John H. Strickler

Locally Advanced, Unresectable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline

PURPOSE To provide evidence-based recommendations to oncologists and others for treatment of patients with locally advanced, unresectable pancreatic cancer. METHODS American Society of Clinical Oncology convened an Expert Panel of medical oncology, radiation oncology, surgical oncology, gastroenterology, palliative care, and advocacy experts and conducted a systematic review of the literature from January 2002 to June 2015. Outcomes included overall survival, disease-free survival, progression-free survival, and adverse events. RESULTS Twenty-six randomized controlled trials met the systematic review criteria. RECOMMENDATIONS A multiphase computed tomography scan of the chest, abdomen, and pelvis should be performed. Baseline performance status and comorbidity profile should be evaluated. The goals of care, patient preferences, psychological status, support systems, and symptoms should guide decisions for treatments. A palliative care referral should occur at first visit. Initial systemic chemotherapy (6 months) with a combination regimen is recommended for most patients (for some patients radiation therapy may be offered up front) with Eastern Cooperative Oncology Group performance status 0 or 1 and a favorable comorbidity profile. There is no clear evidence to support one regimen over another. The gemcitabine-based combinations and treatments recommended in the metastatic setting (eg, fluorouracil, leucovorin, irinotecan, and oxaliplatin and gemcitabine plus nanoparticle albumin-bound paclitaxel) have not been evaluated in randomized controlled trials involving locally advanced, unresectable pancreatic cancer. If there is local disease progression after induction chemotherapy, without metastasis, then radiation therapy or stereotactic body radiotherapy may be offered also with an Eastern Cooperative Oncology Group performance status ≤ 2 and an adequate comorbidity profile. If there is stable disease after 6 months of induction chemotherapy but unacceptable toxicities, radiation therapy may be offered as an alternative. Patients with disease progression should be offered treatment per the ASCO Metastatic Pancreatic Cancer Treatment Guideline. Follow-up visits every 3 to 4 months are recommended. Additional information is available at www.asco.org/guidelines/LAPC and www.asco.org/guidelines/MetPC and www.asco.org/guidelineswiki.

Bevacizumab-Based Therapies in the First-Line Treatment of Metastatic Colorectal Cancer

Since its approval for the first-line treatment of metastatic colorectal cancer (mCRC), bevacizumab has become a standard treatment option in combination with chemotherapy for patients with mCRC. Bevacizumab has demonstrated efficacy in combination with a number of different backbone chemotherapy regimens, and its widespread use has introduced several important questions regarding the selection and optimization of bevacizumab-based treatment regimens, its use in various patient populations, and the identification of associated adverse events. This review discusses the results of several phase II and phase III clinical trials, as well as large observational studies, to address the use of bevacizumab in the treatment of patients with mCRC in the first-line setting.

Targeting BRAF in metastatic colorectal cancer: Maximizing molecular approaches

Oncogenic mutations in B-type Raf kinase (BRAF) occur in 7-10% of metastatic colorectal cancers (mCRC). Despite recent improvements in survival in the general population of patients with mCRC, patients with BRAF-mutant mCRC continue to have poor response to most systemic therapies, and prognosis remains poor. There is a substantial unmet need for novel therapeutic strategies to treat patients with BRAF-mutant mCRC. This review outlines the epidemiology, molecular pathogenesis, prognosis, and mechanisms of treatment resistance of BRAF-mutated CRC. Additionally, this review highlights novel therapeutic strategies aimed at enhancing response and improving outcomes.

Development of a Novel c-MET–Based CTC Detection Platform

Amplification of the MET oncogene is associated with poor prognosis, metastatic dissemination, and drug resistance in many malignancies. We developed a method to capture and characterize circulating tumor cells (CTC) expressing c-MET using a ferromagnetic antibody. Immunofluorescence was used to characterize cells for c-MET, DAPI, and pan-CK, excluding CD45+ leukocytes. The assay was validated using appropriate cell line controls spiked into peripheral blood collected from healthy volunteers (HV). In addition, peripheral blood was analyzed from patients with metastatic gastric, pancreatic, colorectal, bladder, renal, or prostate cancers. CTCs captured by c-MET were enumerated, and DNA FISH for MET amplification was performed. The approach was highly sensitive (80%) for MET-amplified cells, sensitive (40%–80%) for c-MET–overexpressed cells, and specific (100%) for both c-MET–negative cells and in 20 HVs. Of 52 patients with metastatic carcinomas tested, c-MET CTCs were captured in replicate samples from 3 patients [gastric, colorectal, and renal cell carcinoma (RCC)] with 6% prevalence. CTC FISH demonstrated that MET amplification in both gastric and colorectal cancer patients and trisomy 7 with gain of MET gene copies in the RCC patient. The c-MET CTC assay is a rapid, noninvasive, sensitive, and specific method for detecting MET-amplified tumor cells. CTCs with MET amplification can be detected in patients with gastric, colorectal, and renal cancers. Implications: This study developed a novel c-MET CTC assay for detecting c-MET CTCs in patients with MET amplification and warrants further investigation to determine its clinical applicability. Mol Cancer Res; 14(6); 539–47. ©2016 AACR.

Ascertainment, classification, and impact of neoplasm detection during prolonged treatment with dual antiplatelet therapy with prasugrel vs. clopidogrel following acute coronary syndrome

AIMS Studies have suggested increased cancer incidence associated with long-term dual antiplatelet therapy (DAPT) for acute coronary syndrome (ACS). We evaluated cancer incidence and treatment-related differences in an analysis of DAPT for ACS. METHODS AND RESULTS The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial enrolled 9326 participants with ACS, who received aspirin plus clopidogrel or prasugrel. Median treatment exposure was 15 months. Cancer history and screening procedures were collected. Suspected non-benign neoplasm events were reported and adjudicated. The primary outcome was detection of new, non-benign neoplasm. Factors associated with neoplasm events, the relationship of these events to cardiovascular and bleeding endpoints, and treatment-related differences in neoplasm detection were studied. Among 9240 participants who received ≥1 dose of study drug, 1.8% had a confirmed neoplasm event. The efficacy composite of cardiovascular death, myocardial infarction, or stroke occurred more frequently among those with a neoplasm event vs. those without (18.2 vs. 13.5%) as did Global Use of Strategies to Open Occluded Coronary Arteries severe/moderate bleeding (11.2 vs. 1.5%). Screening rates were substantially higher in North America and Western Europe/Scandinavia vs. other regions. Factors most strongly associated with detection of neoplasm events were older age, region, male sex, and current/recent smoking. Among the pre-specified population without a history of neoplasm or previous curative treatment for neoplasm (n = 9105), the incidence of neoplasm events was similar with prasugrel vs. clopidogrel (1.8 vs. 1.7%; HR = 1.04; 95% CI 0.77-1.42; P = 0.79). CONCLUSIONS Neoplasm events were infrequent during long-term DAPT after ACS, were associated with differential cancer-screening practices across regions, and the frequency of neoplasm detection was similar with prasugrel vs. clopidogrel. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00699998.

Palliative Treatment of Metastatic Colorectal Cancer: What is the Optimal Approach?

Worldwide, colorectal cancer (CRC) is responsible for over 600,000 deaths annually and remains a significant public health concern. Because of therapeutic advancements over the past two decades, patients with metastatic CRC are living longer with an improved quality of life. This review will highlight recent trial evidence that improves outcomes for patients with metastatic disease. Topics will include the optimal use of first-line combination chemotherapy, bevacizumab in patients with advanced age or comorbidities, maintenance chemotherapy, first-line use of anti-EGFR therapies, first-line cetuximab versus bevacizumab, anti-angiogenic therapies past progression, and management of treatment-refractory disease. Clinical trial evidence will be presented, along with guidance on how to integrate recent evidence into clinical practice. Finally, this review will examine innovative drug development strategies, and will discuss potentially actionable targets identified by molecular testing.

Maintenance Therapy for First-Line Metastatic Colorectal Cancer: Activity and Sustainability

The role of maintenance therapy for metastatic colorectal cancer is controversial. There are many biological and clinical questions around maintenance therapy and no single study can answer all of them. In addition, there is also likely some degree of semantic confusion around what is meant by maintenance therapy versus simply treatment to progression using whatever components of the initial regimen are tolerable. The MACRO (Maintenance in Colorectal Cancer) study team is to be congratulated on the conduct of the first of many “maintenance” studies that can be expected in the near future. The MACRO study was designed to compare standard capecitabine and oxaliplatin (XELOX) plus bevacizumab, adjusted as appropriate, until disease progression, with the same regimen for only six cycles followed by bevacizumab monotherapy [1]. The authors noted that, although the study did not formally meet its prespecified endpoints for noninferiority, a difference >3 weeks in the median progression-free survival time is unlikely. Several considerations are worth noting. As is well known to clinicians, first-line chemotherapy for metastatic colorectal cancer is not “sustainable” for prolonged periods of time without treatment modifications or treatment breaks. This results not only from the development of debilitating neuropathy from oxaliplatin but also from mild to moderate nausea, diarrhea, and asthenia, which often become intolerable because of their persistence. This dilemma was the rationale for the OPTIMOX1 and OPTIMOX2 (Optimized Leucovorin [LV]–Fluorouracil [FU]–Oxaliplatin) studies [2, 3], as well as the MACRO study and most other “maintenance” approaches. This is also the reason that many first-line studies suffer from nearly half of all patients stopping protocol-defined therapy before the primary study endpoint of disease progression. Historically, early discontinuation of therapy has been attributed to patient or physician unwillingness to comply with the trial protocol. However, rather than blaming the patient or physician for being “noncompliant,” perhaps we should consider that the protocol itself is not “compliable” for a large fraction of patients, particularly over prolonged periods of time. Most protocols require patients to stay on an every 2 or 3 week schedule indefinitely and discourage repeated delays or even short holidays. Even the MACRO study limited treatment breaks for bevacizumab to 3 weeks, which is only one additional half-life for that drug. During the initial few months of most treatments, many if not most side effects are acceptable, particularly in the setting of gratifying tumor responses. However, by 6 months of treatment, particularly when tumor responses have plateaued, the accumulated burden of toxicities can become intolerable. In addition, there are cumulative social and financial hardships associated with treatment, particularly for patients and families for whom repeated visits to the clinic, admissions to the hospital, and copayments for many supportive care medications can stress limited family resources. When patients take prolonged breaks from scheduled treatments, there can be concerns about compliance. When there is uncertainty about the value of protocol-defined treatment, the default position is to simply stop protocol treatment to allow greater flexibility in managing the whole patient. Like many other first-line studies, the MACRO study had nearly half of all patients stop the protocol-defined treatment before progression, even in the bevacizumab monotherapy group. This suggests that treatment breaks are not just related to classical chemotherapy toxicities but may also be a result of the inconvenience of prolonged treatment itself. The importance of this inconvenience to the patient—and how this barrier to continued treatment is overcome—may depend upon many patient- and physician-specific factors as well as the types of available social support, which may vary considerably within and across countries. There is tension between protocol consistency (so results are interpretable) and protocol flexibility (so the trial is practical). The MACRO study highlights the importance of these issues, particularly for the progression-free survival outcome, and especially for studies in which “maintenance” therapy is a potentially major part of the total treatment algorithm. Another consideration is that the MACRO study may have been “underpowered” for its primary endpoint. The study was designed to test for a noninferiority hazard ratio of 1.32. This design would pick up large differences, when the progression-free survival interval between the two arms differed by >32%, but it was also not able to detect smaller differences. Whether smaller differences are clinically meaningful is in the eye of the beholder. It should also be noted that the issue of patient dropout may dilute or obscure treatment differences or limit the generalizability of such conclusions. Similarly, although there was not a statistically significant difference in survival between the two study arms, it should be remembered that overall survival can be affected by postprotocol therapies, including the use or reuse of the agents that were in the protocol-defined regimens. In addition, most patients in the XELOX–bevacizumab arm dropped oxaliplatin after 4 months, consistent with routine care. Thus, the primary comparison of the MACRO study was, to a large degree, capecitabine plus bevacizumab versus bevacizumab alone. An important historical benchmark for the MACRO study is the second-line E3200 study by Giantonio and colleagues, which randomized patients to 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) versus FOLFOX plus bevacizumab versus bevacizumab monotherapy [4]. Bevacizumab monotherapy was inferior to both FOLFOX and FOLFOX plus bevacizumab in terms of the response rate and progression-free survival time, and the overall survival duration was longer for patients receiving FOLFOX plus bevacizumab. These findings supported two conclusions at the time: that all drugs are better than a subset of drugs and that there is no role for bevacizumab monotherapy per se. However, the lack of benefit from bevacizumab monotherapy during the “induction” part of second-line treatment does not preclude benefit during “maintenance” therapy, particularly in the first-line setting. The MACRO investigators are to be congratulated for appreciating these important distinctions, and for conducting a clinical trial to formally test the assumptions. Given the limitations of a single study, the MACRO trial did not address the role of other possible treatment comparators, such as capecitabine alone and observation without treatment. Additional maintenance studies that will provide additional context to the MACRO study are now in progress. The CAIRO-3 (Capecitabine, Irinotecan, and Oxaliplatin in Advanced Colorectal Cancer) study is randomizing patients to maintenance capecitabine plus bevacizumab or observation alone after completing six cycles (4 months) of XELOX plus bevacizumab [5]. The DREAM (Double Inhibition Reintroduction Erlotinib Avastin in Metastatic Colorectal Cancer) study is evaluating the role of maintenance therapy with bevacizumab and erlotinib versus bevacizumab monotherapy after completing six cycles of FOLFOX (or XELOX) plus bevacizumab [6]. At this time, given the limitations of the MACRO study and the lack of other maintenance studies in first-line colorectal cancer patients, it seems most reasonable to continue the components of first-line therapy that are tolerable, including bevacizumab monotherapy, for patients who might not tolerate lower doses of 5-fluorouracil or capecitabine. As the MACRO study illustrates, ensuring this treatment is tolerable and sustainable is an issue for both clinicians and clinical trialists. See the accompanying article on pages 15–25 of this issue.

Treatment of High-Grade Metastatic Pancreatic Neuroendocrine Carcinoma with FOLFIRINOX.

Standard first-line treatment for poorly differentiated or highgrade neuroendocrine carcinoma (NECA) consists of combination chemotherapy with a platinum agent (either cisplatin or carboplatin) and a topoisomerase inhibitor (etoposide) [1]. This recommendation is derived from large trials in patients with small cell lung cancer, an aggressive variant of NECA, and from several small, non-randomized trials in patients with extrapulmonary NECAs [2, 3]. Recently, the combination of 5fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) was shown to significantly improve response rates and overall survival among patients withmetastatic adenocarcinoma of the pancreas [4].We recently treated two patients with pancreatic NECA using FOLFIRINOX in the first line and in the salvage setting.

A within-trial cost-effectiveness analysis of panitumumab compared with bevacizumab in the first-line treatment of patients with wild-type RAS metastatic colorectal cancer in the US

Abstract Aims: This analysis investigated the cost-effectiveness of panitumumab plus mFOLFOX6 (oxaliplatin, 5-fluorouracil, and leucovorin) compared with bevacizumab plus mFOLFOX6 in the first-line treatment of patients with wild-type RAS metastatic colorectal cancer (mCRC). Materials and methods: The cost-effectiveness analysis was developed from a third-party payer perspective in the US and was implemented using a partitioned survival model with health states for first-line treatment (progression-free), disease progression with and without subsequent active treatment, and death. Survival analyses of patients with wild-type RAS mCRC from the PEAK head-to-head clinical trial of panitumumab vs bevacizumab were performed to estimate time in the model health states. Additional data from PEAK informed the amount of each drug consumed, duration of therapy, subsequent therapy use, and toxicities related to mCRC treatment. Literature and US public data sources were used to estimate unit costs associated with treatment and duration of subsequent active therapies. Utility weights were calculated from patient-level data from panitumumab trials in the first-, second-, and third-line settings. A life-time perspective was taken with future costs and outcomes discounted at 3% per annum. Scenario, one-way, and probabilistic sensitivity analyses were performed. Results: Compared with bevacizumab, the use of panitumumab resulted in an incremental cost of US

Cell-Free DNA Profiling to Discover Mechanisms of Exceptional Response to Cabozantinib Plus Panitumumab in a Patient With Treatment Refractory Metastatic Colorectal Cancer

60,286, and an incremental quality-adjusted life-year (QALY) of 0.445, translating into a cost per QALY gained of US