Cancer Therapy Advisor July/August 2018 Issue by Haymarket Media

JULY/AUGUST 2018 | VOL 4, ISSUE 6

30 FEATURE

Assessing Levels of ctDNA for Early-Stage Cancer Diagnosis A new form of liquid biopsy may offer early-stage diagnosis with a single affordable procedure. 32 Q&A

Looking to Broaden CMS Coverage for NGS Tests 35 IN THE CLINIC

Colon Cancer Screening: American Cancer Society Guideline Update 39 TREATMENT REGIMENS

Bladder Cancer  Non-Hodgkin Lymphoma: AIDS-Related B-Cell Lymphomas  Testicular Cancer

36 FACT SHEET Indoor Tanning and Cancer

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Headlines from the 2018 American Society of Clinical Oncology Annual Meeting Upfront NGS Is Faster, More Cost Effective in Metastatic NSCLC Personalized Management of Advanced Kidney Cancer New Therapeutic Directions in Prostate Cancer

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

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Headlines from the 2018 American Society of Clinical Oncology Annual Meeting

Upfront NGS Is Faster, More 24 Cost Effective in Metastatic NSCLC

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.

Management 25 Personalized of Advanced Kidney Cancer

New Therapeutic Directions in Prostate Cancer

CONTENTS 11

LATEST NEWS

FEATURE

Assessing Levels of ctDNA for Early-Stage Cancer Diagnosis Carlos Harrison

4 CANCER THERAPY ADVISOR | JULY/AUGUST 2018 | CancerTherapyAdvisor.com

Q&A

On the Web

Looking to Broaden CMS Coverage for NGS Tests

SKIN CANCER

Frank Luh, MD, and Yun Yen, MD

IN THE CLINIC

Colon Cancer Screening: American Cancer Society Guideline Update C. Andrew Kistler, MD, PharmD

FACT SHEET

Since next-generation sequencing reflex testing has been implemented, several cases of potentially actionable mutations have been identified. Andrea S. Blevins Primeau, PhD, MBA

Indoor Tanning and Cancer

NGS Adds Value by Detecting More Mutations Than PCR in Melanoma

Andrea S. Blevins Primeau, PhD, MBA

GENERAL ONCOLOGY

TREATMENT REGIMENS

Is Genomic Medicine Failing Minority Patients?

39 Bladder Cancer 44 Non-Hodgkin Lymphoma: AIDS-Related B-Cell Lymphomas 47 Testicular Cancer

Racial minorities are poorly represented in genomic research databases, raising important questions about who benefits from advances in precision oncology. Bryant Furlow

MULTIPLE MYELOMA

Value, Not Cost, Should Be Considered for Myeloma Treatment Physicians can serve as advocates for patients struggling to afford recommended treatments. Andrea S. Blevins Primeau, PhD, MBA

GENITOURINARY CANCER

Adding Gemcitabine at the Time of Resection Reduces Recurrence, Cost in Early-Stage Bladder Cancer The decrease in recurrence rates has a meaningful impact on the quality of life for patients. Carlos Harrison

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LATEST NEWS

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Metronomic Maintenance Therapy Significantly Improves Overall Survival in Rhabdomyosarcoma Adding maintenance therapy after completing standard therapy may lead to significantly improved rates of overall survival (OS) among patients with high-risk (HR) rhabdomyosarcoma (RMS), according to a presentation in the plenary session at the 2018 American Society of Clinical Oncology Annual Meeting. Although complete remission rates are high among patients with RMS, anywhere between 20% and 30% of these patients will relapse and have poor outcomes with salvage therapy. Researchers sought to determine if maintenance treatment with metronomic chemotherapy would improve survival outcomes. For this study, researchers enrolled 670 patients between the ages of 6 months and 21 years with nonmetastatic alveolar RMS (ARMS), or incompletely resected embryonal RMS (ERMS) in an unfavorable primary site and/or N1, in complete remission upon the completion of standard therapy (9 cycles of ifosfamide, vincristine, actinomycin D with or without doxorubicin, surgery, with or without radiotherapy). Patients were randomly assigned to stop all treatment (control arm) or receive maintenance therapy with intravenous (IV) vinorelbine 25 mg/m2 and oral cyclophosphamide 25 mg/m2. Of the 371 patients found to be eligible for the study, 186 were assigned to the control arm and 185 were assigned to the maintenance arm. Baseline clinical characteristics were well balanced between the 2 arms. After a median follow-up of 5 years among surviving patients, the 3-year event-free survival (EFS) was 78.4% (95% CI, 71.5-83.8) among patients receiving maintenance chemotherapy compared with 72.3% (95% CI, 65.078.3) among patients who discontinued treatment (P = .061). The 5-year OS rate was 87.3% (95% CI, 81.2-91.6) and 77.4% (95% CI, 70.1-83.1) among patients in the maintenance therapy arm and the control arm, respectively (P = .011). Grade 3 to 4 febrile neutropenia and neurotoxicity were observed in 25% and 1.1% of patients in the maintenance arm, respectively, but toxicity was noted to be manageable. The authors concluded that “the addition of maintenance after standard treatment significantly improves OS in HR RMS patients and support its inclusion in future European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) trials.”

Sunitinib May Eliminate the Need for Cytoreductive Nephrectomy in Metastatic Renal Cell Carcinoma Sunitinib monotherapy was not inferior to cytoreductive nephrectomy (CN) followed by sunitinib among patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC), according to data presented during the plenary session at the 2018 American Society of Clinical Oncology Annual Meeting.

Many studies have supported CN as the standard of care among patients with mRCC, which has led to its utilization in this capacity for more than 2 decades. The emergence and efficacy of targeted therapies, however, has called into question the conventional standard of using CN prior to sunitinib. In the phase 3 CARMENA study researchers randomly assigned 450 patients with synchronous mRCC amenable to CN, to receive sunitinib 50 mg after CN or sunitinib alone. Enrolled participants had clear cell histology, no evidence of

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brain metastases, acceptable organ function, and were eligible for sunitinib therapy. Among patients in the CN arm, 55.6% and 44.4% were categorized by the Memorial Sloan Kettering Cancer Center (MSKCC) risk groups as intermediate and poor risk, respectively, and 58.5% and 41.5% in the sunitinib alone arm were MSKCC intermediate and poor risk, respectively. After a median follow-up of 50.9 months there was a total of 326 deaths. Overall survival was not found to be inferior among patients who received sunitinib alone with 18.4 months compared with 13.9 months among patients who underwent CN before sunitinib (hazard ratio [HR], 0.89; 95% CI, 0.71-1.10). The median progression-free survival was 8.3 months among patients in the sunitinib alone arm versus 7.2 months among patients who received standard of care. The overall response rate was identical with 35.9% in both study arms. The authors concluded that “Sunitinib alone is not inferior to CN followed by sunitinib in synchronous mRCC both in intermediate and poor MSKCC risk groups. CN should not be anymore the standard of care when medical treatment is required.”

Mobile Technology Is Useful in Collecting Patient-Reported Outcomes Using mobile technology is a useful and realistic option for collecting patient-reported outcomes (PROs) in patients with cancer, according to findings presented at the 2018 American Society of Clinical Oncology Annual Meeting. In addition to collecting PROs through mobile technology, the researchers also developed novel emoji PRO scales and associations between PROs and wearable data. Between February 2017 and August 2017, researchers recruited 296 patients who had been diagnosed within the last 5 years with lymphoma, myeloma, brain cancer, pancreatic cancer, breast cancer, and ovarian cancer and who were expected to live longer than 6 months. All patients were given an Apple watch. Patients completed baseline and 12 subsequent weekly PROs, which included PROMIS physical function, fatigue, sleep, social/role function short forms and single-item linear analog self-assessment of quality of life, fatigue, and physical function. The patients were randomly assigned to one of three groups and completed the surveys via paper, iPhone, or

Apple Watch. Patients who completed the surveys digitally (via iPhone or Apple Watch) also completed an emoji mood scale and an emoji ordinal scale for physical, emotional, and overall QOL and researchers also collected data on the activity levels and assessed the relationship between PROs and patient activity levels. The data showed that patients wore their Apple Watch for an average of 9.8 hours per day and completed 4590 mean steps per day. The researchers were able to gather survey responses from an average of 77% of patients in the iPhone group and 60% of patients in the Apple Watch group. The findings indicated that completing more steps per day was associated with less fatigue and sleep disturbance and better global physical quality of life, physical function, and social function. Likewise, patients who had more minutes of exercise per day were associated with better global mental quality of life and sleep. Furthermore, the researchers used Spearman correlations and found strong associations between linear analog self-assessment and the emoji ordinal scale, which were -0.80 for fatigue, 0.70 for physical well-being, 0.68 for emotional well-being, and 0.75 for overall QOL (all P < .001). The researchers concluded that their methods were feasible and may be a promising solution to the challenge of collecting and measuring PROs.

Bevacizumab Plus Erlotinib May Be a New Standard of Care in Non-Small Cell Lung Cancer Bevacizumab plus erlotinib may be a new standard therapy among treatment-naive patients with epidermal growth factor receptor (EGFR)-mutation positive non-small cell lung cancer (NSCLC), according to data presented at the 2018 American Society of Clinical Oncology Annual Meeting. Monotherapy with EGFR-tyrosine kinase inhibitors (TKIs), such as afatinib, erlotinib, and gefitinib, have been explored as therapeutic options among patients with EGFR-positive NSCLC. Recent studies have explored the potential of combination therapy with EGFR-TKIs and VEGF-inhibitors for this patient population. In the phase 3 NEJ026 study, investigators randomly assigned 228 chemotherapy-naive patients to receive oral erlotinib 150 mg daily alone or with bevacizumab 15 mg/kg every 3 weeks. Patients’ EGFR-mutation statuses were monitored throughout the course of the study and a second-line therapy. The median follow-up time was 12.4 months. At the time of data cut-off, the median progression-free survival (PFS) by independent review was 16.9 months (95% CI, 14.2-21.0) among patients in the combination

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LATEST NEWS arm compared with 13.3 months among patients treated with erlotinib alone (hazard ratio [HR], 0.605; 95% CI, 0.417-0.877; P = .0157). PFS by investigator assessment was 16.6 vs 12.4 months among patients in the bevacizumab arm and erlotinib monotherapy arm, respectively [HR, 0.563; 95% CI, 0.394-0.804; P = .00057). Further subgroup analysis based on EGFR-mutation status showed that patients with exon19 deletion had a median PFS of 16.6 months when treated with bevacizumab plus erlotinib compared with 12.4 months among patients who received erlotinib alone (HR, 0.69; 95% CI, 0.41-1.16). Patients with exon21 L858R mutations had a median PFS of 17.4 months and 13.7 months when treated with combination or monotherapy, respectively (HR, 0.57; 95% CI, 0.33-0.97). Patients treated with bevacizumab and erlotinib had significantly higher rates of hemorrhage, proteinuria, and hypertension compared with erlotinib alone, but there were no other significant differences in toxicity profiles between the study arms. Five patients developed low-grade pneumonitis in the erlotinib arm, but no cases were reported in the bevacizumab arm. The authors concluded that “[bevacizumab plus erlotinib] demonstrated a significant prolongation of PFS and [was well tolerated]. This regimen is considered [the] new standard treatment in patients with EGFR-mutated NSCLC.”

PET/CT Accurately Localizes Recurrent Prostate Cancer Imaging with 68Ga-PSMA11 PET/CT is highly accurate in localizing recurrent prostate cancer (PCa), according to data presented at the 2018 American Society of Clinical Oncology Annual Meeting. In addition, salvage therapy guided by 68 Ga-PSMA11 PET/CT resulted in high biochemical response rates. In a phase 2/3 prospective trial conducted by Wolfgang Fendler, MD, and colleagues at the David Geffen School of Medicine at the University of California, Los Angeles, patients who experienced biochemical recurrence following radical prostatectomy (205 patients) or radiation therapy (45 patients) for PCa underwent 68Ga-PSMA11 PET/CT. Lesions were validated in 51% of PET/CT-positive patients by histopathology (33 patients), imaging (62 patients), and/or PSA after targeted radiation therapy (9 patients). PSA response following 68 Ga-PSMA11 PET/CT guided focal salvage therapy (surgery/ radiotherapy) was recorded for 23 of 25 patients.

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The positive predictive value (PPV) by histopathology was 85% on a patient base (primary endpoint). PPV as determined by any type of validation was 89% on a patient base and 91% on a region base. 68Ga-PSMA11PET/CT localized recurrent PCa in 197 (79%) of 250 patients. The rate varied by PSA (in ng/mL): 41% for PSA below 0.5; 66% for 0.5 to less than 1.0; 86% for 1.0 to less than 2.0; 96% for 2.0 to less than 5.0; and 99% for 5.0 ng/mL or higher. 8 Ga-PSMA11 PET/CT localized 35% of lesions in the prostate bed, 61% in the pelvis, 35% outside the pelvis, and 31% in bone. Following salvage therapy alone guided by 68Ga-PSMA11 PET/ CT, 18 patients (78%) had a PSA drop of 50% of more and 7 (30%) had a complete biochemical response (PSA undetectable).

Immune-Related Adverse Events During Anti-PD-1 Therapy May Increase Survival in Head and Neck Cancer Experiencing immune-related adverse events (irAEs) during the course of antiprogrammed death-receptor-1 (PD-1) therapy may be correlated with improved survival and response outcomes among patients with head and neck cancer (HNC), according to findings in poster presentation at the 2018 American Society of Clinical Oncology Annual Meeting. It is thought that immune competence may modify antitumor response with anti-PD-1 therapy. Researchers evaluated whether the development of irAEs — defined as any immune-mediated adverse effects — among patients with metastatic HNC who have failed platinum-based chemotherapy would be associated with improved outcomes. For this prospective study, investigators identified 114 patients unselected for PD-L1 status and treated them with anti-PD-1 therapy. Median follow-up was 8.9 months. Baseline characteristics, including PD-L1-positivity, were comparable between the two study arms. Overall, 59 irAEs occurred in 49 of 108 evaluable patients; 20 dermatologic, 15musculoskeletal, 14 endocrine, 6hepatic,2 ophthalmologic, and 1pulmonary and gastrointestinal irAEs were reported. Five patients (10.2%) experienced a grade 3 or higher irAE. The overall response rate (ORR) was 30.6% among patients who experienced irAEs compared with 12.3% among patients who did not develop any irAEs (P = .02). The median progression-free survival (PFS) was 6.9 months and 2.1 months among patients who were irAE-positive and negative, respectively (P = .0004), and the median overall survival (OS) was nearly doubled among patients who were irAE-positive (12.5 months vs 6.8 months; P = .007). A multivariable analysis revealed that the incidence of irAEs

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was independently associated with enhanced ORR (P = .03), PFS (P = .009), and OS (P = .003). The authors concluded that “the ability to develop irAEs may be an indicator of immune competence and determining patient immune competence more accurately may be clinically useful.”

Bosutinib May Be Effective As First-Line Therapy in Chronic Phase Chronic Myeloid Leukemia Bosutinib may lead to improved 2-year major molecular response (MMR) among patients with newly diagnosed chronic phase chronic myeloid leukemia (CP-CML) compared with imatinib, according to a presentation at the 2018 American Society of Clinical Oncology Annual Meeting. The ongoing phase 3BFOREstudy assessed the efficacy of first-line bosutinib 400 mg once daily — a dual Src/Abl tyrosine kinase inhibitor approved for newly diagnosed CP-CML and relapsed/refractory CML — versus imatinib 400 mg once daily. Researchers randomly assigned 536 patients to bosutinib or imatinib treatment arms, with a planned follow-up period of 5 years. The authors presented findings from the 24-month follow up. Results showed that patients treated with bosutinib had a higher MMR compared with imatinib after 12 months (46.6% vs 37.0%; P = .013). This effect persisted after 18 months (57.0% vs 47%; P = .0198), and even after 24 months (61.2% vs 50.7%; P = .015). The cumulative complete cytogenetic response rate (CCyR) was improved among patients in the bosutinib arm compared with imatinib at both 48 weeks (78% vs 66%, respectively) and 96 weeks (82% vs 76%, respectively). The cumulative incidence of MR4 in the bosutinib arm was 17% versus 10% in the imatinib arm after 48 weeks and was 34% versus 27% after 96 weeks (P = .0249). The cumulative incidence of MR4.5 in the bosutinib arm was 6% versus 3% in the imatinib arm after 48 weeks, and was 20% versus 15% after 96 weeks (P = .0542). The time to MMR and CCyR were longer in the imatinib arm compared with bosutinib at 24 months, which were consistent with findings reported at 12 months. There were 6 and 7 transformations to accelerated and blast phase CML among patients in the bosutinib and imatinib arms, respectively. Seventy-one percent of patients remained on bosutinib therapy after 24 months, and 66% of patients remained on imatinib therapy. Both study arms reported encouraging rates of overall survival, with 99.6% and 98.1% at 12 months in the bosutinib and imatinib

arms, respectively, and 99.2% and 97.0% at 24 months, respectively. The authors concluded that “at 24 [months], a higher MMR rate was maintained with bosutinib vs imatinib. The results support the use of bosutinib as first-line therapy for CP-CML.”

Lenalidomide Plus Rituximab May Be As Effective As Standard of Care in Follicular Lymphoma Lenalidomide plus rituximab may be as effective among patients with previously untreated symptomatic follicular lymphoma (FL) compared with standard immunochemotherapy, according to findings presented in an oral session at the 2018 American Society of Clinical Oncology Annual Meeting. The current standard of care for FL is rituximab plus chemotherapy induction followed by rituximab. Previous studies however, have shown that rituximab plus lenalidomide may not only be as effective but also may improve immune competence in this patient population. In the phase 3 RELEVANCE study, researchers randomly assigned 1030 previously untreated patients with grade 1 to 3a FL to receive lenalidomide plus rituximab (experimental arm) or rituximab plus investigator’s choice-chemotherapy including CHOP, CVP, bendamustine (control arm); responding patients in both groups received rituximab maintenance therapy thereafter. Baseline characteristics were comparable between both study arms. After a median follow-up of 37.9 months, the superiority of the experimental arm to the standard-of-care could not be established. Independent review committee (IRC)-determined complete responses (CR/CRu) were 48% and 53% among patients in the experimental arm and control arm, respectively (P =.013), and investigator-assessed CR/CRu was 55% and 58%, respectively (P = .38). IRC and investigator review showed that there were no significant differences in the risk of disease progression in both study arms. The 2-year PFS rate was approximately 84% and ranged between 83% and 87% for the experimental arm and control arm, respectively. The 3-year PFS rate was 77% and 78%, respectively. The two study groups presented with different safety profiles; patients in the control arm reported higher rates of grade 3 to 4 lab and febrile neutropenia compared with higher grade 3 to 4 cutaneous adverse events (AE) in the experimental arm. Secondary primary malignancies occurred in 7% and 9% of patients in the experimental and control arms, respectively, and both groups reported a 1% rate of grade 5 AEs. Sixty-nine percent of patients in the experimental group and 71% in the control group were able to complete treatment. ■

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VIEWPOINT

Upfront NGS Is Faster, More Cost Effective in Metastatic NSCLC LEAH LAWRENCE

The researchers argue that upfront next-generation sequencing should be the new standard of care.

se of upfront next-generation sequencing (NGS) to test for lung cancer-related gene changes at the time of diagnosis was more cost-effective and faster than testing for a single gene or a limited number of genes at a time, according to the results of a study that compared different types of genetic testing in metastatic non-small cell lung cancer (NSCLC).1 “Every patient with advanced or metastatic non-squamous NSCLC should undergo genetic biomarker testing to guide treatment, and I believe that using NGS is the fastest and most cost-efficient way to do that testing,” said Nathan A. Pennell, MD, PhD, co-director of the Cleveland Clinic Lung Cancer Program in Ohio. Several genes are known to be altered in NSCLC and some genes, such as EGFR, ALK, ROS1, and BRAF are actionable. Dr Pennell and colleagues created a decision analytic model for patients with newly diagnosed metastatic NSCLC to determine which gene testing approach was the most cost effective and efficient. In the study, patients underwent NGS with either sequential tests, exclusionary mutation testing for KRAS followed by sequential tests if KRAS was not mutated, a panel test looking for EGFR, ALK, ROS1 and BRAF, or upfront NGS. Using estimates of the number and age of people with metastatic NSCLC in the United States each year, the researchers estimated that for 1 million-member health plans, 2066 tests would be paid for under CMS and 156 would be paid for by commercial insurers. The model

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also incorporated time to receive results and total cost for test and rebiopsy. In this hypothetical model, estimated time to receive results was 2 weeks for NGS and panel testing; this was 2.7 and 2.8 weeks faster than exclusionary KRAS testing and sequential testing, respectively. Using CMS reimbursement, NGS resulted in a savings of almost $1.4 million compared with exclusionary testing, $1.5 million compared with sequential testing, and more than $2.1 million compared with panel testing. For commercial payers, NGS was the least expensive as well by almost $4,000 compared with exclusionary testing and more than $250,000 compared with panel testing. “NGS at the time of diagnosis to check for actionable genetic changes in patients with advanced NSCLC is the most time-, tissue-, and cost-efficient way to do molecular testing,” Dr Pennell told Cancer Therapy Advisor. “NGS simply provides the best value compared to the alternatives.” According to Dr Pennell, upfront NGS should be the standard of care “instead of single gene tests everywhere” and “payers should be willing to cover NGS testing because it’s the right thing for patients and for the health system as a whole.” He also noted that “patients will squamous cell carcinoma don’t usually need to have this done unless there are scenarios such as being young – under age 50 – or being never or very light smokers.” ■ Reference

1. Pennell NA et al. J Clin Oncol. 2018;36:(suppl; abstr 9031).

FEATURE

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Personalized Management of Advanced Kidney Cancer

MICHELLE DALTON, ELS

n the past decade, cancer research has delved into the biologic factors driving cancer growth — but while there have been impressive successes in finding novel and effective therapies, there has not been as much success in finding the biomarkers in renal cell carcinoma (RCC) that can successfully predict for response or clinical outcomes with specific agents. But that time is coming, according to experts. “Individualized care using predictive biomarkers is central to the treatment of other advanced malignancies,” according to Jeffrey Graham, MD, and coauthors of a recent article entitled “Personalized Management of Advanced Kidney Cancer,” which was published in the 2018 American Society of Clinical Oncology Educational Book.1 “The elucidation of predictive factors is an

Colored computed tomography scan of a diseased kidney. © SALISBURY DISTRICT HOSPITAL / SCIENCE SOURCE

The heterogeneity of kidney cancer makes each tumor unique and, thus, treatment decisions can be especially challenging.

unmet need in metastatic RCC and an area of active research.” The “biggest asset in targeted therapy” has been the improved efficacy, said Ulka Vaishampayan, MD, of the Karmanos Cancer Center in Detroit, Michigan, who was corresponding author of the article. “With newer agents, there is a broader application and better efficacy, a higher response rate, and, overall, we’re now hitting more targets within the tumor.” Prognostic Models The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model is “routinely used for prognostication in clinical practice,” the authors wrote; it identifies six variables as having prognostic significance.1 Since its initial validation, the model has also shown prognostic stratification in both secondand third-line settings, the authors noted.

Factors associated with a poor prognosis are key to tackling challenging cases, but equally important is identifying factors that do not influence outcomes, Dr Vaishampayan said. In metastatic RCC, age is one of those factors that should not automatically be used as an absolute contraindication to targeted therapy — overall comorbidity risk score should be considered, she said. Deferred Systemic Therapy RCC is a highly heterogeneous disease (with clear cell RCC comprising more than 75% of cases) and one that has a varying natural history. Biopsies in RCC tumors “may reveal only a minority of the genetic alterations within the entire tumor” and genomic differences can be noted within a single tumor as well as between primary and metastatic sites.1 For some patients with metastatic RCC, there seems to be a

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FEATURE

less aggressive and more indolent pattern of progression. Those patients may benefit from deferred systemic therapy with active surveillance, the authors noted. Localized therapy to sites of metastatic disease will continue to be an important component in the personalized management of RCC; these can include surgical resection, definitive radiotherapy, and other ablative procedures. However, the role of systemic therapy after complete resection of metastatic disease remains unclear. The role of nephrectomy in the presence of metastatic disease is also changing with contemporary effective therapy. For instance, at the 2018 American Society of Clinical Oncology Annual Meeting, the CARMENA study (a phase 3 randomized study of patients with metastatic RCC) showed median overall survival for people who received only the targeted therapy sunitinib was 18.4 months, which was noninferior when compared with 13.9 months for those who had surgery followed by sunitinib.2 “What this found is that for patients with metastatic disease that is progressing or [for those] who are symptomatic, we should not wait and perform surgery, but we should consider initiating systemic therapy first,” Dr Vaishampayan said. “We’ve been doing that for most of our patients who we thought were symptomatic from their cancer and would benefit from immediate systemic therapy, but that may not have been happening routinely. CARMENA demonstrates that clinicians should consider systemic therapy first in patients with bulky metastatic disease so the nephrectomy time and procedure does not compromise patient care.” “Big Advances” Undoubtedly, the “big advance” in treating RCC has been immunotherapy, Dr Vaishampayan said. “Immune checkpoint inhibitors have rapidly become a means to establish

long-term remission in patients with advanced kidney cancer,” she said. “We are also gradually fine-tuning what we considered routine therapy previously (nephrectomy for metastatic disease).” Kidney cancer is “somewhat unique” compared to other cancers in that regard, Dr Vaishampayan said. “Typically, once a solid tumor is metastatic it’s unusual to remove the primary,” she said. “But for kidney cancer we were still doing that based on randomized trial evidence that showed improved survival.” When these data were published more than a decade ago, there were limited systemic therapeutic options — and those that were available were ineffective. “Now that systemic therapy has remarkably improved accuracy, the need

treatment for your specific tumor. With this treatment, you’ll have a good chance of responding.’ What we don’t want is to give shotgun treatments and hope it works in only about 10% of the patient population.” At this point, however, these types of predictive treatment discussions are still preliminary, as “we are still fairly rudimentary in terms of biomarkers to help guide therapy,” Dr Vaishampayan said. “At this point, all we can really use are the validated clinical characteristics.” Studies are ongoing that may overcome what Dr Vaishampayan says is “currently not validated data to decide therapy.” “A single biomarker is not really going to be useful in kidney cancer,” Dr Vaishampayan explained. “Kidney cancer

“Immune checkpoint inhibitors have become a means to establish long-term remission in patients with advanced kidney cancer.” for surgery has dissipated somewhat. In fact, sometimes the surgery can stand in the way or delay the more effective systemic therapies that the patient needs,” Dr Vaishampayan said. An Ideal World To truly create personalized management in advanced kidney cancer, “it will be critical to … [take] into consideration both tumor and patient characteristics to develop a tailored treatment plan,” the authors wrote.1 Using identified molecular markers as biomarkers, coupled with novel platforms such as circulating tumor DNA analysis, will continue to improve the possibilities for personalized medicine. “In an ideal world, that is what you want,” Dr Vaishampayan said. “You want to be able to say to a patient, ‘This is the

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is too heterogeneous a disease. Finding one biomarker that defines treatment response is uncommon. We may see single-marker tumors in leukemia or hematologic malignancies, but in solid tumors, it is unlikely [single markers] will be the driving force.” A more realistic view is that there may be a panel of 10 to 20 genomic markers. More likely than not, future treatment of kidney cancer will require “a combination of clinical and biologic approaches to fully realize the potential of precision oncology.” ■ References

1. Graham J et al. Am Soc Clin Oncol Educ Book. 2018;38:330-341. doi: 10.1200/EDBK_201215 2. Mejean A et al. J Clin Oncol. 2018:36: (suppl; abstr LBA3).

FEATURE

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New Therapeutic Directions in Prostate Cancer SUSAN JENKS

fforts to unravel prostate cancer’s genetic fingerprints lag behind other cancers, notably breast cancer, experts agree. But, mutations seen in the DNA-repair genes of men with advanced disease have emerged as promising therapeutic targets that may close that gap. Earlier this year, in fact, the National Comprehensive Cancer Network (NCCN) updated its clinical practice guidelines for prostate cancer, recommending doctors consider testing for inherited mutations in DNA-repair genes, such as BRCA1 and BRCA2, in men classified as “high risk, very high risk, regional, or metastatic.”1 The NCCN also recommends that doctors consider testing men with prostate cancer who have strong family histories of this disease, including brothers or fathers diagnosed with the illness before age 60. The recommendations stem, at least in part, from a pivotal 2016 study in The New England Journal of Medicine, which found that nearly 12% of men with prostate cancer harbored one of these genetic errors, as did 6% of men with localized, high-risk prostate cancer and 2% with low-to-intermediate risk.2 “We’re at the point where the data support the idea that there’s a meaningful subset of patients with these targetable mutations,” says Ravi Madan, MD, clinical director of the genitourinary malignancies branch at the National Cancer Institute in Bethesda, Maryland.

According to experts, PARP inhibition, radiopharmaceuticals, and immunotherapy could revolutionize how prostate cancer is treated in the coming decade.

When to do testing, however — early in the disease, or after frontline therapy — remains an open question, he says. For now, most of the advances in the treatment of prostate cancer have come from targeting the hormonal drivers of this systemic disease, according to Dr Madan and others. And genomic testing, increasingly done at diagnosis, may not measure errors in DNA-repair genes — but it can capture the presence of some point mutations, which could help guide treatment decisions in newly diagnosed patients. The American Cancer Society estimates that there will be nearly 165,000 new cases of prostate cancer in the United States in 2018.3 Although research has shown that most men diagnosed with this disease die from other causes, prostate cancer is the second-leading cause of death in men (behind lung cancer), with approximately 29,430 deaths expected this year. Hormonal strategies physicians use to battle these often slow-growing cancers include blocking or suppressing androgens in the testicles, or when that no longer works, blocking receptors on cancer cells with next-generation drugs, such as enzalutamide or apalutamide.4 Another drug that is now undergoing widespread testing, abiraterone acetate, blocks an enzyme that acts as a secondary source of androgen production, which investigators suspect comes from the cancer cells themselves and fuels further growth. Although these strategies represent the most effective therapies in the clinic

CancerTherapyAdvisor.com | JULY/AUGUST 2018 | CANCER THERAPY ADVISOR 27

FOCUS ASCO 2018

FEATURE

today, Dr Madan says, PARP inhibition, radiopharmaceuticals, and immunotherapy could revolutionize how prostate cancer is treated in the coming decade. In a recent article entitled “The Winds of Change: Emerging Therapeutics in Prostate Cancer,” Dr Madan and researchers from Monash University in Melbourne, Australia, focused on these evolving fields, especially in advanced disease, when survival statistics are most grim.5 The paper was published in the 2018 American Society of Clinical Oncology Educational Book ahead of the society’s June 2018 meeting in Chicago. PARP inhibitors, which interfere with an enzyme that allows cancer cells to survive DNA damage, are being evaluated in many ongoing clinical trials, investigators say — sometimes as single agents, but more often in combination with other drugs or other approaches, such as checkpoint inhibitors or radiopharmaceuticals. Dr Madan credits a small phase 2 study of one PARP inhibitor, olaparib, with piquing interest in targeting DNA repair mutations in men facing late-stage prostate cancer (by the time of data cutoff, 35

Olaparib also showed promising results in a phase 2 study, presented at 2018 American Society of Clinical Oncology Annual Meeting, which combined the PARP inhibitor with the hormonal agent, abiraterone.7 The two drugs appear to work synergistically, says Sumit Shah, MD, MPH, clinical assistant professor of medicine at Stanford University Medical Center in Palo Alto, California. Although the men receiving combination therapy had no improvement in overall survival, they did see improvements in progression-free survival (PFS), with the combination group demonstrating a 14-month PFS, compared with 8 months for the men on abiraterone alone. “The most surprising effect is that the benefit was seen in all comers,” independent of whether they had mutations in DNA-repair pathways or not, Dr Shah said. That suggests the combination therapy may work well in a larger group of men in the future, perhaps even in early disease. Meanwhile, clinical trials involving checkpoint inhibitors have not yet shown the success in prostate cancer

PARP inhibitors, which interfere with an enzyme that allows cancer cells to survive DNA damage, are being evaluated. of the original 50 study participants [70%] had died).6 And 14 of the patients with aberrations in DNA-repair genes (predominantly BRCA1/2 or ATM mutations) had a significantly higher response rate to olaparib (P < .001). On the basis of these and other results, the US Food and Drug Administration granted breakthrough status to olaparib, Dr Madan noted. Phase 3 trials are expected to be completed soon.

that has been seen in other cancers, such as melanoma, kidney cancers, or lung cancers, among others. These are considered “hot” cancers, Dr Shah says, because they have tumor-infiltrating immune cells in their microenvironment, whereas “cold” tumors, such as those in prostate cancer, lack T-cell infiltration. (Checkpoint inhibitors work by blocking a mechanism that

28 CANCER THERAPY ADVISOR | JULY/AUGUST 2018 | CancerTherapyAdvisor.com

cancers use to pervert a normal immune response and escape detection by these cancer-fighting cells.) “In prostate cancer, there are several layers of immunosuppression,” in the tumor microenvironment, Dr Shah said, so in cold tumors, “we need to enhance the ability to recognize these tumors, and also to activate an immune response against them.” Therapeutic vaccines illustrate one way in which investigators are trying to heat up the immune system, turning malignancies from cold to hot. Unfortunately, he says, a large phase 3 trial with the PROSTVAC vaccine found no survival benefit over placebo in men with advanced disease, but researchers hope combination vaccine strategies will work better in the future.8 One of the more promising approaches on the horizon may prove to be radiopharmaceuticals, according to Dr Shah. Not only can these agents be used diagnostically, they can be used therapeutically, as well, with the potential to target metastatic disease with considerable precision, he says. Radium-223 (Xofigo), for example, has shown a slight survival advantage in a randomized phase 3 trial in men whose metastatic prostate cancer had spread to the bone.9 Newer imaging with improved sensitivity and specificity are expected to show broader activity in several clinical trials that are now under way. Ultimately, however, no matter what the “winds of change” may bring, all of these promising therapies need further study, investigators say. Where the biggest changes now exist in prostate cancer are in early disease, with oncologists’ growing ability to distinguish between lethal tumors and those that can be actively watched. “Prostate cancer is several different diseases with different genomic signatures that we’re just starting to figure out,” said Otis Brawley, MD, chief medical and

FEATURE scientific officer of the American Cancer Society in Atlanta, Georgia. Nevertheless, the number of actively watched men today attests to clinical progress. “It’s over 50% and approaching 60%,” Dr Brawley said, as genetic tests aid in predicting which tumors have the worst pathology. But, physicians who treat cancer also have gleaned insight into how these tumors behave from several large prevention trials over the years, he said. One of the largest, the landmark Prostate Cancer Prevention Trial, which began 25 years ago, has finally put to rest whether the hormone-blocking drug, finasteride, can reduce the risk of getting prostate cancer.9 The short answer from a long-term analysis, presented at the American Urological Association meeting in May, is “yes.” “We now know finasteride does not cause more aggressive disease because in the finasteride-treated arm, there was less cancer death,” Dr Brawley said,

though initial study results 15 years ago implicated a possible link. ■

FOCUS ASCO 2018

5. Pezaro CJ, Marciscano AE, Madan RA. The Winds of Change: Emerging Therapeutics in Prostate Cancer. Am Soc Clin Oncol Educ

Book. doi: 10.1200/EDBK_201295.

References

1. Mohler J, Bahnson R, Boston B et al. NCCN

6. Mateo, J, Carreira S, Sandhu S, et al. DNA-

clinical practice guidelines in oncology: Prostate

repair defects and olaparib in metastatic

cancer version 3.2018. J Natl Compr Canc Netw.

prostate Cancer. N Eng J Med. 2015. doi/

2010;8:162-200. doi: 10.6004/jnccn.2010.0012 2. Pritchard CC, Mateo J., Walsh MF et al.

full/10.1056/NEJMoa1506859 7. Clarke N, Wiechno PJ, Alekseev B, et al.

Inherited DNA-repair gene mutations in men

Olaparib combined with abiraterone in

with metastatic prostate cancer. N Engl J Med.

patients with metastatic castration-resistent

2016;375:443-453.

prostate cancer: A randomized phase II trial. J

3. American Cancer Society. Key Statistics for Prostate Cancer. https://www.cancer.org/

Clin Oncol. 2018;36 (suppl; abstr 5003). 8. Gulley J, Borre M, Vogelzang N. Prospect: A

cancer/prostate-cancer/about/key-statistics.

randomized phase 3 trial of PROSTVAC-V/F

html. Published January 4, 2018. Accessed

in men with asymptomatic or minimally

June 27, 2018.

symptomatic metastatic castration-re-

4. FDA approves new treatment for certain

sistant prostate cancer. J Clin Oncol.

type of prostate cancer using novel clini-

36, 2018;33:15(suppl). doi: 10.1200/

cal trial endpoint [press release]. https:// www.fda.gov/NewsEvents/Newsroom/

jco.2015.33.15_suppl.tps5081 9. Parker C, Nilsson S, Heinrich D, et al.

PressAnnouncements/ucm596768.htm.

Alpha emitter radium-223 and survival in

Published February 14, 2018. Accessed June

metastatic prostate cancer. N Engl J Med.

27, 2018.

2013;369:213-223.

Oncology Meeting Coverage To read Cancer Therapy Advisor’s complete coverage of the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, including

interviews 25+ video with expert presenters and educational 60+ scientific presentations

Visit www.CancerTherapyAdvisor.com/asco2018

Additional research summaries featured online include: • High Tissue Tumor Mutational Burden May Be Predictive of Improved Immunotherapy Efficacy • Chemoradiotherapy Before Surgery May Improve Outcomes in Resectable Pancreatic Cancer • Bevacizumab Plus Erlotinib May Be a New Standard of Care in Non-Small Cell Lung Cancer

CancerTherapyAdvisor.com | JULY/AUGUST 2018 | CANCER THERAPY ADVISOR 29

FEATURE

Assessing Levels of ctDNA for Early-Stage Cancer Diagnosis

CARLOS HARRISON

growing number of studies have stirred widespread excitement about blood tests as a means of noninvasive cancer detection with the potential for identifying personalized therapies and for assessing treatment response. Much of the published research focuses on circulating tumor DNA (ctDNA) found in patient blood samples, with the majority concentrating on the use of “liquid biopsy” tests in relation to advanced tumor stages. Detection of early-stage malignancies, however, have proven to be more elusive. “Several factors pose particular difficulties and challenges, including the lower frequency and volume of aberrations,” the authors of a recent review wrote, “potentially confounding

A new test is able to identify 8 different cancers by assessing levels of circulating proteins along with mutations in cell-free DNA. phenomena such as clonal expansions of non-tumorous tissues or the accumulation of cancer-associated mutations with age, and the incomplete insight into driver alterations.”1 In fact, they continued, “as cancer is caused by a sequential series of alterations in specific cancer genes that affect the function of certain pathways and usually takes several decades to develop, the vast majority of cancers are not detected in the first 90% of the cancers’ lifetimes.” A new form of liquid biopsy, though, appears to have overcome some of the major challenges of previous tests, offering the promise of early-stage diagnosis of multiple malignancies with a single affordable procedure. Unlike earlier studies which focused on tumor DNA found in blood samples to detect a specific form of cancer,

30 CANCER THERAPY ADVISOR | JULY/AUGUST 2018 | CancerTherapyAdvisor.com

the test developed by researchers from Johns Hopkins University in Baltimore, Maryland, was shown to be capable of identifying eight different cancers by assessing levels of circulating proteins along with mutations in cell-free DNA. “We applied this test, called CancerSEEK, to 1005 patients with nonmetastatic, clinically detected cancers of the ovary, liver, stomach, pancreas, esophagus, colorectum, lung, or breast. CancerSEEK tests were positive in a median of 70% of the eight cancer types,” the authors wrote.2 CancerSEEK also appears to have overcome a major concern for practitioners and patients by reducing false-positive results to a tiny fraction. “The specificity of CancerSEEK was greater than 99%: only 7 of 812 healthy controls scored positive,” they reported. And, they clarified, they took

FEATURE a conservative approach in identifying the 7 instances as false positives, but the possibility exists that the test found a cancer that had not yet been detected by traditional means. “Our study lays the conceptual and practical foundation for a single, multi-analyte blood test for cancers of many types,” the authors concluded. “We estimate the cost of the test to be less than $500, which is comparable or lower than other screening tests for single cancers, such as colonoscopy. The eight cancer types studied here account for 360,000 (60%) of the estimated cancer deaths in the United States in 2017, and their earlier detection could conceivably reduce deaths from these diseases.” Liquid biopsies have been the focus of intense research and, a group of experts impaneled by the American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) reported in March, “studies of multiple cancer types indicate that ctDNA analysis can identify the emergence of resistant mutations months earlier than standard radiologic studies, creating an opportunity to test whether changing therapy before clinical progression could improve outcomes.”3 Advances in genomic analysis have aided the progress of the blood tests, but several factors pose challenges. “Available evidence indicates that patients with early-stage cancers can harbor less than one mutant template molecule per milliliter of plasma,” the CancerSEEK paper’s authors stated, “which is often beyond the limit of detection of previously reported technologies that assess multiple mutations simultaneously. Yet another issue with liquid biopsies is the identification of the underlying tissue of origin. Because the same gene mutations drive multiple tumor types, liquid biopsies based on

genomic analysis alone generally cannot identify the anatomical location of the primary tumor.” Therefore, while the ASCO/CAP panel recognized the promising results of research thus far, they cautioned that blood tests based on ctDNA will require much more extensive and broad-based clinical trials before they can be used in routine practice. “There is no evidence of clinical utility and little evidence of clinical validity of ctDNA assays in early-stage cancer, treatment monitoring, or residual disease detection,” the authors said. “There is no evidence of clinical validity or clinical utility to suggest that ctDNA assays are useful for cancer screening, outside of a clinical trial.” However, as the National Cancer Institute said in an article on its website last November, “There has been a recent surge of research related to liquid biopsy tests that analyze tumor DNA in blood, called circulating tumor DNA (ctDNA), and several ctDNA-based liquid biopsy tests are in clinical development.”4

then a tumor biopsy should be performed to determine if the NSCLC mutations are present.” “Approvals of liquid biopsy tests make it possible to deliver highly individualized health care for patients,” Alberto Gutierrez, PhD, director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health in Silver Spring, Maryland, explained. “Liquid biopsies also have the potential to allow physicians to identify patients whose tumors have specific mutations in the least invasive way possible.” The accelerated pace of research is bringing new evidence supporting the use of liquid biopsies in a variety of ways and quickly addressing some of the concerns. As one of the members of the ASCO/CAP panel, Alexander Lazar, MD, PhD, FCAP, of the departments of pathology and genomic medicine at the University of Texas MD Anderson Cancer Center in Houston, said via email, “The field of liquid biopsies is moving very rapidly. Our comments in

Blood tests based on ctDNA will require much more extensive and broad-based clinical trials before use in routine practice. In fact, the U.S. Food and Drug Administration (FDA) gave approval to a blood-based cancer test for the first time just 2 years ago. The cobas EGFR Mutation Test v2 can detect epidermal growth factor receptor (EGFR) gene mutations in patients with non-smallcell lung cancer and help identify those who “may benefit from treatment with [erlotinib].”5 However, the FDA advised, “if such mutations are not detected in the blood,

the manuscript were based on the literature at the time we discussed and wrote the review — almost a year ago. Because of the excitement and work of many in this field, there is more published literature supporting the use of this approach. Using liquid biopsy results to determine therapy for a positive result is clinically feasible; if a mutation is present, acting upon it is reasonable. There is less certainty regarding clinical action Continued on page 34

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Q&A

Frank Luh, MD, and Yun Yen, MD

Looking to Broaden CMS Coverage for NGS Tests Perspectives on restricting payer coverage to FDA-approved tests and handling test validation and testing center accountability.

hough the establishment of the national coverage determination (NCD) by the Centers for Medicare & Medicaid Services (CMS) for next-generation sequencing (NGS) testing in Medicare has largely been seen as a positive step — or, at the very least, as a recognition of the importance of detecting genetic aberrations to inform cancer diagnosis and care — the policy as written could benefit from some improvements, according to Frank Luh, MD, CEO of the Sino-American Cancer Foundation in Temple City, California, and Yun Yen, MD, president of the Graduate Institute of Medical Informatics at Taipei Medical University in Taiwan. Drs Luh and Yen recently dissected the benefits and harms of the final ruling in a JAMA Oncology viewpoint article.1 Cancer Therapy Advisor asked Drs Luh and Yen to elaborate on their view about restricting payer coverage to FDAapproved tests, handling test validation and testing center accountability, and questions about precision medicine that CMS should consider in the future as it pushes toward further enhancing the clinical utility of genomic sequencing.

CANCER THERAPY ADVISOR (CTA): Do you think the restriction

to use FDA-approved NGS tests was meant to protect payers from being responsible for the cost of egregious sequencing? DRS LUH AND YEN: There is no doubt

that reigning health care costs is a priority for the United States. The US spends more per capita on health care than any other nation, substantially outpacing other high-income countries.1 However, despite high health care expenditure, the US performs poorly in areas such as health outcomes and health care coverage.2 It’s possible that restricting coverage to only FDA-approved NGS tests might control costs and improve price transparency. But I think there are broader issues to consider as to why the CMS policy focused solely on FDA-approved tests. First, providing coverage for tests only approved by the FDA ensures patient safety. Limiting coverage to FDA-approved tests ensures labs and academic centers adhere to the highest quality and safety standards established by one regulatory body. This also assures patients, providers, payers, and the marketplace that the test

32 CANCER THERAPY ADVISOR | JULY/AUGUST 2018 | CancerTherapyAdvisor.com

is reliably valid both clinically and analytically. Restricting use to FDA-approved NGS tests is not an absolute rule that must last forever. But it’s a good start. Second, the cost of sequencing a patient’s genome has decreased over time and is expected to drop even more. The National Human Genome Research Institute estimated that the total cost of obtaining a single human-genome sequence in 2001 was $95 million.3 Costs have subsequently dropped exponentially following a trajectory described as Moore’s Law, which predicts a reduction of cost by 50% every two years.4 The recent introduction of NGS technology has also improved efficiency, accuracy, and affordability of sequencing. While whole-genome sequencing remains expensive compared with current laboratory test standards, the National Academies of Science, Engineering, and Medicine projected that the cost to sequence will drop into the range of many routine clinical tests within a few years.5 A recent study that looked at the price of genomic sequencing found that estimates for a single genomic test ranged from $555 to $5,169 for whole-exome sequencing and from $1,906 to $24,801

Q&A for whole-genome sequencing.6 We do not suspect cost of sequencing was a factor in limiting coverage to only FDAapproved NGS tests. Finally, going back to the issue of centering all NGS tests [on] the FDA — it’s important to realize that translation of genomic testing in clinical practice is an ongoing process. It therefore makes sense to start a reimbursement framework that rests on tests validated by the FDA. Payer coverage may move away from the FDA in the future. But for now, it’s important to allow science, research, and data submitted to the FDA to guide regulatory policies. As we move forward to accrue and review new scientific evidence about clinical testing and technology, the FDA should work with private and public agencies on revisiting regulatory statutes related to NGS technology (whether it involves payer coverage, clinical validity, or access) and adjust accordingly. CTA: Are there labs or academic centers that use tests for evidence development incorrectly? In other words, how does test validation play into the use of nonFDA-approved tests or testing methods?

practice hinges on the ability to provide tests that can accurately detect variants associated with a specific disease or condition for screening, prognosis, and treatment purposes. Important steps to ensure that such tests reliably provide accurate, meaningful data include analytic validation, clinical validation, and clinical utility. Accordingly, validation standards play a key role in ensuring safety and efficacy of NGS testing for patient care. Standards also act as basic guidelines to ensure comparability between different test centers, allow the exchange of experimental data to accelerate the innovation process, and aid improvement of transferability, transparency, and reproducibility of results. Another important factor this question brings up is accountability. To accelerate discovery in precision medicine, all stakeholders involved in the delivery of patient care need to uphold trust and accountability. When participants and consumers submit their samples for genomic analysis, they need to be fully informed of the reasons for testing

CTA: Would unscrupulous testing centers ever be a concern should the CMS coverage condition to use an FDA-approved test be lifted? DRS LUH AND YEN: It would be sad

day for medicine if we had to imagine the emergence of unscrupulous testing centers that intentionally fail to provide safe reliable care to their patients. Precision medicine has come so far in recent years. We are only starting to see genomics being used to direct clinical decision-making. Advances in technology, therapeutics, and research are also starting to increase their contributions to health care. The March 2018 national coverage determination by CMS provides coverage for companion diagnostics that have approved indications by the FDA for patients with advanced cancer.8 Requiring FDA approval to meet eligibility for CMS coverage is one way to ensure testing centers conduct honest practice. I think there are other strate-

DRS LUH AND YEN: While I am not

Validation standards play a key role in ensuring safety and efficacy of next-generation sequencing testing for patient care.

aware of any lab or academic center that specifically used NGS tests with the intention of developing evidence that was not accurate or helpful to patients, your question does raise concerns about NGS testing and the importance of ensuring validation and accountability. (The recent [U.S. Securities and Exchange Commission] investigation and court ruling of the private biotechnology company, Theranos might have some relevancy, but this case does not apply entirely.)7 As mentioned, successful incorporation of genomic technology into clinical

as well as potential risks and benefits involved. Genetic testing companies that use genomic data for alternative research and development purposes on top of the test requested must be fully transparent with patients. Progress in precision medicine will increasingly depend on establishing and strengthening trust between patients and all health care providers. If patient trust is lost, research and development in genomic technology will not prosper.

gies that health care ought to consider to improve safety and patient engagement in NGS testing. First, education plays a key role. Informing patients, providers, insurers, and payers how NGS testing works, how it is validated, and what are questions users need to know will bring stakeholders closer together in improving value in health care. Second, all stakeholders — patients, providers, policy makers, regulators, research industries — should regularly hold open

CancerTherapyAdvisor.com | JULY/AUGUST 2018 | CANCER THERAPY ADVISOR 33

Q&A dialogues about current advances, challenges, and problems in the precision medicine landscape. The current CMS policy is a step forward, but it also opens broader questions to consider — should FDA-approved tests be the only type of tests CMS ought to cover for Medicare beneficiaries? Although the current policy covers only a specific type of testing for a specific patient group, what about general coverage for other NGS tests and/or conditions in the future? Should similar provisions be created for other populations like Medicaid enrollees and uninsured patients? While we are not aware of any reports of unscrupulous NGS testing centers performing fraudulent activity, it is interesting to note the FDA’s recent role in other fields of medicine that are experiencing similar problems. In May 2018, the FDA sought permanent injunctions to stop two stem cell clinics from marketing stem cell products without FDA approval and for significant deviations from current good manufacturing practice requirements.9 The precision medicine community [should] consider these recent events as a warning signal if the industry fails to properly serve our patient community. Overall, we applaud CMS’ recent efforts to accelerate precision medicine

Feature Continued from page 31

on negative results, that is, not seeing a particular mutation. … However,” he continued, “with each study published we are learning how to better apply these tests effectively.” ■

into clinical care. We also recognize all stakeholders must consider emerging challenges and concerns involving NGS technology and public policy to truly improve health and societal outcomes. ■

sequencing. Int Neurourol J. 2016;20(suppl 2):S76-83. 6. National Research Council. Toward precision medicine: Building a knowledge network for biomedical research and a new taxonomy of disease. Washington, DC: The National

References

1. Luh F, Yen Y. Benefits and harms of the

Academies Press; 2011. 7. Schwarze K, Buchanan J, Taylor JC, et al.

Centers for Medicare & Medicaid Services

Are whole-exome and whole-genome

ruling on next-generation sequencing

sequencing approaches cost-effective?

[published online June 28, 2018].

A systematic review of the literature [Epub

JAMA Oncol.

ahead of print]. Genet Med. 2018.

2. Papanicolas I, Woskie LR, Jha AK. Health

8. U.S. Securities and Exchange Commission.

care spending in the United States and

Press release. Theranos, CEO Holmes, and

other high-income countries. JAMA.

Former President Balwani Charged with

2018;319(10):1024–1039.

Massive Fraud. Updated March 14, 2018.

3. Schneider EC, Sarnak DO, Squires D, et al. Mirror, mirror 2017: International comparison reflects flaws and opportunities for better

Accessed June 28, 2018. https://www.sec. gov/news/press-release/2018-41 9. U.S. Centers for Medicare & Medicaid

U.S. health care. Commonwealth Fund.

Services. CMS finalizes coverage of Next

https://www.commonwealthfund.org/

Generation Sequencing tests, ensuring

publications/fund-reports/2017/jul/

enhanced access for cancer patients.

mirror-mirror-2017-international-compar-

https://www.cms.gov/Newsroom/Media

ison-reflects-flaws-and. Updated July 14,

ReleaseDatabase/Press-releases/2018-

2017. Accessed June 28, 2018.

Press-releases-items/2018-03-16.html.

4. National Human Genome Research Institute. Cost of sequencing a genome. https:// www.genome.gov/27541954/dna-sequenc-

Updated March 16, 2018. Accessed June 28, 2018. 10. U.S. Food and Drug Administration. Press

ing-costs-data/. Updated April 25, 2018.

release. FDA seeks permanent injunctions

Accessed June 28, 2018.

against two stem cell clinics. https://bit.

5. Park ST, Kim J. Trends in next-generation sequencing and a new era for whole genome

2017;1:36. doi: 10.1038/s41698-017-0039-5 2. Cohen JD, Li L, Wang Y, et al. Detection and

ly/2L7Fo9o. Updated May 9, 2018. Accessed June 28, 2018.

4. National Cancer Institute. Liquid Biopsy: Using DNA in Blood to Detect, Track, and

localization of surgically resectable cancers

Treat Cancer. https://www.cancer.gov/news-

with a multi-analyte blood test. Science.

events/cancer-currents-blog/2017/liquid-

2018; 359:926-930. doi: 10.1126/science.

biopsy-detects-treats-cancer. Published

aar3247 3. Merker JD, Oxnard, GR, Compton C,

November 8, 2017. Accessed June 19, 2018. 5. Food and Drug Administration. FDA News

et al. Circulating tumor DNA analysis in

Release, FDA approves first blood test to detect

patients with cancer: American Society of

gene mutation associated with non-small cell

References

Clinical Oncology and College of American

lung cancer. https://www.fda.gov/NewsEvents/

1. Heitzer E, Perakis S, Geigl JB, Speicher

Pathologists Joint Review {Published online

Newsroom/PressAnnouncements/

MR. The potential of liquid biopsies for the

March 5, 2018]. Arch Pathol Lab Med. doi:

ucm504488.htm. Published June 1, 2016.

early detection of cancer. NPJ Precis Oncol.

10.5858/arpa.2018-0901-SA

Accessed June 19, 2018.

34 CANCER THERAPY ADVISOR | JULY/AUGUST 2018 | CancerTherapyAdvisor.com

IN THE CLINIC

Changes were made based on an increase in the incidence of colorectal cancer in younger people. C. ANDREW KISTLER, MD, PharmD

ecently, the American Cancer Society (ACS) revised their colorectal cancer (CRC) screening guideline and recommended that people at average risk for CRC undergo screening starting at age 45.1 This represents a change from the prior ACS guidelines, which recommended screening at age 50 for people at average risk for CRC. This change was a result of the increasing CRC incidence in younger people, modeling analyses supporting a benefit to starting screening earlier with an expected drop in CRC incidence and mortality. To develop this new guideline, the ACS used published systematic reviews and clinical studies, modeling studies, and a panel of experts to perform a detailed review of all of the potential benefits and risks of any recommendations they planned to propose. The recommendation to lower the testing age to 45 years was based on the increasing CRC incidence in adults younger than 50 years.2,3,4 Despite there being a steady decline in the incidence of CRC in people 50 years and older, there has been a dramatic 51% increase in CRC incidence in patients younger than 50 years since 1994.4 Interestingly, there has also been evidence to support an increase in the prevalence of polyps 9 mm or larger in people younger than 50 years.5 Therefore, earlier removal of these larger,

more “high-risk” polyps could help reduce the risk of CRC in the future. As starting CRC screening for all patients at age 45 years would represent a relatively new trend, there is a dearth of data available to review the potential benefits of this strategy. Therefore, several modeling analyses were performed during the development of the ACS guideline that predicted a significant benefit and an expected reduction in CRC incidence and mortality. The model calculated that a colonoscopy every 10 years for patients aged 45 to 75 years had 6.2% life-years gained (LYG) and 17% more colonoscopies per 1000 adults over a lifetime of screening compared with the

traditional model, which specifies testing every 10 years from ages 50 to 75 years.1 It is too soon to predict how the ACS recommendations will fully impact CRC screening, but several key points should be considered moving forward. It is currently unclear whether or not insurance companies will begin to cover CRC screening tests for average-risk people between the ages of 45 to 49 years based on this guideline. Therefore, it would be advisable that the health care practitioner contact the patient’s insurance provider prior to undergoing a screening test to avoid potentially high costs (or advise the patient to do so). Assuming structural tests will be covered by insurance for this age range, the access to facilities and physicians that perform them could become a concern, though there have been preliminary studies suggesting that access to colonoscopies should not be an issue in the United States.6 It will also be interesting to see how the other societies, such as the American College of Gastroenterology (ACG), American Gastroenterological Association (AGA), and United States Preventive Services Task Force (USPSTF) react to the ACS Continued on page 38

New guidance recommends screening to begin at age 45.

CancerTherapyAdvisor.com | JULY/AUGUST 2018 | CANCER THERAPY ADVISOR 35

Colon Cancer Screening: American Cancer Society Guideline Update

FACT SHEET

Enhance Your Patients’ Education

Indoor Tanning and Cancer ANDREA S. BLEVINS PRIMEAU, PhD, MBA

ndoor tanning is a popular practice, particularly by adolescent and young women, that results in high levels of ultraviolet (UV) A and B exposure.1 UVA and UVB are both known to induce DNA damage, specifically C to T point mutations. Though many patients believe that sunburn is associated with skin damage, DNA mutations have been shown to occur even before sunburn develops. In addition, a popular reason that individuals use indoor tanning is to create a “base tan” that prevents sunburn or reduces their risk of skin cancer with outdoor sun exposure. However, a population-based case-control study demonstrated that indoor tanning neither prevents subsequent sunburn nor confers protection against skin cancer, and it increases the risk of melanoma regardless of whether individuals develop a sunburn as a result of outdoor sun exposure.2

cancer, the data are somewhat mixed and are based on primarily poor-quality epidemiologic studies. Melanoma u Several meta-analyses of epidemiologic studies suggest an association between indoor tanning and an increased risk of melanoma. The IARC meta-analysis conducted in 2006 included 19 case-control, cohort, or cross-sectional studies and found that “ever use” significantly increased the risk of melanoma compared with “never use” (summary relative risk [SRR], 1.15; 95% CI, 1.00-1.31), but did not find a dose-response relationship.6 However, most of the individual studies included in the analysis found no significant association. Another meta-analysis published in 2012 included 27 studies primarily from Europe (but also some from the United States and Australia) and found a significant association between ever use of indoor tanning beds and melanoma risk compared with never use (SRR, 1.20; 95% CI, 1.08-1.34).7 This analysis showed a dose-response of a 1.8% increase in melanoma risk for each year of tanning bed use. In addition, patients who initiated indoor tanning prior to age 35 demonstrated a greater risk of developing melanoma (SRR, 1.87; 95% CI, 1.41-2.48). u A meta-analysis published in 2014

u In2009, the World Health Organization’s

International Agency for Research on Cancer Working Group (IARC) classified UV-emitting tanning devices as carcinogenic to humans based on evidence from its meta-analysis.3 In 2014, the U.S. Food and Drug Administration (FDA) reclassified sunlamps, or UV-emitting tanning devices, from class 1 to class 2 (special controls) devices, and instituted special measures to ensure reasonable assurance of

safety.4 With this ruling, the FDA required that sunlamps display a visible black box warning that the product should not be used by individuals younger than age 18, and that the warning include information about contraindications in any consumer instructions or consumer-directed catalogs, specification sheets, descriptive brochures, and web pages.5 Though it seems well understood that indoor tanning is associated with skin

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included 31 studies with 14,956 cases and 233,106 controls and similarly demonstrated that indoor tanning bed use was significantly associated with an increased risk of melanoma (odds ratio [OR], 1.16; 95% CI, 1.05-1.28), including studies that enrolled patients from 2000 onward (OR, 1.22; 95% CI, 1.03-1.45).8 Though the authors of these meta-analyses concluded that indoor tanning increases the risk of melanoma, authors of a more recent meta-analysis disagree.

FACT SHEET u This meta-analysis was published

in 2018 and included 31 case-control and cohort studies with 11,706 cases and 93,236 controls, which the authors deemed contained poor-quality data, similar to the findings of the prior meta-analyses.9 Ever use of indoor tanning beds was significantly associated with melanoma compared with never use (OR, 1.19; 95% CI, 1.04-1.35) and in studies conducted in the United States (OR, 1.32; 95% CI, 1.05-1.66) and Australia (OR, 1.30; 95% CI, 1.00-1.69), but not in Europe (OR, 1.10; 95% CI, 0.95-1.27) or among studies at low risk of bias (OR, 1.15; 95% CI, 0.94-1.41). The authors concluded that these data do not support the hypothesis of a causal link between indoor tanning and melanoma due to the moderate association demonstrated by studies of poor quality, such as lack of adjusting for potential confounders and recall bias. u A cohort study published in 2017 that was not included in the 2018 meta-analysis included 141,045 women from the Norwegian Women and Cancer Study, who were recruited between 1991 and 2012 and had a mean follow-up of 13.7 years.10 Ever use of indoor tanning was significantly associated with melanoma compared with never users (RR, 1.24; 95% CI, 1.05-1.46); similarly, current use increased the risk of melanoma compared with noncurrent use (RR, 1.27; 95% CI, 1.10-1.47). Though the risk was present regardless of age of initiation, women who began indoor tanning prior to age 30 were at a greater risk of developing melanoma compared with never users (RR, 1.34; 95% CI, 1.05-1.66).

This study also found a dose-response, with melanoma risk increasing with higher numbers of indoor tanning sessions. Indoor tanning also lowered the age of melanoma diagnosis. Melanoma was diagnosed a mean of 2.2 years earlier among women who started indoor tanning prior to 30 years of age and 1.2 years earlier among women who began indoor tanning at 30 years or older compared with never users. Non-Melanoma Skin Cancers u Indoor tanning has also been associated with non-melanoma skin cancers. A meta-analysis of 12 studies that included 80,661 participants found that ever use of indoor tanning was significantly associated with both squamous cell carcinoma (SCC; SRR, 1.67; 95% CI, 1.29-2.17) and basal cell carcinoma (BCC; SRR, 1.29; 95% CI, 1.08-1.53) compared with never users.11 The risk for BCC was highest among individuals who began indoor tanning before age 25 (SRR, 1.40; 95% CI, 1.29-1.52), but was not significant for SCC (SRR, 2.02; 95% CI, 0.70-5.86). u Since the meta-analysis, an analysis of 106,548 women from the NorwegianSwedish Women’s Lifestyle and Health Cohort study with a mean follow-up of 17.9 years demonstrated a significant increase in SCC with ever use of indoor tanning between ages 10 to 49 compared with never use (SRR, 1.93; 95% CI, 1.27-2.95).12 Similarly, a population-based case-control study conducted in the United States demonstrated that indoor tanning was associated with early-onset BCC (OR, 1.6; 95% CI, 1.3-2.1), with a stronger

All meta-analyses conducted to date show a significant association between indoor tanning and an increased risk of skin cancers.

association among individuals exposed as an adolescent or young adult.13 For each year of younger age at first exposure, the risk of BCC increased by 10% (OR per year of age ≤ 23, 1.1; 95% CI, 1.0-1.2). Other Cancers u An analysis of 73,358 women from the

Nurses’ Health Study II with a follow-up of 20 years found no association between indoor tanning and the risk of total cancer (hazard ratio [HR], 0.99; 95% CI, 0.951.04); or with internal cancers such as those of the breast, thyroid, and endometrium; or colorectal cancer and non-Hodgkin lymphoma (NHL).14 A case-control study in California, however, found an association with indoor tanning and cutaneous NHL, albeit with a very small sample size.15 In this study, indoor tanning was not associated with an increased risk of B-cell NHLs overall, but there was a nonsignificant increase in the risk of cutaneous NHL with indoor tanning use (OR, 1.77; 95% CI, 0.17-18.24). A sunburn with indoor tanning significantly increased the risk of cutaneous NHL (OR, 15.75; 95% CI, 2.56-96.87). Conclusions u All meta-analyses conducted to date show a significant association between indoor tanning use and an increased risk of melanoma or non-melanoma skin cancers. The risks appear to be highest for individuals who begin tanning at a younger age. It is important to consider that most studies in this space are considered low quality due to difficulties with adjusting for potential confounders and recall bias. However, the data are generally consistent across studies and are supported by the known mechanism of DNA damage caused by UV exposure. Therefore, the current data suggest that indoor tanning increases the risk of developing melanoma or non-melanoma skin cancers. ■

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FACT SHEET References

1. Woo DK, Eide MJ. Tanning beds, skin cancer,

6. The International Agency for Research on Cancer Working Group on artificial ultraviolet

11. Wehner MR, Shive ML, et al. Indoor tanning and non-melanoma skin cancer:

and vitamin D: An examination of the scien-

(UV) light and skin cancer. The association

Systematic review and meta-analysis. BMJ.

tific evidence and public health implications.

of use of sunbeds with cutaneous malignant

2012;345:e5909.

Dermatologic Ther. 2010;23:61-71.

melanoma and other skin cancers: A systemat-

2. Vogel RI, Ahmed RL, et al. Exposure to indoor tanning without burning and melanoma risk by sunburn history. J Natl Cancer Inst. 2014;106. 3. El Ghissassi F, Baan R, et al. A review of human carcinogens — Part D: Radiation. Lancet Oncol. 2009;10:751-752. 4. U.S. Food and Drug Administration, HSS. General and plastic surgery devices: Reclassification of ultraviolet lamps for tanning, henceforth to

12. Veierød MB, Cuoto E, et al. Host characteristics,

ic review. Int J Cancer. 2006;120:1116-1122.

sun exposure, indoor tanning and risk of squa-

7. Bunoil M, Autier P, et al. Cutaneous melanoma

mous cell carcinoma of the skin. Int J Cancer.

attributable to sunbed use: Systematic review

2014;135:413-422.

and meta-analysis. BMJ. 2012;345:e4757.

13. Karagas MR, Zens MS, et al. Early-onset basal

8. Colantonio S, Bracken MB, Beecker J. The

cell carcinoma and indoor tanning: A popula-

association of indoor tanning and melanoma in

tion-based study. Pediatrics. 2014;134:e4-e12.

adults: systematic review and meta-analysis.

14. Zhang M, Song F, Hunter DJ et al. Tanning

J Am Acad Dermatol. 2014;70:847:57.e1- e18.

bed use is not associated with internal

9. Burgard B, Schöpe J, et al. Solarium use and

be known as sunlamp products and ultraviolet

risk for malignant melanoma: Meta-analysis

lamps intended for use in sunlamp products.

and evidence-based medicine systematic

Final order. Fed Regist. 2014;79:31205-31214.

review. Anticancer Res. 2018;38:1187-1199.

5. U.S. Food and Drug Administration. General and

10. Ghiasvand R, Rueegg CS, et al. Indoor tanning

cancer risk: Evidence from a large cohort study. Cancer Epidemiol Biomarkers Prev. 2013;22:2425-2429. 15. Wang SS, Luo J, Cozen W, et al. Sun sensitivity, indoor tanning and B-cell non-Hodgkin

plastic surgery devices: Sunlamp products and

and melanoma risk: Long-term evidence from a

lymphoma risk among Caucasian women

ultraviolet lamps intended for use in sunlamp

prospective population-based cohort study. Am

in Los Angeles County. Br J Haematol.

products. Fed Regist. 2014;79:31213.

J Epidemiol. 2017;185:147-156.

2017;177:153-156.

In the Clinic Continued from page 35

guideline and whether or not they follow suit by lowering the screening age in their respective guidelines. Other key points from the recent ACS guideline include the definition of “average risk” persons as those without a family history of CRC, personal history of CRC or polyps, personal history of inflammatory bowel disease (Crohn’s disease or ulcerative colitis), a confirmed or potential hereditary CRC syndrome (eg, Lynch Syndrome), or a personal history of undergoing radiation to the abdomen or pelvis for prior cancer treatment. The ACS guidelines provide several options for CRC screening, including stool-based tests and structural examinations. Stool-based tests include fecal immunochemical test (FIT) every year, high-sensitivity guaiac-based fecal occult blood test every year, or multi-target

stool DNA test every 3 years. Structural exams include colonoscopy every 10 years, CT colonography every 5 years, or flexible sigmoidoscopy every 5 years. It is recommended that any “positive” test outside of colonoscopy is followed up with a colonoscopy. This is an important discussion point to have with the patient so that he or she understands all of the implications of the test. Additional age-specific recommendations from the ACS guideline update include continuing regular CRC screening through the age of 75 years as long as the person has a life expectancy of more than 10 years. The decision to continue screening between the ages of 76 and 85 years is based on many factors including life expectancy, patient preference, and the person’s overall health. ACS recommends against CRC screening in people older than 85. ■

Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society [published online May 30, 2018]. CA Cancer J Clin. doi: 10.3322/ caac.21457 2. O’Connell JB, Maggard MA, Liu JH, et al. Rates of colon and rectal cancers are increasing in young adults. Am Surg. 2003;69(10):866-872. 3. Bailey CE, Hu C-Y, You YN, et al. Increasing disparities in the age-related incidences of colon and rectal cancers in the Unites States, 1975-2010. JAMA Surg. 2015;150:17-22. 4. Siegel RL, Miller KD, Fedewa SA, et al. Colorectal cancer incidence patterns in the United States, 1974-2013. J Natl Cancer Inst. 2017;109(8). doi: 10.1093/jnci/djw322 5. Lieberman DA, Holub JL, Moravec MD, et al. Prevalence of colon polyps detected by colonoscopy screening in asymptomatic black and white patients. JAMA. 2008;300:1417-1422. 6. Joseph DA, Meester RG, Zauber AG, et al. Colorectal cancer screening: estimated future

References

colonoscopy need and current volume and

1. Wolf AMD, Fontham ETH, Church TR, et al.

capacity. Cancer. 2016;122:2479-2486.

38 CANCER THERAPY ADVISOR | JULY/AUGUST 2018 | CancerTherapyAdvisor.com

BLADDER CANCER

TREATMENT REGIMENS Bladder Cancer Treatment Regimens Clinical Trials: The National Comprehensive Cancer Network (NCCN) 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.

uPerioperative

Chemotherapy (Neoadjuvant or Adjuvant)1,a

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

REGIMEN

DOSING

Preferred Regimens Dose-dense methotrexate + vinblastine + doxorubicin + cisplatin (DDMVAC) with growth factor support2,3 Gemcitabine + cisplatin4–6

Day 1: Methotrexate 30mg/m2 IV Day 2: Vinblastine 3mg/m2 IV, plus doxorubicin 30mg/m2 IV, plus cisplatin 70mg/m2 IV Day 4: Granulocyte colony-stimulating factor (G-CSF) 240μg/m2 subcutaneous (SQ) injection for 7 consecutive days (days 4 through 10). May be extended for up to a total of 14 consecutive days. Repeat every 2 weeks for 3–4 cycles. Days 1, 8, and 15: Gemcitabine 1,000mg/m2 IV over 30–60 minutes Day 2: Cisplatin 70mg/m2. Repeat every 4 weeks for 4 cycles.

Other Recommended Regimens Cisplatin + methotrexate + vinblastine (CMV)7

Day 1: Methotrexate 30mg/m2 IV bolus plus vinblastine 4mg/m2 IV bolus Day 2: Cisplatin 100mg/m2 IV infusion; followed by hydration; followed by leucovorin 15mg orally or IV every 6 hours for 4 doses (commencing 24 hours after methotrexate on day 1) Day 8: Methotrexate 30mg/m2 IV bolus plus vinblastine 4mg/m2 IV bolus Day 9: Leucovorin 15mg orally every 6 hours for 4 doses after methotrexate on day 8. Repeat every 3 weeks for 3 cycles.

Principles of Chemotherapy Management • For patients who are not candidates for cisplatin, there are no data to support a recommendation for perioperative chemotherapy. • Randomized trials and meta-analyses show a survival benefit for cisplatin-based neoadjuvant chemotherapy (3 or 4 cycles) in patients with muscle-invasive bladder cancer.2,8,9 • Meta-analysis suggests a survival benefit to adjuvant therapy for pathologic T3, T4, or N+ disease at cystectomy.9 • Neoadjuvant chemotherapy is preferred over adjuvant-based chemotherapy on a higher level of evidence data. • DDMVAC is preferred over standard MVAC based on category I evidence showing DDMVAC to be better tolerated and more effective than conventional MVAC in advanced disease.3,10 Based on these data, the traditional dose and schedule for MVAC is no longer recommended. • Perioperative gemcitabine and cisplatin is a reasonable alternative to DDMVAC based on category I evidence showing equivalence to conventional MVAC in the setting of advanced disease.5,6 • For gemcitabine/cisplatin, both 21- and 28-day regimens are acceptable. Better dose compliance may be achieved with fewer delays in dosing using the 21-day schedule.11 • Neoadjuvant chemotherapy may be considered for select patients with upper tract urothelial carcinoma, particularly for higher stage and/or grade tumors, as renal function will decline after nephroureterectomy and may preclude adjuvant therapy. • Carboplatin should not be substituted for cisplatin in the perioperative setting. • For patients with borderline renal function or minimal dysfunction, a split-dose administration of cisplatin may be considered (such as 35mg/m2 on days 1 and 2 or days 1 and 8; category 2B). Although safer, the relative efficacy of the cisplatin-containing combination administered with such modifications remains undefined. • For patients with borderline renal function, estimate glomerular filtration rate to assess eligibility for cisplatin.

uFirst-Line

Systemic Therapy for Locally Advanced or Metastatic Disease (Stage IV)1,a

Cisplatin Eligible Preferred Regimens Gemcitabine + cisplatin (Category 1)6

Days 1, 8, and 15: Gemcitabine 1,000mg/m2 IV over 30–60 minutes continued

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BLADDER CANCER

TREATMENT REGIMENS Bladder Cancer Treatment Regimens uFirst-Line

Systemic Therapy for Locally Advanced or Metastatic Disease (Stage IV)1,a

(continued) REGIMEN

DOSING

Cisplatin Eligible (continued) Preferred Regimens (continued) Gemcitabine + cisplatin (Category 1)6 (continued)

Day 2: Cisplatin 70mg/m2. Repeat every 4 weeks for a maximum of 6 cycles.

DDMVAC with growth factor support (Category 1)3,10

Day 1: Methotrexate 30mg/m2 IV Day 2: Vinblastine 3mg/m2 IV, plus doxorubicin 30mg/m2 IV, plus cisplatin 70mg/m2 IV Day 4: G-CSF 240μg/m2 SQ injection for 7 consecutive days (days 4 through 10). May be extended for up to a total of 14 consecutive days. Repeat every 2 weeks for 3–4 cycles. OR Day 1: Methotrexate 30mg/m2 IV Day 2: Vinblastine 3mg/m2 IV, plus doxorubicin 30mg/m2 IV, plus cisplatin 70mg/m2 IV Day 3: G-CSF SQ injection for 5 consecutive days (days 3 through 7). Repeat cycle every 15 days.

Cisplatin Ineligible Preferred Regimens Gemcitabine + carboplatin12 Atezolizumab13 Pembrolizumab14

Days 1 and 8: Gemcitabine 1,000mg/m2 over 30 minutes IV Day 1 (every 3 weeks): Carboplatin (4.5 × [glomerular filtration rate + 25]) over 1 hour IV. Atezolizumab 1200mg IV infusion over 60 minutes every 3 weeks. Pembrolizumab 200mg every 3 weeks.

Other Recommended Regimens Gemcitabine15

Gemcitabine 1200mg/m2 administered weekly x3 on a 4-week cycle.

Gemcitabine + paclitaxel16

Gemcitabine 2500mg/m2 over 30 minutes, plus paclitaxel 150mg/m2 over 3 hours given every 2 weeks.

Useful Under Certain Circumstances Ifosfamide + doxorubicin + gemcitabine17 (For patients with good kidney function and good performance status)

Days 1–4: Ifosfamide 1500mg/m2 infused over 3 hours daily, plus MESNa 225mg/m2 over 15 minutes at hours 0, 3, 7, and 11 Day 3: Doxorubicin 45mg/m2 over 15 minutes via peripheral IV or up to 12–18 hours via central line on day 3 only Days 2 and 4: Gemcitabine 150mg/m2 over 30 minutes.

Principles of Chemotherapy Management • The presence of both non-nodal metastases and ECOG performance score >2 strongly predict poor outcome with chemotherapy. Patients without these adverse prognostic factors have the greatest benefit from chemotherapy. The impact of these factors in relation to immune checkpoint inhibition is not fully defined, but they remain poor prognostic indicators in general. • For most patients, the risks of adding paclitaxel to gemcitabine and cisplatin outweigh the limited benefit seen in the randomized trial.18 • A substantial proportion of patients cannot receive cisplatin-based chemotherapy due to renal impairment or other comorbidities. • Participation in clinical trials of new or more tolerable therapy is recommended.

uSubsequent

Systemic Therapy for Locally Advanced or Metastatic Disease (Stage IV) (Post-platinum)1,a

Preferred Regimens Pembrolizumab (Category 1)19

Pembrolizumab 200mg every 3 weeks.

Alternative Preferred Regimens Atezolizumab20

Atezolizumab 1200mg IV winfusion over 60 minutes every 3 weeks.

Nivolumab

Nivolumab 3mg/kg IV every 2 weeks.

Durvalumab22

Durvalumab 10mg/kg once every 2 weeks up to 12 months, unacceptable toxicity, or confirmed progressive disease.

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BLADDER CANCER

TREATMENT REGIMENS Bladder Cancer Treatment Regimens uSubsequent

Systemic Therapy for Locally Advanced or Metastatic Disease (Stage IV) (Post-platinum)1,a (continued)

REGIMEN

DOSING

Alternative Preferred Regimens (continued) Avelumab23,24

Avelumab 10mg/kg IV over 1 hour every 2 weeks.

Other Recommended Regimens Nab-paclitaxel28 Paclitaxel or docetaxel

Nab-paclitaxel at 260mg/m2 IV every 3 weeks. 25,26

Paclitaxel 80mg/m2 every week OR Docetaxel 100mg/m2 over 1 hour every 21 days.

Gemcitabine15

Gemcitabine 1200mg/m2 administered weekly x3 on a 4-week cycle.

Pemetrexed27

Day 1: Pemetrexed 500mg/m2 IV every 21 days, plus vitamin B12, folic acid, and dexamethasone prophylaxis.

Useful in Certain Circumstances Based on Prior Medical Therapy Ifosfamide29

Ifosfamide to 1,500mg/m2 IV with MESNa 750 mg/m2 IV for 5 days every 3 weeks, with doses modified for hematologic, renal, and central nervous system toxicity.

Methotrexate

Follow usual protocols.

Ifosfamide + doxorubicin + gemcitabine17

Gemcitabine + paclitaxel16

Gemcitabine 2500mg/m2 over 30 minutes, plus paclitaxel 150mg/m2 over 3 hours given every 2 weeks.

Gemcitabine + cisplatin

Days 1, 8, and 15: Gemcitabine 1,000mg/m2 IV over 30–60 minutes Day 2: Cisplatin 70mg/m2. Repeat every 4 weeks for a maximum of 6 cycles.

DDMVAC with growth factor support3

Day 1: Methotrexate 30mg/m2 IV Day 2: Vinblastine 3mg/m2 IV, plus doxorubicin 30mg/m2 IV, plus cisplatin 70mg/m2 IV Repeat every 2 weeks for 3–4 cycles.

uSubsequent

Systemic Therapy for Locally Advanced or Metastatic Disease (Stage IV) (Post-checkpoint inhibitor)

Cisplatin Ineligible Preferred Regimens Gemcitabine + carboplatin12

Days 1 and 8: Gemcitabine 1,000mg/m2 over 30 minutes IV Day 1 (every 3 weeks): Carboplatin (4.5 × [glomerular filtration rate + 25]) over 1 hour IV.

Cisplatin Eligible, Chemotherapy Naïve Preferred Regimens Gemcitabine + cisplatin6

Days 1, 8, and 15: Gemcitabine 1,000mg/m2 IV over 30–60 minutes Day 2: Cisplatin 70mg/m2. Repeat every 4 weeks for a maximum of 6 cycles.

DDMVAC + growth factor support3

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BLADDER CANCER

TREATMENT REGIMENS Bladder Cancer Treatment Regimens uSubsequent

Systemic Therapy for Locally Advanced or Metastatic Disease (Stage IV) (Post-checkpoint inhibitor) (continued)

REGIMEN

DOSING

Cisplatin Eligible, Chemotherapy Naïve (continued) Other Recommended Regimens Nab-paclitaxel28

Nab-paclitaxel at 260mg/m2 IV every 3 weeks.

Paclitaxel or docetaxel25,26

Paclitaxel 80mg/m2 every week OR Docetaxel 100mg/m2 over 1 hour every 21 days.

Gemcitabine15

Gemcitabine 1200mg/m2 administered weekly x3 on a 4-week cycle.

Pemetrexed

Day 1: Pemetrexed 500mg/m2 IV every 21 days, plus vitamin B12, folic acid, and dexamethasone prophylaxis.

Useful in Certain Circumstances Based on Prior Medical Therapy Ifosfamide29

Ifosfamide to 1,500mg/m2 IV with MESNa 750 mg/m2 IV for 5 days every 3 weeks, with doses modified for hematologic, renal, and central nervous system toxicity.

Methotrexate1

Follow usual protocols.

Ifosfamide + doxorubicin + gemcitabine17

Gemcitabine + paclitaxel16

Gemcitabine 2500mg/m2 over 30 minutes, plus paclitaxel 150mg/m2 over 3 hours given every 2 weeks.

uRadiosensitizing

Chemotherapy Regimens for Organ-Preserving Chemoradiation1,a,b

Preferred Regimens (Doublet Preferred) Cisplatinc + 5-FU30

Days 1, 2, 3, 15, 16, and 17: IV hydration at a rate of 500mL/hour; followed by 5-FU 400mg/m2 IV push; followed by cisplatin 15mg/m2 IV over 1 hour as induction and consolidation therapy.

Cisplatinc + paclitaxel30,31

Days 1, 8, and 15: Paclitaxel 50mg/m2 Day 1–3, 8–10, 15–17: Cisplatin 15mg/m2; followed by twice-daily radiotherapy for 8 days.f

5-FU + mitomycin32

Day 1 of radiotherapy: Mitomycin 12mg/m2 IV bolus, plus Week 1 (fractions 1–5) and Week 4 (fractions 16–20) of radiotherapy: 5-FU 500mg/m2 continuous IV infusion (10 days total).d

Other Recommended Regimens Low-dose gemcitabine (Category 2B)34,35

Gemcitabine 75mg/m2 IV weekly given concurrently with radiotherapy.

Cisplatin33,c

Cisplatin 100mg/m2 IV every 2 weeks for 3 cycles.

uRadiosensitizing

Chemotherapy With Conventionally Fractionated Radiation for Palliation of Metastases or Recurrence1,a,e

Preferred Regimens Cisplatinc Other Recommended Regimens Taxane (docetaxel or paclitaxel; Category 2B) 5-FU ± mitomycin (both Category 2B) Capecitabine (Category 3) Low-dose gemcitabine (Category 2B)

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BLADDER CANCER

TREATMENT REGIMENS Bladder Cancer Treatment Regimens c d

Participation in clinical trials of new agents is recommended. For bladder-preserving chemoradiation following a maximal transurethral resection of bladder tumor. Carboplatin in not an effective radiation sensitizer and should not be substituted for cisplatin with radiation. On days 1, 3, 15, and 17, radiation was given immediately following the chemotherapy using twice-a-day 3 Gy per fraction cores to the pelvis for a total radiation dose of 24 Gy (with at least a 4-hour interfraction interval). e For palliation of metastases or for pelvic recurrence after cystectomy. f Upon complete or near complete response, patients received consolidation chemoradiation consisting of 1.5 Gy pelvic radiotherapy twice a day for 8 days to 24 Gy (total dose: 64.3 Gy to the tumor and 44.8 Gy to the pelvic lymph nodes) and paclitaxel 50mg/m2 days 1 and 8 and cisplatin 15mg/m2 on days 1, 2, 8, and 9. a

References 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology™. Bladder Cancer. v 2.2018. Available at: http://www.nccn.org/professionals/ physician_gls/PDF/bladder.pdf. Accessed February 23, 2018. 2. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003; 349(9):859–866. 3. Sternberg CN, de Mulder PH, Schornagel JH, et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol. 2001;19(10):2638–2646. 4. Dash A, Pettus JA, Herr HW, et al. A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective experience. Cancer. 2008;113(9):2471–2477. 5. von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18(17):3068–3077. 6. von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005;23(21):4602–4608. 7. Griffiths G, Hall R, Sylvester R, et al. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011;29(16):2171–2177. 8. Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol. 2005;48(2):202–205. 9. Advanced Bladder Cancer (ABC) Meta-analysis Collaboration.Adjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis of individual patient data. Eur Urol. 2005;48(2):189–199. 10. Sternberg CN, de Mulder P, Schornagel JH, et al. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006;42(1):50–54. 11. Soto Parra H, Cavina R, Latteri F, et al. Three-week versus four-week schedule of cisplatin and gemcitabine: results of a randomized phase II study. Ann Oncol. 2002;13(7): 1080–1086. 12. De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012; 30(2):191–199. 13. Balar AV, Galsky MD, Rosenberg JE, et al; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67–76. 14. Balar AV, Castellano DE, O’Donnell PH, et al. Pembrolizumab as first-line therapy in cisplatin-ineligible advanced urothelial cancer: results from the total KEYNOTE-052 study population. J Clin Oncol. 2017;35(suppl 6):284–285. 15. Stadler WM, Kuzel T, Roth B, Raghavan D, Dorr FA. Phase II study of single-agent gemcitabine in previously untreated patients with metastatic urothelial cancer. J Clin Oncol. 1997;15(11):3394–3398. 16. Calabrò F, Lorusso V, Rosati G, et al. Gemcitabine and paclitaxel every 2 weeks in patients with previously untreated urothelial carcinoma. Cancer. 2009;115(12):2652–2659. 17. Siefker-Radtke A, Dinney C, Shen Y, et al. A phase II clinical trial of sequential neoadjuvant chemotherapy with ifosfamide, doxorubicin, and gemcitabine, followed by

18.

19. 20.

21. 22. 23.

24. 25. 26. 27. 28. 29. 30.

31. 32. 33. 34. 35.

cisplatin, gemcitabine, and ifosfamide in locally advanced urothelial cancer: final results. Cancer. 2013;119(3):10.1002/cncr.27751. Bellmunt J, von der Maase H, Mead GM, et al. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study 30987. J Clin Oncol. 2012;30(10):1107–1113. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376 (11):1015–1026. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909–1920. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312–322. Powles T, O’Donnell PH, Massard C, et al. Updated efficacy and tolerability of durvalumab in locally advanced or metastatic urothelial carcinoma. J Clin Oncol. 2017;35(suppl 6):286. Apolo AB, Infante JR, Balmanoukian A, et al. Avelumab, an anti–programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: results from a multicenter, phase 1b study. J Clin Oncol. 2017 Apr 4:JCO2016716795. doi: 10.1200/JCO.2016.71.6795. Patel MR, Ellerton JA, Infante JR, et al. Avelumab in patients with metastatic urothelial carcinoma: Pooled results from two cohorts of the phase 1b JAVELIN Solid Tumor trial. J Clin Oncol. 2017;35(suppl 6):330. Sideris S, Aoun F, Zanaty M, et al. Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in urothelial bladder cancer. Mol Clin Oncol. 2016;4(6):1063–1067. doi:10.3892/mco.2016.821. McCaffrey JA, Hilton S, Mazumdar M, et al. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997;15(5):1853–1857. Sweeney CJ, Roth BJ, Kabbinavar FF, et al. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol. 2006;24(21): 3451–3457. Ko YJ, Canil CM, Mukherjee SD, et al. Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, phase 2 study. Lancet Oncol. 2013;14(8):769–776. Witte RS, Elson P, Bono B, et al. Eastern Cooperative Oncology Group phase II trial of ifosfamide in the treatment of previously treated advanced urothelial carcinoma. J Clin Oncol. 1997;15(2):589–593. Mitin T, Hunt D, Shipley WU, et al. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013;14(9):863–872. Efstathiou JA, Spiegel DY, Shipley WU, et al. Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience. Eur Urol. 2012;61(4):705–711. James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012;366:1477–1488. Coppin CM, Gospodarowicz MK, James K, et al. Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. J Clin Oncol. 1996;14:2901–2907. Kent E, Sandler H, Montie J, et al. Combined-modality therapy with gemcitabine and radiotherapy as a bladder preservation strategy: results of a phase I trial. J Clin Oncol. 2004;22(13):2540–2545. Choudhury A, Swindell R, Logue JP, et al. Phase II study of conformal hypofractionated radiotherapy with concurrent gemcitabine in muscle-invasive bladder cancer. J Clin Oncol. 2011;29(6):733–738. (Revised 2/2018) © 2018 by Haymarket Media, Inc.

CancerTherapyAdvisor.com | JULY/AUGUST 2018 | CANCER THERAPY ADVISOR 43

NON-HODGKIN LYMPHOMA

TREATMENT REGIMENS AIDS-Related B-Cell Lymphomas 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.

uBurkitt

Lymphoma1,a,b,c

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

REGIMEN

DOSING

Preferred Regimens CODOX-M/IVAC (modified) (cyclophosphamide + vincristine + doxorubicin + high-dose methotrexate alternating with ifosfamide + etoposide + high-dose cytarabine)2–4

Day 1: Cyclophosphamide 800mg/m2 IV, followed by Days 2–5: Cyclophosphamide 200mg/m2 IV Day 1: Doxorubicin 40mg/m2 IV Days 1 and 8: Cycle 1: Vincristine 1.5mg/m2 IV; Cycle 2: Days 1, 8, and 15. Day 1: MTX 1,200mg/m2 IV over 1 hour, followed by 240mg/m2/hour over 23 hours. Days 1 and 3: Cytarabine 70mg intrathecally. Day 1: Rituximab 375mg/m2 IV. Day 15: MTX 12mg intrathecally. Alternate with: Days 1–5: Ifosfamide 1,500mg/m2 IV + etoposide 60mg/m2 IV Days 1 and 2: Cytarabine 2,000mg/m2 IV every 12 hours for 4 doses Day 1: Rituximab 375mg/m2 IV Day 15: MTX 12mg intrathecally.

Dose-adjusted EPOCH (etoposide + prednisone + vincristine + cyclophosphamide + doxorubicin) + rituximab6–8

Days 1–4: Etoposide 50mg/m2 IV + prednisone 60mg/m2 orally + vincristine 0.4mg/m2 IV + doxorubicin 10mg/m2 IV Day 1: Rituximab 375mg/m2 IV Day 5: Prednisone 60mg/m2 orally Day 5: Cycle 1: Cyclophosphamide 375mg/m2 IV if CD4 cells ≥100/mm3 OR 187mg/m2 IV if CD4 cells <100/mm3. Cyclophosphamide dose-adjustment (after Cycle 1): If nadir ANC >500/mcL, then increase by 187mg above previous cycle. If nadir ANC <500/mcL, or platelets <25,000/mcL, then decrease by 187mg below previous cycle. Repeat cycle every 3 weeks.

Other Recommended Regimens HyperCVAD (cyclophosphamide + vincristine + doxorubicin + dexamethasone alternating with high-dose methotrexate and cytarabine + rituximab)9–11

Cycles 1, 3, 5, and 7—HyperCVAD Days 1–3: Cyclophosphamide 300mg/m2 IV every 12 hours for 6 doses, plus mesna 600mg/m2 continuous IV Days 4 and 11: Vincristine 2mg IV Day 4: Doxorubicin 50mg/m2 IV. Days 1 and 11: Rituximab 375mg/m2 IV Days 1–4 and Days 11–14: Dexamethasone 40mg daily. Cycles 2, 4, 6, 8—High-dose MTX and Cytarabine Day 1: MTX 1g/m2 IV over 24 hours Days 2 and 3: Cytarabine 3g/m2 IV every 12 hours for 4 doses. Days 1 and 8: Rituximab 375mg/m2 IV Repeat every 3 weeks for 8 cycles.

44 CANCER THERAPY ADVISOR | JULY/AUGUST 2018 | CancerTherapyAdvisor.com

NON-HODGKIN LYMPHOMA

TREATMENT REGIMENS AIDS-Related B-Cell Lymphomas Treatment Regimens uDiffuse

large B-cell lymphoma (DLBCL), HHV8-positive DLBCL, NOS, and Primary Effusion Lymphoma1,a,b,c,d

REGIMEN

DOSING

Dose-adjusted EPOCH (etoposide + prednisone + vincristine + cyclophosphamide + doxorubicin) + rituximab (preferred)6–8

CHOP + rituximab12,13

Option 1—Modified CHOP Day 1: Cyclophosphamide 375mg/m2 IV + doxorubicin 25mg/m2 IV + vincristine 1.4mg/m2 IV (2mg maximum) Days 1–5: Prednisone 100mg orally Day 1: Rituximab 375mg/m2 IV. Repeat cycle every 3 weeks for at least 4 cycles, or for 2 cycles after complete response. Option 2—Standard-dose CHOP Day 1: Cyclophosphamide 750mg/m2 IV + doxorubicin 50mg/m2 IV + vincristine 1.4mg/m2 IV (2mg maximum) Days 1–5: Prednisone 100mg orally Day 1: Rituximab 375mg/m2 IV. Repeat cycle every 3 weeks for at least 4 cycles, or for 2 cycles after complete response.

uPlasmablastic

Lymphoma1,a,e,f,g

CODOX-M/IVAC (modified) (cyclophosphamide + vincristine + doxorubicin + high-dose methotrexate alternating with ifosfamide + etoposide + high-dose cytarabine)2–4

Dose-adjusted EPOCH (etoposide + prednisone + vincristine + cyclophosphamide + doxorubicin) (preferred)5

Days 1–4: Etoposide 50mg/m2 IV + prednisone 60mg/m2 orally + vincristine 0.4mg/m2 IV + doxorubicin 10mg/m2 IV Day 5: Prednisone 60mg/m2 orally Day 5: Cycle 1: Cyclophosphamide 375mg/m2 IV if CD4 cells ≥100/mm3 OR 187mg/m2 IV if CD4 cells <100/mm3. Cyclophosphamide dose-adjustment (after Cycle 1): If nadir ANC >500/mcL, then increase by 187mg above previous cycle. If nadir ANC <500/mcL, or platelets <25,000/mcL, then decrease by 187mg below previous cycle. Repeat cycle every 3 weeks.

HyperCVAD (cyclophosphamide + vincristine + doxorubicin + dexamethasone alternating with high-dose methotrexate and cytarabine)9–11

Cycles 1, 3, 5, and 7—HyperCVAD Days 1–3: Cyclophosphamide 300mg/m2 IV every 12 hours for 6 doses, plus mesna 600mg/m2 continuous IV Days 4 and 11: Vincristine 2mg IV Day 4: Doxorubicin 50mg/m2 IV. Days 1–4 and Days 11–14: Dexamethasone 40mg daily. Cycles 2, 4, 6, 8—High-dose MTX and Cytarabine Day 1: MTX 1g/m2 IV over 24 hours Days 2 and 3: Cytarabine 3g/m2 IV every 12 hours for 4 doses. Repeat every 3 weeks for 8 cycles. continued

CancerTherapyAdvisor.com | JULY/AUGUST 2018 | CANCER THERAPY ADVISOR 45

NON-HODGKIN LYMPHOMA

TREATMENT REGIMENS AIDS-Related B-Cell Lymphomas Treatment Regimens uPrimary

CNS Lymphoma1b

• Initiate ART (antiretroviral therapy), if not already receiving. • Even with poorly controlled HIV and/or marginal performance status, consider high-dose methotrexate. • Consider RT alone for palliation of patients who are not candidates for systemic therapy. • For select patients with good performance status on ART, see NCCN Guidelines for CNS cancers. • Best supportive care. a

b c

d e f g

Antiretrovirals (ARVs) can be administered safely with chemotherapy but consultation with an HIV specialist or pharmacist is important to optimize compatibility. With continued development of new ARVs, effective alternatives are often available to patients when the existing ARVs are expected to affect metabolism of or share toxicities with chemotherapy. In general, avoidance of zidovudine, cobicistat, and ritonavir is strongly recommended. Concurrent ART is associated with higher CR rates.14 Granulocyte colony-stimulating factor (GCSF) should be given to all patients. If CD4 <50, maximize supportive care. Rituximab and hyaluronidase human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion. This substitution cannot be made for rituximab used in combination with ibritumomab tiuxetan. If CD20 negative, rituximab is not indicated. Standard CHOP is not adequate therapy. Management can also apply to HIV-negative plasmablastic lymphoma. Consider high-dose therapy with autologous stem cell rescue in first complete remission in select high-risk patients.

References 1. NCCN Clinical Practice Guidelines in Oncology™. B-cell Lymphomas. v 2.2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed February 27, 2018. 2. Wang ES, Straus DJ, Teruya-Feldstein J, et al. Intensive chemotherapy with cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) for human immunodeficiency virus-associated Burkitt lymphoma. Cancer. 2003;98:1196–1205. 3. Barnes JA, LaCasce AS, Feng Y, et al. Evaluation of the addition of rituximab to CODOX-M/ IVAC for Burkitt’s lymphoma: A retrospective analysis. Ann Oncol. 2011;22:1859–1864. 4. Noy A, Kaplan L, Lee J, et al. Modified dose intensive R-CODOX-M/IVAC for HIV-associated Burkitt (BL) (AMC 048) shows efficacy and tolerability, and predictive potential of IRF4/MUM1 expression. Infectious Agents and Cancer. 2012;7:O14. 5. Little RF, Pittaluga S, Grant N, et al. Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. Blood. 2003;101:4653–4659. 6. Barta SK,Lee JY, Kaplan LD, et al. Pooled analysis of AIDS malignancy consortium trials evaluating rituximab plus CHOP or infusional EPOCH chemotherapy in HIV-associated non-Hodgkin lymphoma. Cancer. 2012;118:3977–3983. 7. Bayraktar UD, Ramos JC, Petrich A, et al. Outcome of patients with relapsed/ refractory acquired immune deficiency syndrome-related lymphoma diagnosed 1999-2008 and treated with curative intent in the AIDS Malignancy Consortium. Leuk Lymphoma. 2012;53:2383–2389.

8. Sparano JA, Lee JY, Kaplan LD, et al. Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma. Blood. 2010;115-:3008-3016. 9. Cortes J, Thomas D, Rios A, et al. Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone and highly active antiretroviral therapy for patients with acquired immunodeficiency syndrome-related Burkitt lymphoma/ leukemia. Cancer. 2002;94:1492–1499. 10. Thomas DA, Faderl S, O’Brien S, et al. Chemoimmunotherpy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer. 2006;106:1569–1580. 11. Thomas DA, Kantarjian HM, Faderl S, et al. Hyper-CVAD and rituximab for de novo Burkitt lymphoma/leukemia [abstract]. Blood. 2011;118:Abstract 2698. 12. Boue F. Gabarre J, Gisselbrecht C, et al. Phase II trial of CHOP plus rituximab in patients with HIV-associated non-Hodgkin’s lymphoma. J Clin Oncol. 2006;24:4123–4128. 13. Ribera JM, Oriol A, Morgades M, et al. Safety and efficacy of cyclophosphamide, adriamycin, vincristine, prednisone and rituximab in patients with human immunodeficiency virus-associated diffuse large B-cell lymphoma: results of a phase II trial. Br J Haematol. 2008;140:411–419. 14. Barta SK, Xue X, Wang D, et al. Treatment factors affecting outcomes in HIVassociated non-Hodgkin lymphomas: a pooled analysis of 1546 patients. Blood. 2013;122(19):3251–3262. (Revised 2/2018) © 2018 by Haymarket Media, Inc.

uResources

for Lymphoma

RECENTLY FEATURED TOPICS INCLUDE: Combined Modality Therapy May Be More Effective Than Radiotherapy Alone in Follicular Lymphoma IFRT followed by R-CVP improved progression-free survival and the rate of relapse outside of radiation fields among patients with follicular lymphoma compared with IFRT alone, according to a study published in the Journal of Clinical Oncology.

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

46 CANCER THERAPY ADVISOR | JULY/AUGUST 2018 | CancerTherapyAdvisor.com

TESTICULAR CANCER

TREATMENT REGIMENS Testicular 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.

uPrimary

Chemotherapy for Germ Cell Tumors1

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

REGIMEN

DOSING

Etoposide + cisplatin (EP)2,a

Days 1–5: Etoposide 100mg/m2 IV + cisplatin 20mg/m2 IV. Repeat cycle every 21 days. Days 1–5: Cisplatin 20mg/m2 IV + etoposide 100mg/m2 IV Days 1, 8, and 15 OR Days 2, 9, and 16: Bleomycin 30 units IV weekly. Repeat cycle every 21 days. Day 1 (before ifosfamide): Mesna 120mg/m2 by slow IV push Days 1–5: Etoposide 75mg/m2 IV + mesna 1,200mg/m2 continuous IV infusion + ifosfamide 1,200mg/m2 IV + cisplatin 20mg/m2. Repeat cycle every 21 days.

Bleomycin + etoposide + cisplatin (BEP)3 Etoposide + ifosfamide + cisplatin + mesna (VIP)4,b,c

uSecond-Line

Chemotherapy For Metastatic Germ Cell Tumors1

Conventional-dose Chemotherapy Regimens Vinblastine + ifosfamide + cisplatin + mesna (VeIP)5,c Paclitaxel + ifosfamide + mesna + cisplatin (TIP)6,c

Days 1–2: Vinblastine 0.11mg/kg IV push; plus Days 1–5: Ifosfamide 1,200mg/m2 IV + cisplatin 20mg/m2 IV + mesna 240mg/m2 IV over 15 minutes before ifosfamide, then at 4 and 8 hours from the start of each ifosfamide dose. Repeat cycle every 3 weeks. Day 1: Paclitaxel 250mg/m2 IV Days 2–5: Ifosfamide 1,500mg/m2 IV + cisplatin 25mg/m2 IV + mesna 300mg/m2 IV over 15 minutes before ifosfamide, then at 4 and 8 hours from the start of each ifosfamide dose. Repeat cycle every 3 weeks.

High-dose Chemotherapy Regimens Carboplatin + etoposide7

Carboplatin 700mg/m2 (body surface area) IV + etoposide 750mg/m2 IV. Administer 5, 4, and 3 days before peripheral blood stem cell infusion for 2 cycles.

Paclitaxel + ifosfamide + mesna + carboplatin + etoposide8

Day 1: Paclitaxel 200mg/m2 IV over 24 hours Days 2–4: Ifosfamide 2,000mg/m2 over 4 hours with mesna protection Repeat every 14 days for 2 cycles; followed by Days 1–3: Carboplatin AUC 7-8mg • min/mL IV over 60 minutes + etoposide 400mg/m2 IV. Administer with peripheral blood stem cell support at 14- to 21-day intervals for 3 cycles.

uThird-line

Chemotherapy For Metastatic Germ Cell Tumors1

Palliative Chemotherapy Regimens Gemcitabine + oxaliplatin9–11

Days 1 and 8: Gemcitabine 1,000mg/m2 IV, plus Day 1: Oxaliplatin 130mg/m2 IV Repeat cycle every 3 weeks. OR Days 1 and 8: Gemcitabine 1,250mg/m2 IV, plus Day 1: Oxaliplatin 130mg/m2 IV. Repeat cycle every 3 weeks. continued

CancerTherapyAdvisor.com | JULY/AUGUST 2018 | CANCER THERAPY ADVISOR 47

TESTICULAR CANCER

TREATMENT REGIMENS Testicular Cancer Treatment Regimens uThird-line

Chemotherapy For Metastatic Germ Cell Tumors1 (continued)

REGIMEN

DOSING

Palliative Chemotherapy Regimens (continued) Gemcitabine + paclitaxel12,13 Gemcitabine + paclitaxel + oxaliplatin14 Etoposlde15 Pembrolizumab (for MSI-H/dMMR tumors)16,17

Days 1, 8, and 15: Gemcitabine 1,000mg/m2 IV over 30 minutes + paclitaxel 100mg/m2 IV over 1 hour. Repeat every 4 weeks for a maximum of 6 cycles. Days 1 and 8: Gemcitabine 800mg/m2 IV + paclitaxel 80mg/m2 IV Day 1: Oxaliplatin 130mg/m2 IV. Repeat every 3 weeks for at least 2 cycles. Etoposlde 50mg/m2 orally daily until progression or toxicity. Day 1: Pembrolizumab 10mg/kg IV. Repeat cycle every 2 weeks.

Option only for good-risk patients, patients with pathologic stage II disease, and patients with viable germ cell tumors (GCT) at surgery following first-line chemotherapy. Option only for intermediate or poor-risk patients or patients with viable GCT at surgery following first-line chemotherapy. c These regimens are high risk for febrile neutropenia and granulocyte colony-stimulating factors (G-CSFs) should be used. a

References 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology™. Testicular Cancer. v 2.2018. Available at: http://www.nccn.org/professionals/ physician_gls/pdf/testicular.pdf. Accessed January 18, 2018. 2. Xiao H, Mazumdar M, Bajorin DF, et al. Long-term follow-up of patients with goodrisk germ cell tumors treated with etoposide and cisplatin. J Clin Oncol. 1997;15(7):2553–2558. 3. Saxman SB, Finch D, Gonin R, Einhorn LH. Long-term f ollow-up of a phase III study of three versus four cycles of bleomycin, etoposide, and cisplatin in favorable-prognosis germ-cell tumors: the Indiana University experience. J Clin Oncol. 1998;16(2):702–706. 4. Nichols CR, Catalano PJ, Crawford ED, et al. Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study. J Clin Oncol. 1998;16(4):1287–1293. 5. Loehrer PJ Sr, Lauer R, Roth BJ, et al. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med. 1988;109(7):540–546. Erratum in: Ann Intern Med. 1988;109(10):846. 6. Kondagunta GV, Bacik J, Donadio A, et al. Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed testicular germ cell tumors. J Clin Oncol. 2005;23(27):6549–6555. 7. Einhorn LH, Williams SD, Chamness A, et al. High-dose chemotherapy and stemcell rescue for metastatic germ-cell tumors. N Engl J Med. 2007;357(4):340–348. 8. Feldman DR, Sheinfeld J, Bajorin DF, et al. TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor analysis. J Clin Oncol. 2010; 28(10):1706–1713. Erratum in: J Clin Oncol. 2010; 28(34):5126. 9. Pectasides D, Pectasides M, Farmakis D, et al. Gemcitabine and oxaliplatin

10. 11. 12. 13. 14.

15. 16. 17.

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