Cancer Therapy Advisor May/June 2018 Issue by Haymarket Media

MAY/JUNE 2018 | VOL 4, ISSUE 5

32 FEATURE

HIV-Associated Cancers: A Paradigm Shift? While many patients with HIV are living longer and may develop subsequent “incidental” cancers, the rates of three cancers that once defined AIDs are declining. 25 EXPERT PERSPECTIVE

Targeted and Immunotherapies for Metastatic Renal Cell Carcinoma 36 IN THE CLINIC

Obstructing Colorectal Cancer: Presentation and Colonic Stenting 38 TREATMENT REGIMENS

Cervical Cancer  Hodgkin Lymphoma  Soft Tissue Sarcoma

34 FACT SHEET Alpha Lipoic Acid and Cancer

CancerTherapyAdvisor.com

FOCUS PROSTATE CANCER

Confronting Racial Disparities in Prostate Cancer Survival Preventive Benefit of Finasteride Can Be Maintained for 16 Years Diet and Dosage: How Much Could Patients Save?

Contact Us CONTACT THE EDITOR Questions or comments for the editor? Email us at editor.cancertherapyadvisor@ haymarketmedia.com

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SUBMIT AN ARTICLE Cancer Therapy Advisor welcomes original content submissions in the form of viewpoints/perspectives, case studies, feature articles, and more. Visit CancerTherapyAdvisor.com/ submissions to learn more. RECEIVE NEWSLETTERS Receive concise news articles and in-depth feature stories to you inbox on a daily or weekly basis. CancerTherapyAdvisor. com/register to sign up. DOWNLOAD THE APP The Cancer Therapy Advisor app is a free, easy-to-use app that offers the latest oncology news, cancer treatment regimens, fulllength features, slideshows, case studies, and drug information for a variety of cancer types and therapeutic areas. Download Cancer Therapy Advisor for free and access us on the go! Register for CTA directly from your device or log in using your existing account details. CONNECT WITH CANCER THERAPY ADVISOR @CancerTherAdvsr facebook.com/cancertherapyadvisor

Confronting Racial Disparities in Prostate Cancer Survival

Preventive Benefit of Finasteride Can Be Maintained for 16 Years

Diet and Dosage: How Much 18 Could Patients Save?

CONTENTS 11 LATEST NEWS

Headlines in oncology research and practice and key findings from the American Association for Cancer Research Annual Meeting. 11 Tisagenlecleucel Indication Expanded To Include Relapsed/Refractory B-cell Lymphomas 11 Online Survey May Allow Patients With Prostate Cancer To Accurately Report Comorbidities 12 Physical Activity Monitors May Accurately Predict Patient Performance Status ...and more

25 EXPERT PERSPECTIVE

Targeted and Immunotherapies for Metastatic Renal Cell Carcinoma Mario Sznol, MD

4 CANCER THERAPY ADVISOR | MAY/JUNE 2018 | CancerTherapyAdvisor.com

FEATURE

HIV-Associated Cancers: A Paradigm Shift? Susan Jenks

MULTIPLE MYELOMA

Do 9/11 Firefighters Really Have A Higher Incidence of MGUS?

FACT SHEET

Alpha Lipoic Acid and Cancer

The firefighting profession has previously been associated with a higher risk of MGUS and myeloma compared with the general population.

Andrea S. Blevins Primeau, PhD, MBA

On the Web

IN THE CLINIC

Leah Lawrence

Obstructing Colorectal Cancer: Presentation and Colonic Stenting

PROSTATE CANCER

Could Diet Adjustment Prevent Aggressive Prostate Cancer?

C. Andrew Kistler, MD, PharmD

A recent article is only the latest in a series of studies drawing attention to the importance of diet in prostate cancer development.

TREATMENT REGIMENS 38 Cervical Cancer

Leah Lawrence

41 Hodgkin Lymphoma 46 Soft Tissue Sarcoma

BREAST CANCER

New Methodology May Advance Precision Medicine

A new technology is being developed by Caris Life Sciences to help improve the understanding of aberrant modulations that drive cancer. Andrea S. Blevins Primeau, PhD, MBA

RENAL CELL CARCINOMA

Does Sunitinib Have A Future in Renal Cell Carcinoma Treatment? Immunotherapy may supplant sunitinib in RCC, except for in patients who cannot tolerate checkpoint inhibition. Carina Storrs, PhD

CancerTherapyAdvisor.com | MAY/JUNE 2018 | CANCER THERAPY ADVISOR 5

Editorial and Business Staff

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10 CANCER THERAPY ADVISOR | MAY/JUNE 2018 | CancerTherapyAdvisor.com

LATEST NEWS | AACR CONFERENCE COVERAGE

Check-Mate 141 Results: Nivolumab Improved OS in Patients With Recurrent or Metastatic Head and Neck Cancer At 2 years, nivolumab — compared with investigator’s choice of therapy — improved survival among patients with recurrent or metastatic head and neck cancer, according to research presented at the 2018 American Association for Cancer Research (AACR) Annual Meeting. Nivolumab, a PD-1 inhibitor, has shown promising activity in recurrent and metastatic squamous cell carcinoma of the head and neck (SCCHN). The phase 3 CheckMate-141 trial evaluated whether nivolumab yields superior outcomes to investigator’s choice of therapy (cetuximab, methotrexate, or docetaxel) in this setting. At this year’s AACR meeting, researchers presented 2-year follow-up data from CheckMate-141. Patients were randomly assigned 2:1 to receive nivolumab (240 patients) or investigator’s choice (121 patients). Compared with investigator’s choice, nivolumab improved overall survival (OS) in the overall population (median 7.7 months with nivolumab vs 5.1 months with investigator’s choice; hazard ratio [HR], 0.68 [95% CI, 0.54-0.86]). The 2-year OS rate was 16.9% with nivolumab vs 6% with investigator’s choice. While OS improvement was seen regardless of PD-L1 levels and human papillomavirus (HPV) status, not all patients who received nivolumab had improved progression-free survival (PFS). Patients with PD-L1 levels lower than 1% had a median PFS of 2 months with nivolumab vs 2.7 months with investigator’s choice; HPV-negative patients had a median PFS of 2.1 vs 3.3 months, respectively. Grade 3 to 4 treatment-related adverse events were noted in 15.3% of patients who received nivolumab vs 36.9% of patients who received investigator’s choice. Two patients in the nivolumab group and 1 patient in the investigator’s choice group died because of toxicity.

The authors concluded that nivolumab “continued to significantly improve OS and maintain a favorable safety profile vs [investigator’s choice]. [Nivolumab] is the only immunotherapy to demonstrate OS benefit irrespective of PD-L1 expression in [patients] with SCCHN.”

BLU-667 Promising in RET-Altered Solid Tumors BLU-667, a RET inhibitor, may be an effective treatment for patients with RET-altered solid tumors, according to data presented at the 2018 American Association for Cancer Research Annual Meeting in Chicago, Illinois. RET is an established oncogene in several cancers, including non–small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC). BLU-667 is a selective and potent inhibitor of RET that may be effective in the clinical setting. For this phase 1 study, researchers are evaluating the safety, efficacy, and pharmacokinetics of BLU-667 among patients with RET-altered solid tumors. The maximum tolerated dose is also being determined. Forty-three patients (15 with RET-fusion NSCLC, 26 with RET-mutant MTC, and 2 patients with non-RET cancers) received BLU-667 (dose range, 30-400 mg/day). The median number of previous therapies was 1. Thirty patients had post-baseline response assessment. Per RECIST 1.1 criteria, the best overall response rate was 37%, including 5 (4 confirmed) partial responses in 11 patients with NSCLC and 5 partial responses (3 confirmed) in 19 patients with MTC. One unconfirmed complete response was observed among patients with MTC. Doses of at least 60 mg yielded tumor reductions of 2% to 70% among 25 of the 30 evaluated patients. The maximum tolerated dose was not reached at time of this analysis. Three dose-limiting toxicities were, however, noted (alanine aminotransferase increase, tumor lysis syndrome, and hypertension; all grade 3). While no grade 4 or 5 adverse events were reported, 6 patients discontinued BLU-667 for progressive disease, 2 discontinued because of adverse events, 1 patient discontinued for an unspecified reason, and 1 patient died. The authors concluded that “BLU-667, a highly potent and selective RET inhibitor has been well tolerated and demonstrates promising clinical activity in RET-altered solid tumors, including [patients] who have failed multikinase inhibitor therapy.” ■

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One instance of grade 3 alanine aminotransferase elevation and 5 instances of reversible immune-related adverse events were observed. Interim data demonstrated a strong association between CPS, pT0, higher TMB, and pT response ≤2, leading the authors to conclude that the study, once completed, may potentially be “practice changing.”

FEATURE

FOCUS PROSTATE CANCER

Confronting Racial Disparities in Prostate Cancer Survival CARLOS HARRISON

liminating the disparity in prostate cancer survival between African American and white men may require more than ensuring both populations get equal care. Not only have mortality rates dropped by about half, but the gap in mortality has narrowed since the adoption of widespread prostate-specific antigen (PSA) screening. Yet African Americans still have a 60% higher incidence of prostate cancer and are about 2 times more likely to die from the disease. How much racial disparities have really changed, however, remains a mystery, according to a new study by Ruth Etzioni, PhD, of the biostatistics program at the Fred Hutchinson Cancer Research Center, in Seattle, Washington, and colleagues.1 “Reductions in disease-specific mortality have been accompanied by a narrowing of racial disparities in disease-specific survival, leading to some optimism about the ability of screening to reduce established inequities in the burden of the disease,” the authors wrote. “We observe that a sizeable portion of these trends in survival, in fact, are not real; rather, they are attributable to artifacts of screening, particularly in older men.” Some of the apparent narrowing of racial disparities in survival is, according to the authors, caused by improper accounting for the impacts of lead time — the amount of time between diagnosis and death — and

African Americans have a 60% higher incidence of prostate cancer and are about 2 times more likely to die from the disease.

by overdiagnosis. These findings raise questions about the guidelines for PSA screening and whether they should apply equally across ethnic groups. But the question of equal care, Dr Etzioni said in an interview with Cancer Therapy Advisor, extends far beyond PSA testing — to prostate cancer care in general. “If we want to equalize mortality we may have to do more for blacks than for whites,” she said. “And the question is why.” One reason has to do with genetics. Changes in DNA associated with chromosome 8q24 indicate a higher or lower risk for prostate cancer. A study of 2973 single nucleotide polymorphisms (SNPs) in 5 distinct populations identified 7 risk variants.2 “Nearly all of the variants associated with an increased risk of developing prostate cancer were found most often in African American/Black men,” the National Cancer Institute (NCI) explains on its website, “and certain combinations of these variants were associated with a five-fold increased risk of prostate cancer in men of this racial/ ethnic group.”3 Prostate cancer also appears to be more aggressive in African American men, transforming into advanced metastatic disease at a 4:1 ratio compared with white patients. Those findings, a study of autopsy data from 1056 black and white men concluded, “support the concept that prostate cancer grows more rapidly in black than in white men and/or earlier transformation from latent to aggressive prostate cancer occurs in black than in white men.”4

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FEATURE

Yet other factors may be at play. Multiple studies found an association between socioeconomic status (SES) and worse prostate cancer outcomes. An analysis of California Cancer Registry data found, for example, that patients living in lower SES neighborhoods had a higher risk of death.5 This finding matches the results of a broader analysis of African American patients with breast, prostate, and colorectal cancer, which found that these patients are more likely to present with more advanced cancer, with the stage at diagnosis explaining 16% to 28% of survival disparities.6 A 2016 review of PubMed literature found that “African American men face several social barriers that [white] men may not, contributing further to their risk of poorer prognoses and outcomes.”7

board certified (77.4 percent) than were the physicians visited by the white patients (86.1 percent)…and also more likely to report that they were unable to provide high-quality care to all their patients,” the authors reported. These discrepancies result in dramatic differences in outcomes, as evidenced by the lower 5-year survival rates for African American patients with the same stage of cancer at the time of diagnosis as white men, according to a study of disparities by race and socioeconomic status.9 It’s an issue, Dr Etzioni said, that has implications for African American men throughout the entire range of treatment. “In screening, for example,” she said, “are they getting biopsied as rigorously white men? In treatment we need to know: are they getting radiation at similar facilities that are able to give you

References

1. Kaur D, Ulloa-Pérez E, Gulati R, Etzioni R. Racial disparities in prostate cancer survival in a screened population: reality versus artifact.

Cancer. 2018 Jan 25. doi: 10.1002/cncr.31253 [Epub ahead of print] 2. Haiman CA, Patterson N, Freedman ML, et al. Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet. 2007;39(5):638-44. 3. Cancer health disparities. National Cancer Institute website. https://www.cancer. gov/about-nci/organization/crchd/cancer-health-disparities-fact-sheet. Updated March 11, 2008. Accessed March 2018. 4. Powell IJ, Bock CH, Ruterbusch JJ, Sakr W. Evidence supports a faster growth rate and/or earlier transformation to clinically significant prostate cancer in black than in white American men, and influences racial progression and mortality disparity.

J Urol. 2010;183(5):1792-6. doi: 10.1016/j. juro.2010.01.015

Multiple studies found an association between socioeconomic status and worse prostate cancer outcomes.

5. DeRouen MC, Schupp CW, Koo J, et al. Impact of individual and neighborhood factors on disparities in prostate cancer survival.

Cancer Epidemiol. 2018 Jan 9. doi: 10.1016/j. canep.2018.01.003 [Epub ahead of print] 6. Ellis L, Canchola AJ, Spiegel D, Ladabaum U, Haile R, and Gomez SL. Racial and ethnic

The review cited a lack of health insurance, poor health–seeking behaviors that delay diagnosis, and “an inherent fear of a cancer diagnosis coupled with a mistrust of the health care system at large, [which] can significantly affect the outcome of African-American men with prostate cancer.” Access to care is an issue across populations in a multitude of cancers, but a 2004 study published in The New England Journal of Medicine reported significant differences in the quality of care African Americans receive.8 “In a comparison of visits by white patients and black patients, we found that the physicians whom the black patients visited were less likely to be

the high quality of treatment, what they call hyperfractionated radiation? “And for surgery — one thing that’s been shown for surgery is that it has to be done at a center where there’s a higher volume of patients. Are black men getting their surgery done at the large high-quality centers?” Yet even if all the treatment and care factors were equalized, African Americans would still face more dismal outcomes given their genetic predisposition for more and more aggressive cases. To fully eliminate racial disparities in prostate cancer mortality, Dr Etzioni said, physicians need to rethink what changes, philosophically and practically speaking, are required. ■

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disparities in cancer survival: the contribution of tumor, sociodemographic, institutional, and neighborhood characteristics. J Clin

Oncol. 2018;36(1):25-33. doi: 10.1200/ JCO.2017.74.2049 7. Shenoy D, Packianathan S, Chen AM, Vijayakumar S. Do African-American men need separate prostate cancer screening guidelines? BMC Urol. 2016;16(1):19. doi: 10.1186/s12894-016-0137-7 8. Bach PB, Pham HH, Schrag D, Tate RC, Hargraves JL. Primary care physicians who treat blacks and whites. N Engl J Med. 2004;351(6):575-84. 9. Ward E, Jemal A, Cokkinides V, et al. Cancer disparities by race/ethnicity and socioeconomic status. CA Cancer J Clin. 2004;54(2):78-93.

VIEWPOINT

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Preventive Benefit of Finasteride Can Be Maintained for 16 Years LEAH LAWRENCE

Results from the Prostate Cancer Prevention Trial (PCPT) indicate that the reduced risk for prostate cancer among men assigned to receive finasteride may continue throughout 16 years of follow-up.

he Prostate Cancer Prevention Trial (PCPT) showed that the use of finasteride, a 5-alpha-reductase inhibitor, for 7 years reduced the risk for prostate cancer by about 25% compared with placebo.1 A new study published in the Journal of the National Cancer Institute indicates that the reduced risk for prostate cancer among men in the PCPT assigned to receive finasteride continued throughout 16 years of follow-up.2 “After the Prostate Cancer Prevention Trial a lot of questions remained, including questions about the long-term survival patterns of these patients,” explained Joseph Unger, PhD, a health services researcher at the Fred Hutchinson Cancer Research Center in Seattle, Washington. “We were interested in figuring out whether 7 years was sufficient to determine the maximum benefit of finasteride, and whether or not that benefit was maintained after 7 years.” Previously, Dr Unger and colleagues had tried to investigate long-term survivorship of patients enrolled in a large breast cancer prevention trial by going back and trying to re-enroll women from the original investigation. However, this process was difficult and expensive, and the researchers were only able to enroll about 16% of the original patients, Dr Unger explained. Instead, to investigate the long-term survivorship of the PCPT, Dr Unger and colleagues obtained a data use agreement from the Centers for Medicare & Medicaid Services (CMS) to access

records from Medicare and link patients enrolled in the PCPT to their Medicare claims from 1999 through 2011. “We were able to link 75% of the patients, which is really excellent,” Dr Unger said. “We could use those Medicare claims to figure out what these men’s long-term prostate cancer diagnoses patterns were through a median of 16 years of follow-up, adding 9 years to the 7 years on the trial.” Overall, men in the finasteride arm of the PCPT had a 21.1% decrease in the risk for prostate cancer (hazard ratio, 1.10; 95% CI, 0.96-1.26; P < .001). The effect of finasteride was most pronounced in the first 7.5 years, which was consistent with findings from the PCPT. However, after 7.5 years, there was no increased risk for prostate cancer for men assigned to the finasteride arm. “One concern with these kinds of interventions is that while people are taking the intervention that prostate cancer may be prevented, but then rates snap back once the intervention is discontinued,” Dr Unger said. “That did not happen here. The preventive benefit of finasteride was maintained over the 16 years.” Dr Unger also mentioned that finasteride is a low-cost generic drug that has minimal side effects. In fact, in a previous analysis of the PCPT and linked Medicare claims, Dr Unger and colleagues looked at longterm consequences of finasteride use.3 The study showed that patients assigned to receive finasteride had a 10% increased risk for new claims for depression, but a 6% lower risk for procedures for benign Continued on page 24

CancerTherapyAdvisor.com | MAY/JUNE 2018 | CANCER THERAPY ADVISOR 17

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VIEWPOINT

CARLOS HARRISON

Knowing that food increases the absorption of some therapies presents the possibility of easily — and very significantly — lowering treatment costs for patients.

he authors of a recent prostate cancer study claim that a drug manufacturer and the US Food and Drug Administration (FDA) ignored a chance to cut medication costs by disregarding the impact of food intake on drug absorption.1 The study focused on abiraterone acetate, “the most widely prescribed first-line medication” for metastatic castration-resistant prostate cancer (mCRPC). But the authors raise questions about the possibility of slashing treatment costs with many more anticancer agents simply by focusing on the effect of dosing with meals as opposed to while fasting. Remarkably, both the manufacturer and the FDA knew during the approval process that taking the drug with food led to an exponential increase in the medication’s absorption. “According to the drug label, food leads to a five- to seven-fold increase in drug concentration with a low-fat meal and a 10- to 17-fold increase with a high-fat meal,” the authors wrote. As a result, the study found, patients taking one-fourth the recommended dosage with a low-fat meal instead of on an empty stomach realized a greater effect on prostate-specific antigen (PSA) (58% vs 50%, respectively). The median progression-free survival was approximately 9 months for both groups. “The pharmacoeconomic implications of this study’s findings are compelling,” the authors wrote. “[Abiraterone acetate] has an approximate retail cost of $10,000 per month. With a median time

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receiving treatment of 16.5 months in metastatic CRPC, the per-patient cost savings with the LOW dosing would exceed $100,000.” One of the study’s authors, Mark Ratain, MD, director of the University of Chicago Medicine Center for Personalized Therapeutics and associate director for clinical sciences of its Comprehensive Cancer Center in Illinois, said abiraterone acetate is only one example of the potential of this food effect. “There are many opportunities with oral oncology drugs to increase absorption with food,” he said. “We picked abiraterone just because it had a particularly large food effect and its formulation was such that we could readily do it. But it’s not unique. And the data is hiding in plain sight, as they say.” Food doesn’t increase the absorption of every oral therapy. A 2014 review of known food and drug interactions on anticancer agents found that, in some cases, taking medications with high-fat meals could increase systemic exposure.2 A similar meal, though, could decrease uptake by as much as 50%, as is the case with afatinib, an EGFR inhibitor. Still, Dr Ratain says, knowing that food increases the absorption of some therapies presents the possibility of easily — and significantly — lowering treatment costs. “I think in any resource-constrained space or in any scenario where patients have significant copayments,” he said, “I think that physicians could offer this as an alternative.” It’s not the first time Dr Ratain has challenged drug companies over the food effect. In a 2007 article commenting on

Diet and Dosage: How Much Could Patients Save?

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VIEWPOINT

a study that found that concentrations of lapatinib increased when it was taken with food, he and his co-author wrote: “The economic implications of this food effect study are particularly remarkable. At the current price of

(n=3) were labeled to be administered in ‘fasted’ states.”4 The then-director of the FDA’s Office of Clinical Pharmacology in the Center for Drug Evaluation and Research responded in an editorial that “although

sticks associated with getting the dose right and we don’t really have that. “The only thing that seems to matter is first to market as opposed to being right.” ■ References

1. Szmulewitz RZ, Peer CJ, Ibraheem A, et al. Prospective international randomized phase II study

Taking one-fourth the recommended dosage with a low-fat meal instead of on an empty stomach realized a greater effect on PSA.

of low-dose abiraterone with food versus standard dose abiraterone in castration-resistant prostate cancer. J Clin Oncol. 2018 Mar 28. doi: 10.1200/JCO.2017.76.4381 [Epub ahead of print] 2. Segal EM, Flood MR, Mancini RS, et al. Oral chemotherapy food and drug interactions: a comprehensive review of the literature.

J Oncol Pract. 2014;10(4):e255-68. doi:

$2,900 per month, a cost savings of 60% or $1,740 per month would be realized if the drug were taken with food.”3 In 2010, Dr Ratain and a colleague reviewed 99 oral oncology and non-oncology drugs approved by the FDA in the previous decade. They found a stark contrast between the dosing recommendations. “When food markedly enhanced bioavailability,” they wrote, “8 out of 9 non-oncology drugs were labeled ‘fed’ to take advantage of the food-drug interaction while all oncology drugs

Viewpoint Continued from page 17

prostate hyperplasia (BPH)-related events. No other differences in longterm consequences were found between finasteride or placebo arms. It is important to note that finasteride has not been approved by the US Food and Drug Administration (FDA) for prostate cancer prevention, and is most often used for treatment of hair loss or BPH. “There is no strong evidence of longterm detrimental effects, including sexual dysfunction, which was an initial concern,” Dr Unger said.

it is true that consistent co-administration with a high-fat meal may allow a lower-dosing level, inconsistent dietary habits could result in significant intradose variation in bioavailability.”5 Dr Ratain, however, contends that the potential for reducing dosages, and costs, demands further study. “There are many drugs for which we can reduce treatment costs without reducing price by giving lower dosages or giving them less frequently,” he said. “There should be carrots and

According to Dr Unger, this study shows the value of using Medicare claims to extend follow-up for trial participants and answer new questions about cancer care and prevention, including questions about quality of life. “Increasingly the question for patients [with cancer] is not only how to keep them alive but how to have a good quality of life over the long-term,” Dr Unger said. “By using secondary data sources we can extend the life of trials for quite a few years to get at a difficult question of how patients are doing in the longterm. That is invaluable information for patients and researchers.” ■

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10.1200/JOP.2013.001183 3. Ratain MJ, Cohen EE. The value meal: how to save $1,700 per month or more on lapatinib. J

Clin Oncol. 2007;25(23):3397-8. 4. Kang SP, Ratain MJ. Inconsistent labeling of food effect for oral agents across therapeutic areas: differences between oncology and non-oncology products. Clin Cancer Res. 2010;16(17):4446-51. doi: 10.1158/1078-0432.CCR-10-0663 5. Jain RK, Brar SS, Lesko LJ. Food and oral antineoplastics: more than meets the eye.

Clin Cancer Res. 2010;16(17):4305-7. doi: 10.1158/1078-0432.CCR-10-1857

References

1. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349:215-224. 2. Unger JM, Hershman DL, Till C, et al. Using Medicare claims to examine long-term prostate cancer risk of finasteride in the Prostate Cancer Prevention Trial [published online March 9, 2018]. J Natl Cancer Inst. doi: 10.1093/jnci/djy035 3. Unger JM, Till C, Thompson IM Jr, et al. Longterm consequences of finasteride vs placebo in the Prostate Cancer Prevention Trial. J Natl

Cancer Inst. 2016;108(12). doi: 10.1093/jnci/ djw168

EXPERT PERSPECTIVE

Targeted and Immunotherapies for Metastatic Renal Cell Carcinoma VEGF and PD-1 pathway inhibitors show promising improvements compared with single-agent VEGF pathway inhibitors. MARIO SZNOL, MD

Mario Sznol, MD Title Professor of Medicine

Affiliation Yale Cancer Center

Notable for Research in immunotherapy, particularly for renal cell carcinoma and melanoma

oth immune modulators and inhibitors of the VEGF pathway provide clinical benefit for patients with metastatic clear cell renal carcinoma (mRCC). Inhibitors of the VEGF pathway include the antibody bevacizumab (approved for the treatment of mRCC in combination with interferon-alfa), and the small molecules sorafenib, sunitinib, pazopanib, axitinib, cabozantinib, and lenvatinib (the latter is approved in combination with the mTOR inhibitor everolimus).1 The small molecules are not identical and generally inhibit additional receptor tyrosine kinases, although most of their anti-tumor activity in mRCC is attributed to VEGF receptor inhibition and the consequent anti-angiogenesis effect. VEGF pathway inhibitors rarely produce complete responses, and resistance almost always develops over time. Options for immune therapy of mRCC were expanded by the approval of nivolumab (anti-PD-1), which improved survival compared with everolimus in patients whose disease progressed after treatment with a VEGF pathway inhibitor.2 More recently, a phase 3 randomized trial in mRCC with no prior systemic therapy demonstrated a survival advantage for the combination of ipilimumab (anti-CTLA-4) and nivolumab over sunitinib.3 In this trial,

the primary analysis for survival was conducted in patients with intermediate- and poor- risk disease as assessed by the International Metastatic Renal Cell Carcinoma Database (IMDC) criteria. In the subset of patients with good-risk disease, sunitinib produced a higher rate of objective response and longer progression-free survival compared with ipilimumab/nivolumab, but survival data were not presented separately for this cohort. An important feature of the PD-1 or PD-L1 inhibitors is their ability to produce prolonged responses, which persist in a subset of patients even after treatment is stopped. The substantial clinical activity of both VEGF and PD-1 pathway inhibitors in mRCC, and their distinct mechanisms of action, provided a rationale for testing combinations of these agents in the clinic. An early phase 1/2 study combined sunitinib (33 patients) or pazopanib (20 patients) with nivolumab, producing promising objective response rates, at 52% and 45%, respectively.4 The combinations were, however, associated with higher than expected rates of renal and liver toxicity compared with historical data for the single agents, although the toxicities were considered manageable. The high objective response rates observed in this trial supported further studies combining other VEGF and PD-1 pathway inhibitors. In a small cohort of a phase 1 trial, the combination of bevacizumab

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EXPERT PERSPECTIVE (anti-VEGF) with atezolizumab (an anti-PD-L1) was active in mRCC. 5 Pre- and post-treatment tumor biopsies demonstrated that a single cycle of bevacizumab alone given prior to the combination increased intra-tumoral T cell numbers, suggesting a potential mechanism by which VEGF inhibition would increase the activity of an anti-PD-L1. In a subsequent randomized phase 2 study evaluating atezolizumab/bevaci-

to sunitinib, at 43% vs 35%. Similar trends were noted in the overall intentto-treat population. The improvement in median PFS for atezolizumab/bevacizumab over sunitinib was similar to that observed in the randomized trial of ipilimumab/nivolumab vs sunitinib, although overall survival data have not yet been released for the atezolizumab/bevacizumab combination. In phase 1b/2 trials conducted in mRCC, combinations of axitinib with

“VEGF pathway inhibitors rarely produce complete responses, and resistance almost always develops over time.” zumab, atezolizumab alone, or sunitinib, the combination increased progression-free survival compared with sunitinib in the subset of patients whose tumors were PD-L1-positive.6,7 PD-L1 was assessed in the tumor immune cells using the SP142 assay; exploratory analyses indicated that atezolizumab was most effective in the subset of patients with a baseline intra-tumoral T-lymphocyte effector gene signature. Bevacizumab restored sensitivity to atezolizumab in T-cell-infiltrated tumors that also demonstrated a high myeloid inflammatory gene signature. At the 2018 Genitourinary Cancers Symposium, Motzer et al presented the results of the IMmotion151 trial, in which patients with untreated mRCC were randomly assigned to receive bevacizumab plus atezolizumab or sunitinib.8 In the PD-L1-positive population, progression-free survival was improved by the combination from 7.7 to 11.2 months, and objective responses rates were also numerically higher compared

avelumab (anti-PD-L1) or pembrolizumab (anti-PD-1) produced high objective response rates. 9,10 In the phase 1b trial of axitinib in combination with avelumab, the objective response rate was 58.2%, and was 65.9% in the subset with tumor cells positive for PD-L1 (greater than 1%) by the SP263 assay. For the combination of axitinib and pembrolizumab, the objective response rate was 73% and median progression-free survival was 20.9 months. Phase 3 randomized trials are in progress. Other VEGF pathway inhibitors, such as cabozantinib, which shows superior activity to sunitinib in previously untreated patients, are being combined with PD-1 or PD-L1 antagonists.11,12 Overall, data from trials conducted to date with combinations of VEGF and PD-1 pathway inhibitors show promising improvements in objective response rates and median durations of progression-free survival compared with single-agent VEGF pathway inhibitors.

26 CANCER THERAPY ADVISOR | MAY/JUNE 2018 | CancerTherapyAdvisor.com

The specific subgroups that derive the most benefit from the combinations remain undefined, and future studies will likely evaluate potential predictive biomarkers using both clinical (IMDC) and tumor-related features (for example, PD-L1-positive expression and gene signatures for angiogenesis and immune cell infiltrates). Longer follow-up from phase 3 trials will be required to assess effects on overall survival and the ability of the combinations to produce durable and treatment-unmaintained responses. Additional data will, furthermore, be necessary to determine whether the different VEGF pathway inhibitors (for example, bevacizumab vs the small molecule inhibitors, or different small molecule inhibitors) produce different outcomes in combination with PD-1 pathway inhibitors. Other important questions include the relative efficacy of ipilimumab/nivolumab or other immune agent combinations vs combinations of PD-1/VEGF pathway inhibitors, and optimal sequencing of these therapies. Studies have been initiated to assess the safety and activity of triplets including ipilimumab, nivolumab, and a VEGF pathway inhibitor.12 ■ References

1. Osorio JC, Motzer RJ, Voss MH. Optimizing treatment approaches in advanced renal cancer. Oncology (Williston Park). 2017;31(12):919-26, 928-30. 2. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J

Med. 2015;373(19):1803-13. doi: 10.1056/ NEJMoa1510665 3. Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: efficacy and safety of nivolumab + ipilimumab (N+I) v sunitinib (S) for treatment-naïve advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups.

EXPERT PERSPECTIVE Ann Oncol. 2017;28(suppl_5). doi: 10.1093/

cell carcinoma (mRCC) patients (pts). J Clin

annonc/mdx440.029

Oncol. 2017;35(suppl):431.

4. Amin A, Plimack ER, Infante JR, et al.

7. Atkins MB, McDermott DF, Powles T, et al.

10. Atkins MB, Plimack ER, Puzanov I, et al. Safety and efficacy of axitinib (axi) in combination with pembrolizumab (pembro) in patients

Nivolumab (anti-PD-1; BMS-936558, ONO-

IMmotion150: A phase II trial in untreated met-

(pts) with advanced renal cell cancer (aRCC).

4538) in combination with sunitinib or

astatic renal cell carcinoma (mRCC) patients

J Clin Oncol. 2018;36(suppl):579.

pazopanib in patients (pts) with metastatic

(pts) of atezolizumab (atezo) and bevacizum-

renal cell carcinoma (mRCC). J Clin Oncol.

ab (bev) vs and following atezo or sunitinib

Cabozantinib versus sunitinib as initial target-

2014;32(suppl):5010.

(sun). J Clin Oncol. 2017;35(suppl):4505.

ed therapy for patients with metastatic renal

5. Sznol M, McDermott DF, Jones SF, et al.

8. Motzer RJ, Powles T, Atkins MB, et al.

11. Choueiri TK, Halabi S, Sanford BL, et al.

cell carcinoma of poor or intermediate risk:

Phase Ib evaluation of MPDL3280A (anti-

IMmotion151: a randomized phase III study of

the Alliance A031203 CABOSUN trial. J Clin

PDL1) in combination with bevacizumab

atezolizumab plus bevacizumab vs sunitinib

Oncol. 2017;35:591-7.

(bev) in patients (pts) with metastatic

in untreated metastatic renal cell carcinoma

renal cell carcinoma (mRCC). J Clin Oncol. 2015;33(suppl):410.

(mRCC). J Clin Oncol. 2018;36(suppl):578. 9. Choueiri TK, Larkin JMG, Oya M, et al. First-line

12. Nadal RM, Mortazavi A, Stein M, et al. Results of phase I plus expansion cohorts of cabozantinib (Cabo) plus nivolumab (Nivo) and CaboNivo

6. McDermott DF, Atkins MB, Motzer RJ, et al.

avelumab + axitinib therapy in patients (pts)

plus ipilimumab (Ipi) in patients (pts) with with

A phase II study of atezolizumab (atezo)

with advanced renal cell carcinoma (aRCC):

metastatic urothelial carcinoma (mUC) and

with or without bevacizumab (bev) versus

results from a phase Ib trial. J Clin Oncol.

other genitourinary (GU) malignancies. J Clin

sunitinib (sun) in untreated metastatic renal

2017;35(suppl):4504.

Oncol. 2018;36(suppl):515.

Decisions In The Clinic Looking for more expert perspectives? Cancer Therapy Advisor has interviewed experts in oncology from around the country to learn about their treatment considerations for various types of cancer.

Visit CancerTherapyAdvisor.com/asktheexperts to read the following interviews and more.

Treating Patients With Waldenstrรถm Macroglobulinemia An interview series on recommended treatment modalities with James R. Berenson, MD, Jorge J. Castillo, MD, and Rafael Fonseca, MD.

Treating Patients With Multiple Myeloma An interview series on recommended treatment modalities with Melissa Alsina, MD, Sarah Holstein, MD, PhD, and Paul G. Richardson, MD.

Treating Patients With Hepatocellular Carcinoma An interview series on recommended treatment modalities with Ghassan K. Abou-Alfa, MD, Jesse Civan, MD, and Richard Kim, MD.

CancerTherapyAdvisor.com | MAY/JUNE 2018 | CANCER THERAPY ADVISOR 27

FEATURE

HIV-Associated Cancers: A Paradigm Shift?

SUSAN JENKS

n increasing number of patients with HIV now live long enough to get the “incidental” cancers seen in the general population. Yet these patients are also less likely to get the 3 cancers that once defined AIDS — Kaposi sarcoma, aggressive B-cell lymphoma, and invasive cervical cancer — which were frequently seen when the disease was first observed. Researchers attribute the significant decline in the burden of AIDS-related cancers to successful combination antiretroviral therapies that emerged in the mid-1990s. These therapies can keep HIV quiescent for years, enabling the immune system in some patients to fully or partially recover. “It’s a complex story,” said Robert Yarchoan, MD, chief of the HIV

Many HIVassociated cancers develop with the help of oncoviruses — some of which are sexually transmitted. and AIDS malignancy branch at the National Cancer Institute (NCI) in Bethesda, Maryland, and co-author of a recent review of HIV-associated cancers in The New England Journal of Medicine.1 “With the dramatic drop in AIDS-defining cancers, a number of my colleagues thought cancer would be mostly going away as a problem in HIV patients.” Instead, while the number of AIDSdefining cancers has held relatively steady in the United States for 2 decades, he said, the incidence of other cancers is rising, as HIV-infected individuals are living longer. The proportion of HIV-infected individuals who develop cancer-related complications or die from cancer remains undetermined, with one French study suggesting it’s now the leading cause of death in HIV patients.2 Yet

32 CANCER THERAPY ADVISOR | MAY/JUNE 2018 | CancerTherapyAdvisor.com

many clinicians shy away from offering standard cancer therapies to these patients, Dr Yarchoan said, calling this an under-appreciated situation slowly gaining recognition in the medical community.3 Although early in the AIDS epidemic many patients were too fragile to withstand the rigors of chemotherapy, that’s no longer the case today with improved antiretroviral therapies, he said, adding that “many HIV cancer patients can tolerate chemotherapy just as well as uninfected individuals.” Richard Ambinder, MD, PhD, director of the division of hematologic malignancies at Johns Hopkins Hospital in Baltimore, Maryland, agreed. “Not treating HIV-infected patients who develop cancer with chemotherapy — that’s a real problem,” he said. “HIV should be seen as a chronic disease,

FEATURE which, like diabetes, carries other health ailments that need to be addressed, but should not preclude cancer treatment.” I n F e b r u a r y, t h e N a t i o n a l Comprehensive Cancer Network (NCCN) took steps to remedy this “disparity in cancer care,” issuing the first treatment guidelines for people living with HIV who are later diagnosed with cancer.4 According to the most recent data, an estimated 7760 patients in 2010 had these overlapping medical conditions, yet were 2 to 3 times less likely to receive appropriate cancer care. The NCCN guidelines call for clinicians to treat these patients with the same cancer therapies as offered to HIV-negative individuals. They also call on physicians to work with oncologists and HIV specialists to manage potentially toxic interactions between cancer drugs and antiretroviral drugs before initiating therapy. “Treating people living with HIV for cancer is a relatively new concern,” said Robert Carlson, MD, chief executive officer of NCCN, in a prepared statement.5 “It’s both a testament to the successes of HIV treatments in recent years and a reminder that the quest for healthier outcomes is ongoing.” Among the most common non-AIDS defining cancers in HIV-infected individuals are lung, liver, anal cancer, and Hodgkin lymphoma. Of these, lung cancers occur not only with increasing frequency compared with the general population, but also often present at a more advanced stage of disease . This greater lung cancer risk in HIV patients is not understood. “We don’t know whether HIV infection increases the risk of lung cancer or whether high rates of smoking or other exposures increases the risk, or both,” Dr Ambinder said. Many HIV-associated cancers, including those labeled AIDS-defining cancers, develop with the help of oncoviruses

— some, but not all of which, are sexually transmitted. Kaposi sarcoma, for example, Dr Ambinder said, requires co-infection with Kaposi sarcoma–associated herpesvirus (KSHV), a virus in the herpes family discovered in 1994. Although KSHV is transmitted primarily through saliva between men who have sex with other men, why they constitute the highest risk group is not yet understood.6 “It’s a bit like smoking,” Dr Ambinder said. “Many people smoke, but most smokers don’t get lung cancer.” “The issue is [that] after you take an individual with HIV infection and they are treated with antiretroviral medication and achieve suppression of the virus, are they totally healthy?” said Jeffrey Martin, MD, MPH, an epidemiologist and phy-

strongest predictor of HIV progression — are a factor in some, but not all nonAIDS defining cancers, Dr Martin said. Although the more damage HIV does to these immune cells, the more likely a cancer is to develop, differences in risk are small, he said, and nothing like the decimation seen in the cancers that have long defined AIDS. “It may be that a low CD 4 count six years ago may be the impetus for lung cancer development 6 years later,’ he said, “whereas with Kaposi sarcoma, low CD4 numbers translate into KS within months.” Surprisingly, perhaps, people living with HIV infections have not seen a rise, so far, in the incidence of the most common cancers: breast, prostate, and colon cancers.

“HIV should be seen as a chronic disease, which, like diabetes, carries other health ailments that need to be addressed.” sician at the University of California, San Francisco School of Medicine. “We don’t know the answer yet.” What researchers do know, he said, is that when measuring particular biochemicals in the blood between HIVinfected individuals and those without this viral infection, “the HIV-infected persons have many more chemical abnormalities,” especially related to inflammation. HIV-infected people also have more oncoviruses, in general, than the HIV-free population, primarily those that are sexually transmitted. “If and how these chemical abnormalities translate into disease is what researchers are trying to understand.” Even CD4 counts — a blood marker of immune strength, considered the

Dr Martin suggested that the reason for this may be the biological differences between these and other cancers. “HIV is not a general stimulant for hundreds of different cancers,” he said. Dr Yarchoan, however, suggested another reason. “My take is immunologic control may not be as important in these cancers’ earlier development,” he said. He added that less screening may be done in this group of patients than in the general population, because physicians are focusing on HIV and think of cancer as a distant threat. Yet with the improving life expectancy of patients with HIV, the hope is this should change — and change quickly. ■ Continued on page 35

CancerTherapyAdvisor.com | MAY/JUNE 2018 | CANCER THERAPY ADVISOR 33

FACT SHEET

Alpha Lipoic Acid and Cancer

uTwo studies evaluated the effect of ALA

on overall outcomes among patients with several cancer types. In an open-label, single-arm study, a combination of ALA and N-acetyl cysteine or carbocysteine lysine salt plus recombinant interleukin-2 and medroxyprogesterone acetate administered for 1 year as maintenance therapy resulted in a 50% objective response rate with a median duration of response of 19 months, median progression-free survival of 33 months, and median overall survival was not reached.12 A case series of 10 patients with advanced cancer with a life expectancy of 2 to 6 months suggested that the combination of ALA with hydroxycitrate and low-dose naltrexone had limited toxicity and 7 of the patients experienced a response.13

ANDREA S. BLEVINS PRIMEAU, PhD, MBA

u ALA has also been studied as supportive

care for patients with cancer, though the results have been mixed. For peripheral neuropathy associated with cancer treatment, a combination of ALA with Boswellia Serrata, methylsulfonylmethane, and bromelain reduced pain on the visual analog scale and sensor and motor impairment.14 A small randomized controlled trial found no difference between ALA alone and placebo for the prevention of neurotoxicity when taken during chemotherapy.15 This study, however, noted that poor patient compliance may have affected the results. An open-label single-arm phase 2 trial demonstrated that a combination of a diet high in polyphenols with antioxidant supplementation with ALA, carbocysteine lysine salt, and vitamins A, E, and C, plus omega-3 fatty acids, medroxyprogesterone acetate, and celecoxib for 4 months resulted in improved quality of life measures, fatigue, body weight, lean body mass, and appetite compared with baseline.16 Of the 39 evaluable patients, 10 experienced partial or complete response, 6 experienced stable disease, and 16 experienced disease progression.

lpha lipoic acid (ALA) is synthesized within the mitochondria as a cofactor necessary during mitochondrial energy metabolism.1 It is also a potent antioxidant that is used as a health supplement and is being studied as a therapy for diabetes, vascular disease, hypertension, inflammation, and cancer. Few prospective in-human studies have been conducted among patients with cancer, though multiple studies have shown promising cytotoxic effects in vitro. ALA alone has been shown to decrease cell viability and proliferation in breast, ovarian, colorectal, and lung cancer cell lines, and was synergistic with chemotherapy.2-6 ALA also decreased cell migration and invasion in thyroid cancer cell lines.7 In prostate cancer cells, however, ALA did not affect cell proliferation compared with the control.8 In mice xenograft models, ALA suppressed tumor growth alone and in combination with hydroxycitrate against several tumor types.7,9

In-Human Studies u Several case reports have been published in scientific journals suggesting that ALA, typically in combination with other agents, may have anticancer activity among patients with advanced metastatic cancers. One case series reported that 4 patients with pancreatic cancer experienced a complete response after receiving treatment with intravenous ALA (300 to 600

mg twice weekly) plus oral low-dose naltrexone (4.5 mg once daily).10 The authors also reported efficacy of this regimen in a patient with non-Hodgkin lymphoma who refused conventional treatment. Another study reported promising results with a combination of ALA and hydroxycitrate with gemcitabine in a patient with metastatic pancreatic cancer.11

34 CANCER THERAPY ADVISOR | MAY/JUNE 2018 | CancerTherapyAdvisor.com

ÂŠ MOLEKUUL / GETTY IMAGES

Enhance Your Patientsâ&#x20AC;&#x2122; Education

FACT SHEET Conclusions Though randomized, controlled trials are needed, preliminary studies suggest that ALA, particularly in combination with other compounds, may improve quality of life and may have some anticancer activity. ALA is well tolerated and does not appear to cause toxicities when used orally or intravenously. ■

Grb2-mediated EGFR downregulation. Biochem

experimental results and case report. Invest

Biophys Res Commun. 2017;494:325-331. doi:

New Drugs. 2012;30:200-211. doi: 10.1007/

10.1016/j.bbrc.2017.10.030

12. Mantovani G, Madeddu C, Gramignano G, et

α-Lipoic acid sensitizes lung cancer cells to

al. Subcutaneous interleukin-2 in combina-

chemotherapeutic agents and anoikis via

tion with medroxyprogesterone acetate and

integrin β1/β3 downregulation. Int J Oncol.

antioxidants in advanced cancer responders

2016;49:1445-1456. doi: 10.3892/ijo.2016.3624

to previous chemotherapy: phase II study

7. Jeon MJ, Kim WG, Lim S, et al. Alpha lipoic acid inhibits proliferation and epithelial mesenchy-

References

mal transition of thyroid cancer cells. Mol Cell

1. Petersen Shay K, Moreau RF, Smith EJ,

Endocrinol. 2016;419:113-123. doi: 10.1016/j.

et al. Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and

s10637-010-9552-x.

6. Puchsaka P, Chaotham C, Chanvorachote P.

mce.2015.10.005 8. Kismali G, Yurdakok-Dikmem B, Kuzukiran O,

evaluating clinical, quality of life, and laboratory parameters. J Exp Ther Oncol. 2003;3:205-219. 13. Schwartz L, Buhler L, Icard P, et al. Metabolic treatment of cancer: intermediate results of a prospective case series. Anticancer Res. 2014;34:973-980.

therapeutic potential. Biochim Biophys

et al. Phthalate induced toxicity in prostate

Acta. 2009;1790:1149-1160. doi: 10.1016/j.

cancer cell lines and effects of alpha lipoic

of an alpha lipoic, methylsulfonylmethane and

bbagen.2009.07.026

acid. Bratisl Med J. 2017;118:460-466. doi:

bromelain dietary supplement (Opera®) for

10.4149/BLL_2017_089

chemotherapy-induced peripheral neuropathy

2. Kuban-Jankowska A, Gorska-Ponikowska M, Wozniak M. Lipoic acid decreases the viability

9. Schwartz L, Abolhassani M, Guais A, et al. A

of breast cancer cells and activity of PTP1B and

combination of alpha lipoic acid and calcium

SHP2. Anticancer Res. 2017;37:2893-2898.

hydroxycitrate is efficient against mouse

3. Kafara P, Icard P, Guillamin M, et al. Lipoic acid decreases Mcl-1, Bcl-xL and up regulates Bim on ovarian carcinoma cells leading to

management, a prospective study. Med Oncol. 2017;34:46. doi: 10.1007/s12032-017-0907-4 15. Guo Y, Jones D, Palmer JL, et al. Oral alpha-li-

cancer models: preliminary results. Oncol Rep.

poic acid to prevent chemotherapy-induced

2010;23:1407-1416.

peripheral neuropathy: a randomized, dou-

10. Berkson BM, Rubin DM, Berkson AJ.

cell death. J Ovarian Res. 2015;8:36-49. doi:

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10.1186/s13048-015-0165-z

Low-Dose Naltrexone) protocol for people

4. Dorsäm B, Göder A, Seiwert N, et al. Lipoic

14. Desideri I, Francolini G, Becherini C, et al. Use

ble-blind, placebo-controlled trial. Support

Care Cancer. 2014;22:1223-1231. 16. Mantovani G, Macció A, Madeddu C, et al. A

with metastatic and nonmetastatic pan-

phase II study with antioxidants, both in the

acid induces p53-independent cell death

creatic cancer: a report of 3 new cases.

diet and supplemented, pharmaconutritional

in colorectal cancer cells and potentiates

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support, Progestagen, and anti-cyclooxygen-

the cytotoxicity of 5-fluorouracil. Arch

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ase-2 showing efficacy and safety in patients

Toxicol. 2015;89:1829-1846. doi: 10.1007/

11. Guais A, Baronzio G, Sanders E, et al. Adding a

with cancer-related anorexia/cachexia and

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oxidative stress. Cancer Epidemiol Biomarkers

(METABLOC™) to chemotherapy improves

Prev. 2006;15:1030-1034. doi:10.1158/1055-

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9965.EPI-05-0538

Feature

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February 27, 2018. https://www.nccn.org/about/

Continued from page 33

QAD.0000000000000222

news/newsinfo.aspx?NewsID=1010. Accessed

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3. Suneja G, Lin CC, Simard EP, Han X, Engels EA, References

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1. Yarchoan R, Uldrick TS. HIV-associated

April 2018. 5. Shiels MS, Pfeiffer RM, Gail MH, et al. Cancer

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in the United States. J Natl Cancer Inst.

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doi: 10.1002/cncr.30052

NEJMra1615896 2. Morlat P, Roussillon C, Henard S, et al. Causes

4. More people living with HIV and cancer should

2011;103(9):753-62. doi: 10.1093/jnci/djr076 6. Kaposi sarcoma: causes, risk factors, and preven-

get appropriate cancer treatment, according to

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France in 2010 (national survey): trends since

PA: National Comprehensive Cancer Network;

es-risks-prevention.html. Accessed April 2018.

CancerTherapyAdvisor.com | MAY/JUNE 2018 | CANCER THERAPY ADVISOR 35

IN THE CLINIC

Obstructing Colorectal Cancer: Presentation and Colonic Stenting Stenting can be used to help bridge the patient to surgery to optimize treatment timing.

atients with colorectal cancer (CRC) can present in a variety of ways: iron deficiency, rectal bleeding, change in bowel habits, abdominal pain, palpable rectal or abdominal mass, or without symptoms altogether.1 One extreme presentation of CRC, however, involves an acute colonic obstruction, where the lumen of the colon can be almost entirely occluded by the malignancy. These patients can present with peritonitis, severe abdominal pain, abdominal distension, and absence of bowel movements and/or flatus. These patients may initially be thought to have a small bowel obstruction (SBO), as these are more common, though up to 25% of all intestinal obstructions are found in the colon.2 When a large bowel obstruction (LBO) is found, approximately 70% of all cases are found distal to the transverse colon.3 Although primary CRC is a common cause of LBO, other etiologies should also be kept on the differential until a definitive diagnosis is made. Patients can have metastatic disease within the colonic lumen causing obstruction, such as those from pancreatic or gynecologic malignancies.2,3 Adhesive disease is significantly more associated with SBO but can also contribute to LBOs. Prior episodes of diverticulitis, abdominal or pelvic

radiation, and inflammatory bowel disease (IBD) can predispose the colon to stricture development that can present as an LBO. Malignant colonic obstructions can be diagnosed with imaging studies such as obstruction series or computed tomography (CT) of the abdomen and pelvis, though the latter is more specific; CT also has the advantage of identifying metastatic disease. Once a suspicious obstructing colonic lesion is identified, endoscopic examination is often pursued both to confirm malignancy and to offer temporary decompression via stenting. It may also be valuable to obtain both surgical and oncologic consultation to assist in management.

ÂŠ GASTROLAB / SCIENCE SOURCE

C. ANDREW KISTLER, MD, PharmD

The risks and benefits of endoscopic diagnostic and therapeutic examination should, furthermore, be discussed with the patient before proceeding. The typical risks of infection, bleeding, and perforation may be higher in patients with obstructing CRC. It is beneficial to use carbon dioxide instead of ambient air for insufflation to reduce the risk of perforation during the exam. Complete bowel preparation can also be challenging in patients with more proximal lesions and if they are completely or near completely obstructed. Patients with more distal lesions may not require a full bowel preparation and need only several enemas prior to the procedure. During the endoscopic exam, biopsies can be taken of any suspicious mucosa to assist in diagnosing primary vs metastatic disease. Endoscopy can also help to determine whether the suspicious lesion is intrinsic or extrinsic. Then, pending the clinical scenario, colonic stenting can be considered for those lesions that appear amenable. Colonic stenting can be used as a temporizing measure to help bridge the patient to surgery for optimal timing. Stenting can

Endoscopic view of an adenocarcinoma and tubulovillous adenoma.

36 CANCER THERAPY ADVISOR | MAY/JUNE 2018 | CancerTherapyAdvisor.com

IN THE CLINIC Iron Deficiency Anemia (SAMI). Br J Surg.

“The typical risks of infection, bleeding, and perforation may be higher in patients with obstructing colorectal cancer.”

2017;104(10):1393-404. 2. Markogiannakis H, Messaris E, Dardamanis D, et al. Acute mechanical bowel obstruction: clinical presentation, etiology, management and outcome. World J Gastroenterol. 2007;13(3):432-7. 3. Aslar AK, Ozdemir S, Mahmoudi H, Kuzu MA.

also be used as a palliative measure in those patients who are not surgical candidates. If colonic stenting is considered a reasonable option prior to starting the exam, it is helpful to have fluoroscopy available to aid in the placement of the stent. In the United States, uncovered self-expanding metal stents (SEMS) are typically used in obstructing CRC.4 The vast majority of CRC stenting cases are for left-sided lesions, as proximal lesions are more challenging and carry a higher risk of migration. A large systematic review noted a median technical success rate (defined as passing of a guidewire and appropriate placement of the stent) of about 96%.5 Clinical success was more difficult to normalize between all of the included studies, but was reported at a median rate of 92%. In patients who underwent stenting for palliation, the median patency duration was 106 days. The median rate of re-intervention in these patients was 20%. Patients who received stenting as a bridge to surgery had a median time to surgery of 7 days and a median rate of re-intervention of only 7%. The median complication rates were stent migration in 11%, perforation in 4.5%, and re-obstruction in 12%.5 Another systematic review found similar rates of technical (94%) and clinical success

(91%), though clinical success decreased to 72% when the indication was a bridge to surgery.6 Complication rates were also similar: stent migration in 12%, perforation in 4%, and re-obstruction in 7.3%. Colonic stenting may be a contraindication in patients who are completely obstructed, have an intra-abdominal abscess, or have evidence of colonic ischemia and/or perforation.7,8 There are also data to support avoiding colonic stenting in patients receiving bevacizumab, as this drug carries an increased risk of perforation.8,9 Once a colonic stent is placed, patients must follow a special diet to avoid obstructing the stent itself. Patients should follow a low-residue/low-fiber diet and keep their stools soft with polyethylene glycol (if needed). Colonic stents can also migrate, which may cause obstructive symptoms, abdominal pain and/or distension, or rectal bleeding. Patients should be aware of these possible complications and alert their physicians immediately if there is evidence of any of them. ■

Analysis of 230 cases of emergent surgery for obstructing colon cancer-lessons learned. J

Gastrointest Surg. 2011;15(1):110-9. 4. Baron TH, Wong Kee Song LM, Repici A. Role of self-expandable stents for patients with colon cancer (with videos). Gastrointest Endosc. 2012;75(3):653-62. 5. Watt AM, Faragher IG, Griffin TT, et al. Selfexpanding metallic stents for relieving malignant colorectal obstruction: a systematic review. Ann Surg. 2007;246(1):24-30. 6. Sebastian S, Johnston S, Geoghegan T, Torreggiani W, Buckley M. Pooled analysis of the efficacy and safety of self-expanding metal stenting in malignant colorectal obstruction. Am J Gastroenterol. 2004;99(10):2051-7. 7. van Halsema EE, van Hooft JE, Small AJ, et al. Perforation in colorectal stenting: a meta-analysis and search for risk factors.

Gastrointest Endosc. 2014;79(6):970-82.e7. 8. Van Hooft JE, van Halsema EE, Vanbiervliet G, et al. Self-expandable metal stents for obstructing colonic and extracolonic cancer: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline.

Endoscopy. 2014;46(11):990-1053. 9. Small AJ, Coelho-Prabhu N, Baron TH.

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72. doi: 10.1016/j.gie.2009.10.012

Clinical Treatment Regimens Review all regimens at CancerTherapyAdvisor.com/treatmentregimens

CancerTherapyAdvisor.com | MAY/JUNE 2018 | CANCER THERAPY ADVISOR 37

GYNECOLOGIC CANCER

TREATMENT REGIMENS Cervical Cancer Treatment Regimens Clinical Trials: The National Comprehensive Cancer Network recommends cancer patient participation in clinical trials as the gold standard for treatment. Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are only provided to supplement the latest treatment strategies. These Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

uChemoradiation

for Cervical Cancer1,a,c

Note: All recommendations are category 2A unless otherwise indicated.

REGIMEN

DOSING

Preferred Regimens

Cisplatin2,3

Cisplatin 40mg/m2 IV once weekly for up to 6 doses (total dose not to exceed 70mg per week).

Cisplatin + 5-FU4,5

Days 1–5 of radiotherapy: Cisplatin 75mg/m2 IV over 4 hours, followed by 5-FU 4,000mg/m2 IV over 96 hours (begin chemotherapy within 16 hours after radiotherapy). Repeat cycle every 3 weeks for 2 additional cycles. OR Days 1 and 29: Cisplatin 50mg/m2 IV infusion (4 hours prior to external-beam radiotherapy) at 1mg/minute with standard hydration, plus Days 2–5, and 30–33: 5-FU 1,000mg/m2 IV continuous infusion over 24 hours (total dose 4,000mg/m2 each course).

uMetastatic

or Recurrent Cervical Cancer1,c

First-Line Combination Therapyd,f Cisplatin + paclitaxel + bevacizumab (Category 1)6

Day 1: Cisplatin 50mg/m2 IV + paclitaxel 135–175mg/m2 IV + bevacizumab 15mg/kg IV. Repeat cycle every 21 days until disease progression, unacceptable toxicity, or complete response.

Paclitaxel + cisplatin (Category 1)7,8

Day 1: Paclitaxel 135mg/m2 IV over 24 hours Day 2: Cisplatin 50mg/m2 IV at a rate of 1mg/minute. Repeat cycle every 3 weeks for 6 cycles.

Topotecan + paclitaxel + bevacizumab (Category 1)6

Day 1: Bevacizumuab 15mg/kg IV + Paclitaxel 175 mg/m2 over 3 hours Days 1–3: Topotecan 0.75mg/m2 IV over 30 minutes. Repeat cycle every 21 days until disease progression or unacceptable toxicity.

Paclitaxel + carboplatin (Category 1 for patients with prior cisplatin therapy)9,10

Day 1: Paclitaxel 175mg/m2 IV over 3 hours, followed by 1-hour carboplatin IV at AUC 5mg•mL/min. Repeat cycle every 3 weeks for a maximum of 6 cycles or until disease progression or unacceptable toxicity.

Carboplatin + paclitaxel + bevacizumab6,10

Day 1: Paclitaxel 175mg/m2 IV over 3 hours, followed by 1-hour carboplatin IV at AUC 5mg•mL/min + bevacizumab 15mg/kg IV. Repeat cycle every 3 weeks for a maximum of 6 cycles or until disease progression or unacceptable toxicity.

Cisplatin + topotecan11

Days 1–3: Topotecan 0.75mg/m2 IV over 30 minutes, followed by Day 1: Cisplatin 50mg/m2 IV. Repeat cycle every 3 weeks.

Topotecan + paclitaxel6e

Days 1–3: Topotecan 0.75mg/m2 IV over 30 minutes, followed by Day 1: Paclitaxel 175 mg/m2 IV.

Cisplatin + gemcitabine (Category 3)12

Days 1 and 8: Cisplatin 30mg/m2 IV followed by gemcitabine 800mg/m2 IV. Repeat cycle every 4 weeks.

38 CANCER THERAPY ADVISOR | MAY/JUNE 2018 | CancerTherapyAdvisor.com

GYNECOLOGIC CANCER

TREATMENT REGIMENS Cervical Cancer Treatment Regimens uMetastatic

or Recurrent Cervical Cancer1,c (continued)

REGIMEN

DOSING

Possible First-Line Single-Agent Therapyf Cisplatin (preferred as a single agent)8

Day 1: Cisplatin 50mg/m2 IV. Repeat every 3 weeks for 6 cycles.

Carboplatin13

Day 1: Carboplatin 400mg/m2 IV. Repeat every 4 weeks.

Paclitaxel14,15

Day 1: Paclitaxel 250mg/m2 IV over 3 hours. Repeat every 3 weeks.

Second-Line Therapy Note: Agents listed below are category 2B unless otherwise indicated.

Bevacizumab16

Day 1: Bevacizumab 15mg/kg IV. Repeat cycle every 3 weeks until disease progression or unacceptable toxicity.

Albumin-bound paclitaxel (nab-paclitaxel)17

Days 1, 8, and 15: Nab-paclitaxel 125mg/m2 IV over 30 minutes. Repeat cycle every 4 weeks until disease progression or unacceptable toxicity.

Docetaxel18

Day 1: Docetaxel 100mg/m2 IV over 1 hour. Repeat cycle every 3 weeks until disease progression or unacceptable toxicity.

5-FU19

Days 1–5: Leucovorin 200mg/m2 IV bolus + 5-FU 370mg/m2 IV bolus every 4 weeks for the first 2 courses with subsequent courses given every 5 weeks.

Gemcitabine20

Days 1, 8, and 15: Gemcitabine 800mg/m2 IV over 30 minutes, with a 1-week rest until disease progression or unacceptable toxicity.

Ifosfamide21,22

Days 1–5: Ifosfamide 1.5g/m2 IV over 30 minutes; dose reduced to 1.2g/m2 in patients with prior radiotherapy. Repeat cycle every 3 weeks.

Irinotecan23

Irinotecan 125mg/m2 IV over 90 minutes weekly for 4 weeks. Repeat cycle every 6 weeks.

Mitomycin24

Day 1: Mitomycin 6mg/m2 IV. Repeat cycle every 4 weeks.

Pemetrexed25

Day 1: Pemetrexed 900mg/m2 IV over 10 minutes. Repeat cycle every 21 days.

Topotecan26,27

Days 1–5: Topotecan 1.5mg/m2 IV. Repeat cycle every 3 to 4 weeks.

Vinorelbine28

Days 1 and 8: Vinorelbine 30mg/m2; dose omitted on day 8 for grade 3 or 4 neutropenia OR reduced to 20 mg/m2 for grade 2 neutropenia. Repeat cycle every 3 weeks.

Pembrolizumab (for MSI-H/dMMR tumors)29

Days 1: Pembrolizumab 200 mg IV over 30 minutes. Repeat cycle every 3 weeks until disease progression or unacceptable toxicity.

Includes patients with stage 2B to 4A disease, but can be extended to include patients with 1B2 and 2A2 disease in the advanced disease category. Given concurrently with pelvic radiotherapy and brachytherapy; category 1 for patients without nodal disease or with disease limited to the pelvis as determined through surgical staging. In patients with positive para-aortic and pelvic lymph nodes on imaging studies, extraperitoneal lymph node dissection should be considered, followed by extended-field radiotherapy, concurrent cisplatin-containing chemotherapy, and brachytherapy. c Cisplatin, carboplatin, docetaxel, and paclitaxel may cause drug reactions, which can be managed following recommendations in NCCN Guidelines for Ovarian Cancer—Management of Drug Reaction [OV-C]. d Cost and toxicity should be carefully considered when selecting an appropriate regimen for treatment. e Although topotecan + paclitaxel was not shown to be superior to cisplatin + paclitaxel, it may be considered an alternative in patients who are not candidates for cisplatin. f These agents can be used as second-line therapy if not used previously. a

continued

CancerTherapyAdvisor.com | MAY/JUNE 2018 | CANCER THERAPY ADVISOR 39

GYNECOLOGIC CANCER

TREATMENT REGIMENS Cervical Cancer Treatment Regimens References 1. NCCN Clinical Practice Guidelines in Oncology™. Cervical Cancer. v 1.2018. Available at: http://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf. Accessed November 21, 2017. 2. Keys HM, Bundy BN, Stehman FB, et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med. 1999;340(15):1154–1161. 3. Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 1999;340(15):1144–1153. 4. Morris M, Eifel PF, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med. 1999;340(15):1137–1143. 5. Whitney CW, Sause W, Bundy BN, et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIBIVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol. 1999;17(5):1339–1348. 6. Tewari KS1, Sill MW, Long HJ 3rd, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014;370(8):734–743. 7. Monk BJ, Sill MW, McMeekin DS, et al. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2009;27(28):4649–4655. 8. Moore DH, Blessing JA, McQuellon RP, et al. Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol. 2004;22(15):3113–3119. 9. Moore KN, Herzog TJ, Lewin S, et al. A comparison of cisplatin/paclitaxel and carboplatin/paclitaxel in stage IVB, recurrent or persistent cervical cancer. Gynecol Oncol. 2007;105(2):299–303. 10. Kitagawa R, Katsumata N, Shibata T, et al. Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical cancer: the open-label randomized phase III trial JCOG0505. J Clin Oncol. 2015;33(19):2129–2135. 11. Long HJ 3rd, Bundy BN, Grendys EC Jr, et al; Gynecologic Oncology Group Study. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group study. J Clin Oncol. 2005;23(21):4626–4633. 12. Brewer CA, Blessing JA, Nagourney RA, et al. Cisplatin plus gemcitabine in previously treated squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2006;100(2):385–388. 13. Weiss GR, Green S, Hannigan EV, et al. A phase II trial of carboplatin for recurrent or metastatic squamous carcinoma of the uterine cervix: a Southwest Oncology Group study. Gynecol Oncol. 1990;39(3):332–336. 14. Tinker AV, Bhagat K, Swenerton KD, Hoskins PJ. Carboplatin and paclitaxel for advanced and recurrent cervical carcinoma: the British Columbia Cancer Agency experience. Gynecol Oncol. 2005;98:54–58. 15. McGuire WP, Blessing JA, Moore D, Lentz SS, Photopulos G. Paclitaxel has moderate activity in squamous cervix cancer. A Gynecologic Oncology Group study. J Clin Oncol. 1996;14:792–795.

16. Monk BJ, Sill MW, Burger RA, et al. Phase II trial of bevacizumab in the treatment of persistent or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol. 2009;27(7):1069–1074. 17. Alberts DS, Blessing JA, Landrum LM, et al. Phase II trial of nab-paclitaxel in the treatment of recurrent or persistent advanced cervix cancer: a Gynecologic Oncology Group study. Gynecol Oncol. 2012;127(3):451–455. 18. Garcia AA, Blessing JA, Vaccarello L, et al. Phase II clinical trial of docetaxel in refractory squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Am J Clin Oncol. 2007;30(4):428–431. 19. Look KY, Blessing JA, Gallup DG, Lentz SS. A phase II trial of 5-fluorouracil and high-dose leucovorin in patients with recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Am J Clin Oncol.1996;19(5):439–441. 20. Schilder RJ, Blessing J, Cohn DE. Evaluation of gemcitabine in previously treated patients with non-squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2005;96(1):103–107. 21. Coleman RE, Harper PG, Gallagher C, et al. A phase II study of ifosfamide in advanced and relapsed carcinoma of the cervix. Cancer Chemother Pharmacol. 1986;18(3):280–283. 22. Sutton GP, Blessing JA, McGuire WP, Patton T, Look KY. Phase II trial of ifosfamide and mesna in patients with advanced or recurrent squamous carcinoma of the cervix who had never received chemotherapy: a Gynecologic Oncology Group study. Am J Obstet Gynecol. 1993;168(3 Pt 1):805–807. 23. Verschraegen CF, Levy T, Kudelka AP, et al. Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix. J Clin Oncol. 1997;15(2):625–631. 24. Wagenaar HC, Pecorelli S, Mangioni C, et al. Phase II study of mitomycin-C and cisplatin in disseminated, squamous cell carcinoma of the uterine cervix. A European Organization for Research and Treatment of Cancer (EORTC) Gynecological Cancer Group study. Eur J Cancer. 2001;37(13):1624–1628. 25. Miller DS, Blessing JA, Bodurka DC, Bonebrake AJ, Schorge JO; Gynecologic Oncology Group. Evaluation of pemetrexed (Alimta, LY231514) as second line chemotherapy in persistent or recurrent carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2008;110(1):65–70. 26. Bookman MA, Blessing JA, Hanjani P, Herzog TJ, Andersen WA. Topotecan in squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2000;77(3):446–449. 27. Muderspach LI, Blessing JA, Levenback C, Moore JL Jr. A phase II study of topotecan in patients with squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 2001;81(2):213–215. 28. Muggia FM, Blessing JA, Method M, et al; Gynecologic Oncology Group study. Evaluation of vinorelbine in persistent or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 2004; 92(2):639–643. 29. Schellens JHM, Marabelle A, Zeigenfuss S, et al. Pembrolizumab for previously treated advanced cervical squamous cell cancer: preliminary results from the phase 2 KEYNOTE-158 study. J Clin Oncol. 2015;35(15 suppl):abstr 5514.

uResources

for Gynecologic Cancers

RECENTLY FEATURED TOPICS INCLUDE: Highly Selective, First-in-Class CDK4 Inhibitor Promising in Ovarian Cancer Mice treated with 2-94 had few or no signs of lymphopenia or neutropenia, common adverse events associated with palbociclib.

To read more about recent FDA approvals, drug trials, and interviews with leading researchers visit www.CancerTherapyAdvisor.com/Gynecologic-Cancers.

40 CANCER THERAPY ADVISOR | MAY/JUNE 2018 | CancerTherapyAdvisor.com

LYMPHOMA

TREATMENT REGIMENS Hodgkin Lymphoma Treatment Regimens Clinical Trials: The National Comprehensive Cancer Network recommends cancer patient participation in clinical trials as the gold standard for treatment. Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced health care team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are provided only to supplement the latest treatment strategies. These Guidelines are a work in progress that may be refined as often as new significant data become available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

uClassical

Hodgkin Lymphoma1

Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

Primary Treatment Stage IA, IIA Favorable (No Bulky Disease, <3 Sites of Disease, ESR <50, and No E-lesions) Doxorubicin + Bleomycin + Vinblastine + Dacarbazine (ABVD) (Category 1)2-5

Days 1 and 15: Doxorubicin 25mg/m2 IV push + bleomycin 10units/m2 IV push + vinblastine 6mg/m2 IV over 5–10 minutes + dacarbazine 375mg/m2 IV over 60 minutes. Repeat cycle every 4 weeks for 2 cycles followed by radiation therapy.

ABVD (Preference to treat with chemotherapy alone)2-5

ABVD (Preference to treat with combined modality therapy)2-5

Doxorubicin + Vinblastine + Mechlorethamine + Etoposide + Vincristine + Bleomycin + Prednisone (Stanford V)6-9

Days 1 and 15: Doxorubicin 25mg/m2 IV push + vinblastine 6mg/m2 IV over 5–10 minutes Day 1: Mechlorethamine 6mg/m2 IV push Days 8 and 22: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5–10 minutes + bleomycin 5units/m2 IV push Days 15 and 16: Etoposide 60mg/m2 IV over 60 minutes Days 1–28: Prednisone 40mg/m2 orally every other day. Taper prednisone dose by 10mg every other day beginning Day 15 of Cycle 2. Repeat cycle every 4 week for 2 cycles followed by radiation therapy, optimally within 3 weeks of chemotherapy completion.

Stage I–II Unfavorable (Bulky or Non-bulky Disease) Doxorubicin + Bleomycin + Vinblastine + Dacarbazine (ABVD) (Category 1 for Bulky Disease)2-5

Days 1 and 15: Doxorubicin 25mg/m2 IV push + bleomycin 10units/m2 IV push + vinblastine 6mg/m2 IV over 5–10 minutes + dacarbazine 375mg/m2 IV over 60 minutes. Bulky or non-bulky disease: Repeat cycle every 4 weeks for 4-6 cycles total of ABVD or 4 cycles of AVD with or without subsequent radiation therapy (category 1 for bulky disease); or, for select patients younger than 60 years, repeat for 2 cycles, following 2 cycles of escalated BEACOPP, with or without subsequent radiation therapy.

Doxorubicin + Vinblastine + Mechlorethamine + Etoposide + Vincristine + Bleomycin + Prednisone (Stanford V)6-9

Days 1 and 15: Doxorubicin 25mg/m2 IV push + vinblastine 6mg/m2 IV over 5–10 minutes Day 1: Mechlorethamine 6mg/m2 IV push Days 8 and 22: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5–10 minutes + bleomycin 5units/m2 IV push Days 15 and 16: Etoposide 60mg/m2 IV over 60 minutes Days 1–28: Prednisone 40mg/m2 orally every other day. Taper prednisone dose by 10mg every other day beginning Day 15 of Cycle 3. Repeat cycle every 4 weeks for 3 cycles with or without subsequent radiation therapy.

Bleomycin + Etoposide + Doxorubicin + Cyclophosphamide + Vincristine + Procarbazine + Prednisone (Escalated BEACOPP) (In selected patients if IPS≥4, age <60)10,11

Day 1: Cyclophosphamide 1,250mg/m2 IV over 60 minutes + doxorubicin 35mg/m2 IV push Days 1–3: Etoposide 200mg/m2 IV over 2 hours Days 1–7: Procarbazine 100mg/m2 orally. Day 8: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5–10 minutes + bleomycin 10units/m2 IV push. Days 1–14: Prednisone 40mg/m2 orally daily. Repeat cycle every 3 weeks for 2 cycles followed by ABVD for 2 cycles and then by radiation therapy. continued

CancerTherapyAdvisor.com | MAY/JUNE 2018 | CANCER THERAPY ADVISOR 41

LYMPHOMA

TREATMENT REGIMENS Hodgkin Lymphoma Treatment Regimens uClassical

Hodgkin Lymphoma1 (continued)

REGIMEN

DOSING

Primary Treatment (continued) Stage III–IV Doxorubicin + Bleomycin + Vinblastine + Dacarbazine (ABVD)2-5

Doxorubicin + Vinblastine + Mechlorethamine + Etoposide + Vincristine + Bleomycin + Prednisone (Stanford V) (In selected patients if IPS ≤3)6-9

Days 1 and 15: Doxorubicin 25mg/m2 IV push + vinblastine 6mg/m2 IV over 5–10 minutes Day 1: Mechlorethamine 6mg/m2 IV push Days 8 and 22: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5–10 minutes + bleomycin 5units/m2 IV push Days 15 and 16: Etoposide 60mg/m2 IV over 60 minutes Days 1–28: Prednisone 40mg/m2 orally every other day. Taper prednisone dose by 10mg every other day beginning Day 15 of Cycle 3. Repeat cycle every 4 weeks for 3 cycles with or without subsequent radiation therapy.

Bleomycin + Etoposide + Doxorubicin + Cyclophosphamide + Vincristine + Procarbazine + Prednisone (Escalated BEACOPP) (In selected patients if IPS≥4, age <60)10,11

Day 1: Cyclophosphamide 1,250mg/m2 IV over 60 minutes + doxorubicin 35mg/m2 IV push Days 1–3: Etoposide 200mg/m2 IV over 2 hours Days 1–7: Procarbazine 100mg/m2 orally daily. Day 8: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5–10 minutes + bleomycin 10units/m2 IV push. Days 1–14: Prednisone 40mg/m2 orally daily. Repeat cycle in selected patients (IPS≥4, aged <60 years) every 3 weeks for 6 cycles, with or without subsequent radiation therapy.

Brentuximab Vedotin + Doxorubicin + Vinblastine + Dacarbazine (BV + AVD)12 (Category 2B) (Category 2A in select patients if IPS>4, bleomycin contraindicated, no known neuropathy)

Days 1 and 15: Brentuximab vedotin 1.2mg/kg IV over 30 minutes + doxorubicin 25mg/m2 IV push + vinblastine 6mg/m2 IV over 5–10 minutes + dacarbazine 375mg/m2 IV over 60 minutes. Repeat cycle every 4 weeks for up to 2 cycles.

Second-line Systemic Therapy Options1 Note: No data have established the superiority of any of the subsequent chemotherapy options, and NCCN guidelines recommend an individualized approach.

Brentuximab vedotin22 (Alone or in combination with the second-line regimens below)

Day 1: Brentuximab 1.8mg/kg (maximum 180mg) IV over 30 minutes; for patients with hepatic impairment: 1.2mg/ kg (up to 120mg). Repeat cycle every 3 weeks until disease progression or unacceptable toxicity.

Dexamethasone + Cytarabine + Cisplatin (DHAP)23,24

Days 1–4: Dexamethasone 40mg orally or IV daily Day 1: Cisplatin 100mg/m2 IV continuous infusion over 24 hours Day 2: Cytarabine 2,000mg/m2 IV over 3 hours every 12 hours. Repeat cycle every 3 to 4 weeks for 2–4 cycles (transplant candidates) or 4–8 cycles (nontransplant candidates).

Etoposide + Methylprednisolone + Cytarabine + Cisplatin (ESHAP)25–27

Days 1–4: Etoposide 40mg/m2 IV over 60 minutes + methylprednisolone 500mg IV over 15 minutes + cisplatin 25mg/m2 continuous IV infusion over 24 hours Day 5: Cytarabine 2,000mg/m2 IV over 3 hours. Repeat cycle every 3–4 weeks for 2–4 cycles (transplant candidates) or 4–8 cycles (nontransplant candidates).

Gemcitabine + Bendamustine + Vinorelbine (BeGEV)28

Day 1: Vinorelbine 20mg/m2 IV Days 1 and 4: Gemcitabine 800mg/m2 IV Days 2 and 3: Bendamustine 90mg/m2 IV. Repeat cycle every 3 weeks for 4 cycles.

Gemcitabine + Vinorelbine + Pegylated liposomal doxorubicin (GVD)29

For transplant-naive patients: Days 1 and 8: Gemcitabine 1,000mg/m2 IV over 30 minutes + vinorelbine 20mg/m2 IV over 5–10 minutes + pegylated liposomal doxorubicin 15mg/m2 IV over 60 minutes. Repeat cycle every 3 weeks for 2–4 cycles (transplant candidates) or 4–8 cycles (nontransplant candidates). For post-transplant patients: Days 1 and 8: Gemcitabine 800mg/m2 IV over 30 minutes + vinorelbine 15mg/m2 IV over 5–10 minutes + pegylated liposomal doxorubicin 10mg/m2 IV over 60 minutes. Repeat cycle every 3 weeks for 2–4 cycles (transplant candidates) or 4–8 cycles (nontransplant candidates).

42 CANCER THERAPY ADVISOR | MAY/JUNE 2018 | CancerTherapyAdvisor.com

TREATMENT REGIMENS LYMPHOMA

TREATMENT REGIMENS Hodgkin Lymphoma Treatment Regimens uClassical

Hodgkin Lymphoma1 (continued)

REGIMEN

DOSING

Second-line Systemic Therapy Options1 (continued) Ifosfamide + Carboplatin + Etoposide (ICE)30,31

Days 1–3: Etoposide 100mg/m2 IV over 60 minutes Day 2: Carboplatin AUC 5mg • min/mL (max 800mg) IV + ifosfamide 5,000mg/m2 IV + mesna 5,000mg/m2 IV administered concurrently as a continuous infusion over 24 hours. Repeat cycle every 2–3 weeks for 2–4 cycles (transplant candidates) or 4–8 cycles (nontransplant candidates).

Ifosfamide + Gemcitabine + Vinorelbine (IGEV)32

Days 1–4: Ifosfamide 200mg/m2 IV over 2 hours plus mesna 2,600mg/m2 IV Days 1 and 4: Gemcitabine 800mg/m2 IV over 30 minutes Day 1: Vinorelbine 20mg/m2 IV over 5–10 minutes Days 1–4: Prednisone 100mg PO daily. Repeat cycle every 3 weeks for 2–4 cycles (transplant candidates) or 4–8 cycles (nontransplant candidates).

Subsequent Systemic Therapy Options Bendamustine33

Days 1 and 2: Bendamustine 70–120mg/m2 IV over 30 minutes. Repeat cycle every 4 weeks until maximal response or unacceptable toxicity.

Cyclophosphamide + Vincristine + Procarbazine + Prednisone (C-MOPP) (Category 2B)1

Day 1: Cyclophosphamide 650mg/m2 IV over 30 minutes + vincristine 1.4mg/m2 (maximum 2mg) IV Days 1–7: Procarbazine 100mg/m2 orally daily Days 1–14: Prednisone 40mg/m2 orally daily. Repeat cycle every 4 weeks for 4–8 cycles. OR Days 1 and 8: Cyclophosphamide 500mg/m2 IV over 30 minutes + vincristine 1.4mg/m2 (maximum 2mg) IV over 5–10 minutes Days 1–14: Procarbazine 100mg/m2 orally daily. Days 1–3 and 8–10: Prednisone 40mg/m2 orally daily. Repeat cycle every 4 weeks for 4–8 cycles.

Everolimus34

Everolimus 10mg orally daily until disease progression or unacceptable toxicity.

Gemcitabine + Carboplatin + Dexamethasone (GCD)35,36

Days 1 and 8: Gemcitabine 1000mg/m2 IV over 30 minutes Day 1: Carboplatin AUC 5mg • min/mL (maximum 800mg) IV over 60 minutes Days 1–4: Dexamethasone 40mg orally daily. Repeat cycle every 3 weeks for 2–4 cycles (transplant candidates) or 4–8 cycles (nontransplant candidates).

Lenalidomide37

Days 1–21: Lenalidomide 25mg orally daily. Repeat cycle every 4 weeks until disease progression or unacceptable toxicity.

Carmustine + Cytarabine + Etoposide + Melphalan (Mini-BEAM)39,40

Day 1: Carmustine 60mg/m2 IV over 2 hours Days 2–5: Etoposide 75mg/m2 IV over 60 minutes daily + cytarabine 100mg/m2 IV over 3 hours every 12 hours Day 6: Melphalan 30mg/m2 IV over 15 minutes. Repeat cycle every 4–6 weeks for 2–4 cycles.

Mitoxantrone + Ifosfamide + Mesna + Etoposide (MINE)38

Days 1–3: Mesna 1.33 g/m2 IV daily, and 500 mg PO daily 4 hours after each IV dose plus ifosfamide 1.33 g/m2 IV daily, given concurrently with mesna, for 3 days. Day 1: Mitoxantrone 8mg/m2 IV over 30 minutes. Repeat cycle every 3 weeks for 2–4 cycles (transplant candidates) or 4–8 cycles (nontransplant candidates).

Nivolumab41,42,a

Nivolumab 3mg/kg IV every 2 weeks until disease progression or unacceptable toxicity.

Pembrolizumab43,a

Pembrolizumab 10mg/kg IV every 2 weeks until disease progression or unacceptable toxicity.

Maintenance Therapy Brentuximab vedotin44

Day 1: Brentuximab 1.8mg/kg (maximum 180mg) IV over 30 minutes. Repeat cycle every 3 weeks until disease progression or unacceptable toxicity for a maximum of 1 year after HDT/SCR (if primary refractory disease or relapse occurred <12 months after primary therapy). continued

CancerTherapyAdvisor.com | MAY/JUNE 2018 | CANCER THERAPY ADVISOR 43

LYMPHOMA

TREATMENT REGIMENS Hodgkin Lymphoma Treatment Regimens uNodular

Lymphocyte-Predominant Hodgkin Lymphoma1

REGIMEN

DOSING

Primary Treatment Doxorubicin + Bleomycin + Vinblastine + Dacarbazine (ABVD) ± Rituximab13,14

Days 1 and 15: Doxorubicin 25mg/m2 IV push + bleomycin 10units/m2 IV push + vinblastine 6mg/m2 IV over 5–10 minutes + dacarbazine 375mg/m2 IV over 60 minutes, ± Day 1: Rituximab 375mg/m2 IV for all cycles. OR Days 1, 8, 15, and 22: Rituximab 375mg/m2 IV for cycle 1 only. Repeat cycle every 4 weeks for 3-4 cycles with subsequent radiation or 6-8 cycles without subsequent radiation.

Cyclophosphamide + Doxorubicin + Vincristine + Prednisone (CHOP) ± Rituximab15

Day 1: Cyclophosphamide 750mg/m2 over 60 minutes + doxorubicin 50mg/m2 IV push + vincristine 1.4mg/m2 (maximum 2mg) IV over 5–10 minutes Days 1–5: Prednisone 100mg orally daily, ± Day 1: Rituximab 375mg/m2 IV. Repeat cycle every 3 weeks for 3-4 cycles with subsequent radiation or 6-8 cycles without subsequent radiation.

Cyclophosphamide + Vincristine + Prednisone (CVP) ± Rituximab16

Day 1: Cyclophosphamide 750mg/m2 OR 1,000mg/m2 over 60 minutes + vincristine 1.4mg/m2 (maximum 2mg) IV over 5–10 minutes Days 1–5: Prednisone 100mg orally daily, ± Day 1: Rituximab 375mg/m2 IV. Repeat cycle every 3 weeks for 3-4 cycles with subsequent radiation or 6 cycles without subsequent radiation.

Rituximab17–21

Day 1: Rituximab 375mg/m2 IV. Repeat cycle every 7 days for 4 weeks with or without maintenance rituximab (375mg/m2 IV once weekly for 4 weeks every 6 months for up to 2 years).

Second-line Systemic Therapy Options1 Dexamethasone + Cytarabine + Cisplatin (DHAP)15,16

Etoposide + Methylprednisolone + Cytarabine + Cisplatin (ESHAP)17,18

Ifosfamide + Carboplatin + Etoposide (ICE)16,21

Ifosfamide + Gemcitabine + Vinorelbine (IGEV)22

a Checkpoint inhibitors (CPI) are commonly recommended for patients with refractory CHL who are transplant-ineligible based on comorbidity or failure of first salvage chemotherapy, and any patient who has relapsed after autologous HSCT+brentuximab vedotin. Nivolumab or pembrolizumab can be administered to patients post-allogeneic transplant; there is limited data regarding the use of CPI following allogeneic transplantation. Caution is advised due to increased risk of GVHD (graft-versus-host disease) and other immunological complications.

44 CANCER THERAPY ADVISOR | MAY/JUNE 2018 | CancerTherapyAdvisor.com

LYMPHOMA

TREATMENT REGIMENS Hodgkin Lymphoma Treatment Regimens References 1. NCCN Clinical Practice Guidelines in Oncology™. Hodgkin Lymphoma.V.3.2018. Available at: http://www.nccn.org/professionals/physician_gls/pdf/hodgkins.pdf. Accessed April 12, 2018. 2. Engert A, Plutschow A, Eich HT, et al. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med. 2010;363:640–652. 3. Radford J, Illidge T, Counsell N, et al. Results of a trial of PET-directed therapy for early-stage Hodgkin’s lymphoma. N Engl J Med. 2015;372:1598-1607. 4. Raemaekers JM, André MP, Federico M, et al. Omitting radiotherapy in early positron emission tomography–negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014;32:1188-1194. 5. Eich HT, Diehl V, Gorgen H, et al. Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin Study Group HD 11 trial. J Clin Oncol. 2010;28:4199-4206. 6. Advani RH, Hoppe RT, Baer D, et al. Efficacy of abbreviated Stanford V chemotherapy and involved- eld radiotherapy in early-stage Hodgkin lymphoma: mature results of the G4 trial. Ann Oncol. 2013;24:1044-1048. 7. Gordon LI, Hong F, Fisher RI, et al. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol. 2013; 31:684-691. 8. Advani RH, Hong F, Fisher RI, et al. Randomized phase III trial comparing ABVD plus radiotherapy with the Stanford V regimen in patients with stages I or II locally extensive, bulky mediastinal Hodgkin hymphoma: a subset analysis of the north american Intergroup E2496 trial. J Clin Oncol. 2015;33: 1936-1942. 9. Edwards-Bennett SM, Jacks LM, Moskowitz CH, et al. Stanford V program for locally extensive and advanced Hodgkin lymphoma: the Memorial Sloan-Kettering Cancer Center experience. Ann Oncol. 2010;21:574–581. 10. Engert A, Haverkamp H, Cobe C, et al. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet. 2012; 379(9828):1791-1799. 11. von Tresckow B, Plutschow A, Fuchs M, et al. Dose-intensification in early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin Study Group HD14 trial. J Clin Oncol. 2012:30:907-913. 12. Connors JM, Jurczak W, Straus DJ, Ansell SM, Kim WS, Gallamini A et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2018; 378(4): 331-344. 13. Savage KJ, Skinnider B, Al-Mansour M, et al. Treating limited stage nodular lymphocyte predominant Hodgkin lymphoma similarly to classical Hodgkin lymphoma with ABVD may improve outcome. Blood. 2011;118:4585-4590. 14. Canellos GP, Mauch P. What is the appropriate systemic chemotherapy for lymphocyte-predominant Hodgkin’s Lymphoma? J Clin Oncol. 2010;28:e8. 15. Fanale MA, Cheah CY, Rich A, et al. Encouraging activity for R-CHOP in advanced stage nodular lymphocyte-predominant Hodgkin lymphoma. Blood. 2017;130:472- 477. 16. Shankar A, Hall GW, Gorde-Grosjean S, et al. Treatment outcome after low intensity chemotherapy [CVP] in children and adolescents with early stage nodular lymphocyte predominant Hodgkin’s lymphoma - an Anglo-French collaborative report. Eur J Cancer. 2012;48:1700-1706. 17. Advani RH, Hoppe RT. How I treat nodular lymphocyte predominant Hodgkin lymphoma. Blood. 2013;122:4182-4188. 18. Advani RH, Horning SJ, Hoppe RT, et al. Mature results of a phase II study of rituximab therapy for nodular lymphocyte-predominant Hodgkin lymphoma. J Clin Oncol. 2014;32:912-918. 19. Schulz H, Rehwald U, Morschhauser F, et al. Rituximab in relapsed lymphocyte-predominant Hodgkin lymphoma: long-term results of a phase 2 trial by the German Hodgkin Lymphoma Study Group (GHSG). Blood. 2008;111(1):109-111. 20. Eichenauer DA, Fuchs M, Pluetschow A, et al. Phase 2 study of rituximab in newly diagnosed stage IA nodular lymphocyte-predominant Hodgkin lymphoma: a report from the German Hodgkin Study Group. Blood. 2011;118:4363-4365. 21. Eichenauer DA, Plutschow A, Fuchs M, et al. Long-Term Course of Patients With Stage IA Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A Report From the German Hodgkin Study Group. J Clin Oncol. 2015;33:2857-2862. 22. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30:2183- 2189.

23. Josting A, Rudolph C, Reiser M, et al. Time-intensified d examethasone/cisplatin/ cytarabine: an effective salvage therapy with low toxicity in patients with relapsed and refractory Hodgkin’s disease. Ann Oncol. 2002;13(10):1628-1635. 24. Abali H, Urün Y, Oksüzoglu B, Budakoglu B, et al. Comparison of ICE (ifosfamide-carboplatin-etoposide) versus DHAP (cytosine arabinoside-cisplatin-dexamethasone) as salvage chemotherapy in patients with relapsed or refractory lymphoma. Cancer Invest. 2008;26(4):401-406. 25. Aparicio J, Segura A, Garcera S, et al. ESHAP is an active regimen for relapsing Hodgkin’s disease. Ann Oncol. 1999; 10(5):593-595. 26. Fernández de Larrea C, Martínez C, et al. Salvage chemotherapy with alternating MINE-ESHAP regimen in relapsed or refractory Hodgkin’s lymphoma followed by autologous stem cell transplantation. Ann Oncol. 2010;21(6):1211-1216. 27. Labrador J, Cabrero-Calvo M, Perez-Lopez E, et al. ESHAP as salvage therapy for relapsed or refractory Hodgkin’s lymphoma. Ann Hematol. 2014;93:1745-1753. 28. Santoro A, Mazza R, Pulsoni A, et al. Bendamustine in combination with gemcitabine and vinorelbine is an e ective regimen as induction chemotherapy before autologous stem-cell transplantation for relapsed or refractory Hodgkin lymphoma: final results of a multicenter phase II study. J Clin Oncol. 2016;34:3293-3299. 29. Bartlett N, Niedzwiecki D, Johnson J, et al. Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin’s lymphoma: CALGB 59804. Ann Oncol. 2007;18(6):1071-1079. 30. Moskowitz CH, Nimer SD, Zelenetz AD, et al. A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hogdkin disease: analysis by i ntent to treat and development of a prognostic model. Blood. 2001; 97(3):616–623. 31. Abali H, Urün Y, Oksüzoglu B, Budakoglu B, et al. Comparison of ICE (ifosfamide-carboplatin-etoposide) versus DHAP (cytosine arabinoside-cisplatin-dexamethasone) as salvage chemotherapy in patients with relapsed or refractory lymphoma. Cancer Invest. 2008;26(4):401-406. 32. Santoro A, Magagnoli M, Spina M, et al. Ifosfamide, gemcitabine, and vinorelbine: a new induction regimen for refractory and relapsed Hodgkin’s lymphoma. Haematologica. 2007;92(1): 35-41. 33. Moskowitz AJ, Hamlin PA, Perales M-A, et al. Phase II study of bendamustine in relapsed and refractory Hodgkin lymphoma. J Clin Oncol. 2013;31:456-460. 34. Johnston PB, Inwards DJ, Colgan JP, et al; A Phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma. Am J Hematol. 2010;85(5):320-324. 35. Crump M, Kuruvilla J, Couban S, et al. Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol. 2014;32:3490-3496. 36. Gopal AK, Press OW, Shustov AR, et al. Effcacy and safety of gemicitabine, carboplatin, dexamethasone, and rituximab in patients with relapsed/refractory lymphoma: a prospective multi-center phase II study by Puget Sound Oncology Consortium. Leuk Lymphoma. 2010;51:1523-1529. 37. Fehniger TA, Larson S, Trinkaus K, et al; A phase 2 multicenter study of lenalidomide in relapsed or refractory classical Hodgkin lymphoma. Blood.2011;118(19):5119-25. 38. Rodriguez MA, Cabanillas FC, Hagemeister FB, et al. A phase II trial of mesna/ifosfamide, mitoxantrone and etoposide for refractory lymphoma. Ann Oncol. 1995;6(6):609-611. 39. Colwill R, Crump M, Couture F, et al. Mini-BEAM as salvage therapy for relapsed or refractory Hodgkin’s disease before intensive therapy and autologous bone marrow transplantation. J Clin Oncol. 1995;13:396-402. 40. Martín A, Fernández-Jiménez MC, Caballero MD, et al. Long-term follow-up in patients treated with Mini-BEAM as salvage therapy for relapsed or refractory Hodgkin’s disease. Br J Haematol. 2001;113(1):161-171. 41. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 Blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311-319. 42. Timmerman J, Armand P, Lesokhin AM, et al. Nivolumab in patients with relapsed or refractory lymphoid malignancies and classical Hodgkin lymphoma: Updated results of a phase 1 study (CA 209-039) [abstract]. Hematol Oncol. 2015;33:Abstract 010. 43. Armand P, Shipp MA, Ribrag V, et al. Programmed Death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol. 2016; 34(31):3733-3739. 44. Moskowitz CH, Nademanee A, Masszi T, et al. Brentuximab vedotin as a consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385(9980)1853–1862. (Revised 4/2018) © 2018 by Haymarket Media, Inc.

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SARCOMA

TREATMENT REGIMENS Soft Tissue Sarcoma Treatment Regimens Clinical Trials: The National Comprehensive Cancer Network recommends cancer patient participation in clinical trials as the gold standard for treatment. Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced health care team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are provided only to supplement the latest treatment strategies. These Guidelines are a work in progress that may be refined as often as new significant data become available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

uSystemic

Therapy With Activity in Soft Tissue Sarcoma Subtypes With Non–Specific Histologies1,a,b,c

Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

Combination Regimens Doxorubicin + dacarbazine (AD)2-5

Days 1–4: Doxorubicin 60mg/m2 + dacarbazine 750mg/m2 as a continuous IV infusion over 96 hours. Repeat cycle every 3 weeks.

Doxorubicin + ifosfamide + mesna (AIM)4-7

Days 1 and 2: Doxorubicin 30mg/m2/day IV + ifosfamide 3,750mg/m2/day IV + mesna 750mg/m2 IV immediately preceding and then 4 and 8 hours after ifosfamide administration. Repeat cycle every 3 weeks.

Mesna + doxorubicin + ifosfamide + dacarbazine (MAID)4,5,8,9

Days 1–3: Doxorubicin 20mg/m2/day + ifosfamide 2,500mg/m2/day + dacarbazine 300mg/m2/day as continuous IV infusion over 72 hours, plus Mesna 2,500mg/m2/day IV for 84 to 96 hours. Repeat cycle every 3 weeks.

Ifosfamide + epirubicin + mesna10

Days 1 and 2: Epirubicin 60mg/m2/day IV Days 1–5: Ifosfamide 1.8g/m2/day IV over 1 hour + mesna at 20% of the ifosfamide dose IV immediately preceding and then 4 and 8 hours after ifosfamide administration. Repeat cycle every 3 weeks for 5 cycles.

Gemcitabine + docetaxel11,12

Days 1 and 8: Gemcitabine 900mg/m2 IV Day 8: Docetaxel 100mg/m2 IV. Repeat cycle every 3 weeks.

Gemcitabine + vinorelbine13

Days 1 and 8: Vinorelbine 25mg/m2 IV over 10 minutes + gemcitabine 800mg/m2 IV over 90 minutes. Repeat cycle every 3 weeks.

Gemcitabine + dacarbazine14

Day 1: Gemcitabine 1,800mg/m2 IV + dacarbazine 500mg/m2 IV. Repeat cycle ever 2 weeks for a total of 12 cycles; continuation of treatment after 24 weeks was allowed at investigator discretion.

Doxorubicin + olaratumab15,e

Day 1: Doxorubicin 75mg/m2 IV Days 1 and 8: Olaratumab 15mg/kg IV. Repeat cycle every 3 weeks for up to 8 cycles.

Single Agents Doxorubicin4,5,16

Doxorubicin 60–75mg/m2 IV every 3 weeks.

Ifosfamide10,17

Ifosfamide 2,000–3,000mg/m2/day IV for 3 to 4 days + mesna at 20% of the ifosfamide dose IV immediately preceding and then 4 and 8 hours after ifosfamide administration every 3 weeks. OR Ifosfamide 5,000mg/m2 + mesna 5,000mg/m2 as a continuous IV infusion over 24 hours followed by additional mesna 400–600mg/m2 IV over 2 hours after completion of ifosfamide administration. Repeat every 3 weeks.

46 CANCER THERAPY ADVISOR | MAY/JUNE 2018 | CancerTherapyAdvisor.com

SARCOMA

TREATMENT REGIMENS Soft Tissue Sarcoma Treatment Regimens uSystemic

Therapy With Activity in Soft Tissue Sarcoma Subtypes With Non–Specific Histologies1,a,b,c (continued)

REGIMEN

DOSING

Single Agents (continued) Epirubicin18

Epirubicin 160mg/m2 IV every 3 weeks.

Gemcitabine

Days 1 and 8: Gemcitabine 1,200mg/m2 IV over 90 to 120 minutes. Repeat cycle every 3 weeks.

Dacarbazine

Dacarbazine 250mg/m2/day IV for 5 days every 3 weeks. OR Dacarbazine 800–1,000mg/m2 IV every 3 weeks.

Liposomal doxorubicin19

Liposomal doxorubicin 30–50mg/m2 IV every 4 weeks.

Temozolomide20,d

Temozolomide 200mg/m2 orally twice daily for 5 days, followed by 9 doses of 90mg/m2 orally every 4 weeks.

Vinorelbine21,d

Vinorelbine 30mg/m2 IV weekly for 6 weeks during an 8-week interval.

Pazopanib22,d,f

Pazopanib 800mg orally once daily without food until disease progression or unacceptable toxicity.

Eribulin23,d,g

Days 1 and 8: Eribulin mesylate 1.4mg/m2 IV. Repeat every 3 weeks until disease progression or unacceptable toxicity.

Trabectedin24-26,d,h

Trabectedin 1.5mg/m2 as a 24-hour continuous IV infusion every 3 weeks.

c d e f g h a

Alveolar soft part sarcomas (ASPS), well-differentiated liposarcoma/atypical lipomatous tumor, and clear cell sarcomas are generally non sensitive to cytotoxic chemotherapy. Anthracycline-based regimens are preferred in the neoadjuvant and adjuvant setting. Regimens appropriate for pleomorphic rhabdomyosarcoma. Recommended only for palliative therapy. For use in STS histologies for which an anthracycline-containing regimen is appropriate. Pazopanib should not be used for lipogenic sarcomas. Category 1 recommendation for liposarcoma. Category 1 recommendation for liposarcoma and leiomyosarcoma (L-types).

References 1. Referenced with permission from NCCN Clinical Practice Guidelines in Oncology™ Soft Tissue Sarcoma. V1.2018. Available at: http://www.nccn.org/professionals/ physician_gls/pdf/sarcoma.pdf. Accessed February 2, 2018. 2. Zalupski M, Metch B, Balcerzak S, et al. Phase III comparison of doxorubicin and dacarbazine given by bolus versus infusion in patients with soft-tissue sarcomas: A Southwest Oncology Group Study. J Natl Cancer Inst. 1991;83:926–932. 3. Antman K, Crowley J, Balcerzak SP, et al. An intergroup phase Ill randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol. 1993;11:1276–1285. 4. Adjuvant chemotherapy for localized resectable soft-tissue sarcoma of adults: Meta-analysis of individual data. Sarcoma Meta-analysis Collaboration. Lancet. 1997;350:1647–1654. 5. Pervaiz N, Colterjohn N, Farrokhyar F, et al. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer. 2008;113:573–581. 6. Grobmyer SR, Maki RG, Demetri GD, et al. Neo-adjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma. Ann Oncol. 2004;15:1667–1672. 7. Edmonson J, Ryan L, Blum R, et al. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol. 1993;11:1269–1275.

8. Elias A, Ryan L, Sulkes A, et al. Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. J Clin Oncol. 1989;7:1208–1216. 9. Kraybill WG, Harris J, Spiro IJ, et al. Long-term results of a phase 2 study of neoadjuvant chemotherapy and radiotherapy in the management of high-risk, highgrade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514. Cancer. 2010;116:4613–4621. 10. Frustaci S, Gherlinzoni F, De Paoli A, et al. Adjuvant chemotherapy for soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. J Clin Oncol. 2001;19:1238–1247. 11. Hensley ML, Maki R, Venkatraman E, et al. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol. 2002;20:2824–2831. 12. Maki RG, Wathen JK, Patel SR, et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002. J Clin Oncol. 2007; 25:2755–2763. 13. Dileo P, Morgan JA, Zahrieh D, et al. Gemcitabine and vinorelbine combination chemotherapy for patients with advanced soft tissue sarcomas: results of a phase II trial. Cancer. 2007;109:1863–1869. 14. Garcia-Del-Muro X, Lopez-Pousa A, Maurel J, et al. Randomized phase II study

continued

CancerTherapyAdvisor.com | MAY/JUNE 2018 | CANCER THERAPY ADVISOR 47

SARCOMA

TREATMENT REGIMENS Soft Tissue Sarcoma Treatment Regimens References (continued)

15. 16. 17. 18. 19.

20.

comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients with previously treated soft tissue sarcoma: a Spanish Group for Research on Sarcomas study. J Clin Oncol. 2011;29:2528–2533. Tap WD, Jones RL, Van Tine BA, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016;388:488-497. Mack LA, Crowe PJ, Yang JL, et al. Preoperative chemoradiotherapy (modified Eilber protocol) provides maximum local control and minimal morbidity in patients with soft tissue sarcoma. Ann Surg Oncol. 2005;12:646–653. Antman KH, Elias A. Dana-Farber Cancer Institute studies in advanced sarcoma. Semin Oncol. 1990;1(Suppl 2):7–15. Petrioli R, Coratti A, Correale P, et al. Adjuvant epirubicin with or without Ifosfamide for adult soft-tissue sarcoma. Am J Clin Oncol. 2002;25:468–473. Judson I, Radford J, Harris M, et al. Randomized phase II trial of pegylated liposomal doxorubicin versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2001; 37:870–877. Talbot SM, Keohan ML, Hesdorffer M, et al. A Phase II trial of temozolomide in patients with unresectable or metastatic soft tissue sarcoma. Cancer. 2003; 98:1942–1946.

21. Kuttesch JF Jr, Krailo MD, Madden T, et al. Phase II evaluation of intravenous vinorelbine (Navelbine) in recurrent or refractory pediatric malignancies: a Children’s Oncology Group study. Pediatr Blood Cancer. 2009; 53:590–593. 22. van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379:1879–1886. 23. Schöffski P, Ray-Coquard IL, Cioffi A, et al. Activity of eribulin mesylate in patients with soft-tissue sarcoma: a phase 2 study in four independent histological subtypes. Lancet Oncol. 2011;12(11):1045–1052. 24. Demetri GD, von Mehren M, Jones RL, et al. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. J Clin Oncol. 2015;33:1–8. 25. Kawai A, Araki N, Sugiura H, et al. Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study. Lancet Oncol. 2015;16(4):406–416. 26. Samuels BL, Chawla S, Patel S, et al. Clinical outcomes and safety with trabectedin therapy in patients with advanced soft tissue sarcomas following failure of prior chemotherapy: results of a worldwide expanded access program study. Ann Oncol. 2013;24(6):1703–1709. (Revised 2/2018) © 2018 by Haymarket Media, Inc.

uResources

for Sarcoma

RECENTLY FEATURED TOPICS INCLUDE: Hyperthermia Plus Chemotherapy Improves Survival in Soft Tissue Sarcoma The study was halted after the experimental arm showed significantly improved relapse-free and overall survival rates compared with the control. Nivolumab With Ipilimumab Promising for Pretreated Metastatic Sarcoma Previous research suggested that PD-1 and CTLA-4 checkpoint inhibition may be effective in this patient population regardless of PD-L1 status. Crizotinib May Be Safe, Effective for TFE3-Rearranged Alveolar Soft Part Sarcoma Patients in the MET+ cohort had a disease control rate of 90%, a 1-year progression-free survival rate of 37.5%, and a 1-year overall survival rate of 97.4%. Complete Resection of Metastatic Soft Tissue Sarcoma Associated With Improved Disease-Specific Survival Researchers attempted to determine factors associated with DSS after patients with metastatic disease undergo surgical resection. Olaratumab Monotherapy Benefits Patients With Soft Tissue Sarcoma Post-Chemotherapy Researchers presented olaratumab monotherapy subgroup results from a phase 2 trial of patients who were previously treated with olaratumab plus doxorubicin or doxorubicin alone.

To read more about recent FDA approvals, drug trials, and interviews with leading researchers visit www.CancerTherapyAdvisor.com/Sarcoma.

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