination in improving outcomes, McAneny said, &ldquo;Care coordination occurs with the simplest things in the clinic, such as when a doctor speaks to a nurse about adjusting a chemotherapy dose. It&rsquo;s therefore a mat- ter of documenting these daily coordination activities.&rdquo; She told the audience that the unique experience with the OCM is that she felt she was on the same page with CMS on this. &ldquo;We, at our clinics, have now set up a way for patients to sit down with a midlevel provider to talk about the care plan, their goals of care, and distress issues that we can help them with.&rdquo; She emphasized that vendors need to create a platform that does not interfere with the practice work ow or make the oncologist a data-entry operator.

&ldquo;The government really wants this to work...if we don&rsquo;t succeed they don&rsquo;t succeed,&rdquo; Patton added.

Speaking to the aspect of nancial risks associated with the OCM, which are 1-sided in the first 2 years and then become 2-sid- ed, McAneny said that she has very smart data managers working for her &ldquo;who used a Monte Carlo scenario.&rdquo; Using this model, they try to identify those patients whose cost of care would result in the practice paying back to Medicare. &ldquo;Through the National Cancer Care Alliance, we are trying to develop a process where we share a larger group of patients and reinsure these patients to balance the associated actuarial risk,&rdquo; McAneny said.

&ldquo;You don&rsquo;t have to assume a 2-sided risk at all during the entire 5-year period. But with 1-sided risk, you have to show savings after 2 years,&rdquo; Kline told the audience.

McAneny BL. The future of oncology? COME HOME, the oncology medical home. Am J Manag Care. 2013;19(spec no 1):SP41-SP42.

Discussing the challenges that clinical practices will face as they implement the Medicare Oncology Care Model (OCM), the strategies that have worked for practices using similar payment models, and how the CMMI hope to work with oncologists for the success of the OCM.

Strategies for OCM Implementation at the COA Payer Summit

A study presented at the 2017 Cancer Survivorship Symposium revealed a long-term cardiovascular risk associated with administration of levothyroxine. The risk of coronary heart disease and ischemic stroke was found to be higher in patients with thyroid cancer who received a thyroidectomy, and levothyroxine dosage appeared to play a major role in that risk.

This is particularly noteworthy in the current context of recent controversy surrounding the overdiagnosis of thyroid cancer. &ldquo;In most industrialized countries, the incidence of thyroid cancer has significantly increased in recent decades,&rdquo; said investigator Dong Wook Shin, MD, DrPH, MBA. &ldquo;In Korea in particular, we have observed a 10-fold increase in the past decade alone.&rdquo; This drastic increase in incidence rates has caused concerns regarding overdiagnosis and, consequently, overtreatment. Therefore, according to Shin, assistant professor of the Cancer Survivorship Clinic at Seoul National University Cancer Hospital, Korea, balancing the benefits and harms of thyroid stimulating hormone (TSH) suppression is an important issue.

Until recently, suppression of TSH was routinely prescribed to patients with thyroid cancer to reduce recurrence of their disease after total thyroidectomy, with or without radioactive iodine (RAI) ablation, which often translated into a lifetime treatment.

Hyperthyroidism is a well-known risk factor for atrial fibrillation and ischemic stroke, and has been reported to cause angina or myocardial infarction in patients with underlying coronary heart disease. Therefore, in the study presented by Shin and col- leagues, they assumed that overt or subclinical hyperthyroidism induced by long-term administration of supra-physiologic dos- age of levothyroxine can be associated with an elevated cardiovascular risk.

According to a previous single-center study, 606 patients reported increased long-term cardiovascular mortality in patients with differentiated thyroid cancer, particularly in those patients who had low TSH levels. The study assessed the risk of cardiovascular mortality in patients with differentiated thyroid carcinoma, evaluated all-cause mortality, and explored the relation between TSH level and these outcome parameters. It demonstrated that overall cardiovascular mortality, including deaths from myocardial infarction, stroke, abdominal aortic aneurysm, and pulmonary embolism were composite outcomes.

Patients with differentiated thyroid cancer had an increased risk of cardiovascular and all-cause mortality, with hazard ratios (HRs) of 3.35 (95% CI, 1.66-6.74) and 4.40 (95% CI, 3.15-6.14), respectively. Within the differentiated thyroid cancer group, TSH level was predictive for cardiovascular mortality; the adjusted HR was 3.08 (95% CI, 1.32-7.21) for each 10-fold decrease in geometric mean TSH level.

However, this study was matched to controls from a separate general population cohort, limiting the comparability of the 2 groups.

The retrospective cohort study led by Shin used claims data from the Korean National Health Insurance database. From this database, Shin and his colleagues selected cases of patients who received thyroidectomy to treat their thyroid cancer from 2003 to 2013. After exclusion criteria, 182,419 patients were selected and matched to noncancer controls by propensity score matching in a 1:1 ratio based on baseline age, sex, residence, insurance premium level, disability, hypertension levels, and diabetes mellitus status.

The study looked for coronary heart disease and incidence of ischemic stroke over a mean follow-up of 4.3 years. Patients were categorized into quartiles based on their dosage of levothyroxine.

The study found that patients with thyroid cancer had an elevated risk for both coronary heart disease (HR, 1.15; 95% CI, 1.19-1.22), and for stroke (HR, 1.15; 95% CI, 1.09-1.22). The risk was particularly marked among those patients who received a total thyroidectomy, and for those who took a higher dosage of levothyroxine.

Patients with thyroid cancer were also more likely to develop atrial brillation when they were administered a high dose of levothyroxine. However, levothyroxine dose does not appear to make a significant difference in the risk of ischemic stroke upon atrial brillation occurrence.

The increased risk in the third and fourth quartile of the study can be explained by hyperthyroidism, which can cause atrial bril- lation, Shin explained. However, it appears that ischemic stroke developed by atrial brillation comprises only a small proportion of ischemic stroke incidence (4.4% in the study). &ldquo;Other studies suggest systolic hypertension, arterial stiffness, enhanced LDL oxidation, hypercoagulability, and change in heart function can be caused by hyperthyroidism,&rdquo; Shin said.

Among the patients with thyroid cancer, those who took either a lower or higher dose of levothyroxine showed increased risk for both coronary heart disease and ischemic stroke, suggesting a &ldquo;J-shaped pattern&rdquo; in the risk.

In the first quartile of the study, the increased risk may be linked to hypothyroidism, which is also associated with dyslipidemia, LDL oxidation, atherosclerosis, and diastolic hypertension. Notably, the second quartile group of the study showed an even lower risk of developing coronary heart disease or ischemic stroke compared with the noncancer control group. Shin said that this may be due to differences in the patients themselves rather than in the treatment: &ldquo;Thyroid cancer screening by ultrasonography in Korea is provided at the patient&rsquo;s own cost. Those who elect to receive private health screening are likely to be more engaged in healthier behavior, vigilant follow-up, and proactive prevention.&rdquo;

&ldquo;Our study, to our knowledge, is the rst to directly investigate the relative risk of coronary heart disease and ischemic stroke incidence among thyroid cancer patients. We also found that the post-thyroidectomy levothyroxine dosage, which serves as a proxy marker for level of TSH suppression, is key in such risk,&rdquo; Shin said.

The study did have some limitations, including the relatively short follow-up period. The investigators used levothyroxine dos- age as a proxy marker for the level of TSH suppression, so they could not make any specific interpretations about optimal TSH targets. They also did not include data on the type of thyroid cancer or stage for the study cohort but, according to Shin, they did not believe this affected their investigation.

&ldquo;As addressed by recently revised guidelines, the results of our study call for more caution for the type of thyroidectomy chosen and TSH suppression therapy,&rdquo; Shin concluded.

Shin DW, Suh B, Yoon JM, et al. Risk of coronary heart disease and ischemic stroke in thyroid cancer patients taking levothyroxine. J Clin Oncol. 2017;35(suppl 5S; abstr 105).

Klein Hesselink EN, Klein Hesselink MS, de Bock GH, et al. Long-term cardiovascular mortality in patients with differentiated thyroid carcinoma: an observational study. J Clin Oncol. 2013;31(32):4046-4053. doi: 10.1200/JCO.2013.49.1043.

A study presented at the 2017 Cancer Survivorship Symposium revealed a long-term cardiovascular risk associated with administration of levothyroxine.

Levothyroxine Linked to Heart Risks in Patients With Thyroid Cancer

While PD-1, PD-L1, and CTLA-4 checkpoint inhibitors have proven to be effective in treating patients with melanoma, not all patients respond to immunotherapy. To help nonresponders, additional targets and immunotherapy strategies are being investigated in clinical trials to boost the immune system&rsquo;s response, according to Michael A. Postow, MD. These agents are being incorporated into experimental regimens that improve the efficacy of the immunotherapy agents they are combined with, such as the existing checkpoint inhibitors.

Postow, a medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center, highlighted a number of promising approaches in development in a presentation during the 13th Annual International Symposium on Melanoma and Other Cutaneous Malignancies&reg; hosted by Physicians' Education Resource. Specifically, Postow addressed targeting the activating receptors OX40, GITR, and CD137 to further stimulate the T cells to fight the tumor cells.

(TTO) following his presentation, Postow discussed the mechanism of action of these 3 targets that make them promising approaches in combination immunotherapy regimens.

Could you please provide an overview of your presentation?

Postow: Immunotherapy is a big treatment for metastatic melanoma as we know from our prior studies of CTLA-4 blockade. But really this is just the tip of the iceberg. There are a number of additional targets out there that are being tested in clinical trials, either alone or in combination with different strategies, to use the immune system in new ways beyond PD-1/PD-L1, beyond CTLA-4, to see if that can help patients with cancer as well.

My talk focused on 2 main strategies: other costimulatory molecules that you can enhance the T-cell activity with, and ways of reducing immunosuppression within the tumor microenvironment. It&rsquo;s not just about boosting the T cells, it might be also about reducing negative immunosuppressive cells in the tumor microenvironment. There are a lot of different strategies to block inhibitory cells or inhibitory molecules in tumors to try to help the T cells ght the tumor cells more strongly.

What other costimulatory molecules are being investigated currently?

My talk focused on 3 types of costimulatory molecules: OX40, CD137, and GITR. Some data have been presented on these 3 targets already, not only for patient outcomes but on the immunologic effects of some of these treatments.

OX40, for example, there&rsquo;s published data of a mouse antibody that has been given to patients in early-phase clinical studies. For CD137 there&rsquo;s also published data of antibodies that agonize T cells through CD137, and there are a number of combination studies going on with that area. Then for GITR, there have been presented data and some preliminary data that suggest that there are some immunologic changes that happen with pretty much all of these types of costimulatory molecules.

I think that even if we don&rsquo;t see a lot of activity as single agents with these drugs, it&rsquo;s important to really study them thoroughly so that we can be certain if they could have a role in combination settings. I think all of us believe that the role for these agents will mostly be in combination settings, so we don&rsquo;t have to worry that there might not be huge responses to the single agent. Maybe it&rsquo;s just going to enhance other immune therapies&rsquo; efficacies.

Have any of these agents shown promising data that suggest they would do well in a combination treatment?

Among all the combinations out there already, I think the one that&rsquo;s furthest along is an IDO inhibitor called epacadostat in combination with a PD-1 drug pembrolizumab (Keytruda), which is now in a phase III clinical study in a randomized setting (NCT02752074). This IDO inhibitor has the mechanism of action of eliminating immunosuppression within the tumor microenvironment. I think that is a very promising combination approach right now and I think it&rsquo;s a real testament to a drug where we didn&rsquo;t see a lot of activity as a single agent, yet in combination with PD-1, although preliminary, we see impressive early efficacy.

That&rsquo;s 1 example but there are a number of other strategies that are being employed, including a lot of strategies we&rsquo;re excited about that inhibit myeloid-derived suppressor cellsthese are immunosuppressive myeloid cells that are in tumors, and in blood&mdash;and blocking them through different mechanisms are also interesting ways of testing whether we can enhance T cells&rsquo; ability to kill tumors.

Michael A. Postow, MD, discusses&nbsp;argeting the activating receptors OX40, GITR, and CD137 to further stimulate the T cells to fight the tumor cells.

March 2017 | Targeted Therapies in Oncology

Brentuximab Vedotin Benefits Offset Risk of Peripheral Neuropathy, Patients Say

Tumor Sidedness Findings Could Change Trials and Treatments in Colorectal Cancer

Strategies for OCM Implementation at the COA Payer Summit

Levothyroxine Linked to Heart Risks in Patients With Thyroid Cancer

New Targets Explored to Boost Immunotherapy in Melanoma