Neal J. Meropol

Bevacizumab in Combination With Oxaliplatin, Fluorouracil, and Leucovorin (FOLFOX4) for Previously Treated Metastatic Colorectal Cancer: Results From the Eastern Cooperative Oncology Group Study E3200

PURPOSEnColorectal cancer is the second leading cause of cancer mortality in the United States. Antiangiogenic therapy with bevacizumab combined with chemotherapy improves survival in previously untreated metastatic colorectal cancer. This study was conducted to determine the effect of bevacizumab (at 10 mg/kg) on survival duration for oxaliplatin-based chemotherapy in patients with previously treated metastatic colorectal cancer.nnnPATIENTS AND METHODSnEight hundred twenty-nine metastatic colorectal cancer patients previously treated with a fluoropyrimidine and irinotecan were randomly assigned to one of three treatment groups: oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) with bevacizumab; FOLFOX4 without bevacizumab; or bevacizumab alone. The primary end point was overall survival, with additional determinations of progression-free survival, response, and toxicity.nnnRESULTSnThe median duration of survival for the group treated with FOLFOX4 and bevacizumab was 12.9 months compared with 10.8 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for death = 0.75; P = .0011), and 10.2 months for those treated with bevacizumab alone. The median progression-free survival for the group treated with FOLFOX4 in combination with bevacizumab was 7.3 months, compared with 4.7 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for progression = 0.61; P < .0001), and 2.7 months for those treated with bevacizumab alone. The corresponding overall response rates were 22.7%, 8.6%, and 3.3%, respectively (P < .0001 for FOLFOX4 with bevacizumab v FOLFOX4 comparison). Bevacizumab was associated with hypertension, bleeding, and vomiting.nnnCONCLUSIONnThe addition of bevacizumab to oxaliplatin, fluorouracil, and leucovorin improves survival duration for patients with previously treated metastatic colorectal.

Phase II, Randomized Trial Comparing Bevacizumab Plus Fluorouracil (FU)/Leucovorin (LV) With FU/LV Alone in Patients With Metastatic Colorectal Cancer

PURPOSEnThis phase II trial investigated the safety and efficacy of two doses of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, plus fluorouracil (FU)/leucovorin (LV) versus FU/LV alone in patients with metastatic colorectal cancer.nnnPATIENTS AND METHODSnOne hundred four previously untreated patients with measurable metastatic colorectal cancer were randomly assigned to one of the following three treatment groups: 36 to FU (500 mg/m(2))/LV (500 mg/m(2)) alone, 35 to FU/LV + low-dose bevacizumab (5 mg/kg every 2 weeks), and 33 to FU/LV + high-dose bevacizumab (10 mg/kg every 2 weeks). FU/LV was given weekly for the first 6 weeks of each 8-week cycle.nnnRESULTSnCompared with the FU/LV control arm, treatment with bevacizumab (at both dose levels) plus FU/LV resulted in higher response rates (control arm, 17%, 95% confidence interval [CI], 7% to 34%; low-dose arm, 40%, 95% CI, 24% to 58%; high-dose arm, 24%, 95% CI, 12% to 43%), longer median time to disease progression (control arm, 5.2 months, 95% CI, 3.5 to 5.6 months; low-dose arm, 9.0 months, 95% CI, 5.8 to 10.9 months; high-dose arm, 7.2 months, 95% CI, 3.8 to 9.2 months), and longer median survival (control arm, 13.8 months; 95% CI, 9.1 to 23.0 months; low-dose arm, 21.5 months, 95% CI, 17.3 to undetermined; high-dose arm, 16.1 months; 95% CI, 11.0 to 20.7 months). After cross-over, two of 22 patients had a partial response to bevacizumab alone. Thrombosis was the most significant adverse event and was fatal in one patient. Hypertension, proteinuria, and epistaxis were other potential safety concerns.nnnCONCLUSIONnThe encouraging results of this randomized trial support further study of bevacizumab 5 mg/kg plus chemotherapy as first-line therapy for metastatic colorectal cancer.

Relationship of Circulating Tumor Cells to Tumor Response, Progression-Free Survival, and Overall Survival in Patients With Metastatic Colorectal Cancer

PURPOSEnAs treatment options expand for metastatic colorectal cancer (mCRC), a blood marker with a prognostic and predictive role could guide treatment. We tested the hypothesis that circulating tumor cells (CTCs) could predict clinical outcome in patients with mCRC.nnnPATIENTS AND METHODSnIn a prospective multicenter study, CTCs were enumerated in the peripheral blood of 430 patients with mCRC at baseline and after starting first-, second-, or third-line therapy. CTCs were measured using an immunomagnetic separation technique.nnnRESULTSnPatients were stratified into unfavorable and favorable prognostic groups based on CTC levels of three or more or less than three CTCs/7.5 mL, respectively. Patients with unfavorable compared with favorable baseline CTCs had shorter median progression-free survival (PFS; 4.5 v 7.9 months; P = .0002) and overall survival (OS; 9.4 v 18.5 months; P < .0001). Differences persisted at 1 to 2, 3 to 5, 6 to 12, and 13 to 20 weeks after therapy. Conversion of baseline unfavorable CTCs to favorable at 3 to 5 weeks was associated with significantly longer PFS and OS compared with patients with unfavorable CTCs at both time points (PFS, 6.2 v 1.6 months; P = .02; OS, 11.0 v 3.7 months; P = .0002). Among nonprogressing patients, favorable compared with unfavorable CTCs within 1 month of imaging was associated with longer survival (18.8 v 7.1 months; P < .0001). Baseline and follow-up CTC levels remained strong predictors of PFS and OS after adjustment for clinically significant factors.nnnCONCLUSIONnThe number of CTCs before and during treatment is an independent predictor of PFS and OS in patients with metastatic colorectal cancer. CTCs provide prognostic information in addition to that of imaging studies.

Activity of Sunitinib in Patients With Advanced Neuroendocrine Tumors

PURPOSEnStandard cytotoxic chemotherapy has limited efficacy in metastatic neuroendocrine tumor patients. Neuroendocrine tumors express vascular endothelial growth factor (VEGF) and its receptor (VEGFR). Sunitinib malate, an oral tyrosine kinase inhibitor, has activity against VEGFRs as well as platelet-derived growth factor receptors, stem-cell factor receptor, glial cell line-derived neurotrophic factor, and FMS-like tyrosine kinase-3. We evaluated the efficacy of sunitinib in a two-cohort, phase II study of advanced carcinoid and pancreatic neuroendocrine tumor patients.nnnPATIENTS AND METHODSnPatients were treated with repeated 6-week cycles of oral sunitinib (50 mg/d for 4 weeks, followed by 2 weeks off treatment). Patients were observed for response, survival, and adverse events. Patient-reported outcomes were assessed.nnnRESULTSnAmong 109 enrolled patients, 107 received sunitinib (carcinoid, n = 41; pancreatic endocrine tumor, n = 66). Overall objective response rate (ORR) in pancreatic endocrine tumor patients was 16.7% (11 of 66 patients), and 68% (45 of 66 patients) had stable disease (SD). Among carcinoid patients, ORR was 2.4% (one of 41 patients), and 83% (34 of 41 patients) had SD. Median time to tumor progression was 7.7 months in pancreatic neuroendocrine tumor patients and 10.2 months in carcinoid patients. One-year survival rate was 81.1% in pancreatic neuroendocrine tumor patients and 83.4% in carcinoid patients. No significant differences from baseline in patient-reported quality of life or fatigue were observed during treatment.nnnCONCLUSIONnSunitinib has antitumor activity in pancreatic neuroendocrine tumors; its activity against carcinoid tumors could not be definitively determined in this nonrandomized study. Randomized trials of sunitinib in patients with neuroendocrine tumors are warranted.

American Society of Clinical Oncology Guidance Statement: The Cost of Cancer Care

Advances in early detection, prevention, and treatment have resulted in consistently falling cancer death rates in the United States. In parallel with these advances have come significant increases in the cost of cancer care. It is well established that the cost of health care (including cancer care) in the United States is growing more rapidly than the overall economy. In part, this is a result of the prices and rapid uptake of new agents and other technologies, including advances in imaging and therapeutic radiology. Conventional understanding suggests that high prices may reflect the costs and risks associated with the development, production, and marketing of new drugs and technologies, many of which are valued highly by physicians, patients, and payers. The increasing cost of cancer care impacts many stakeholders who play a role in a complex health care system. Our patients are the most vulnerable because they often experience uneven insurance coverage, leading to financial strain or even ruin. Other key groups include pharmaceutical manufacturers that pass along research, development, and marketing costs to the consumer; providers of cancer care who dispense increasingly expensive drugs and technologies; and the insurance industry, which ultimately passes costs to consumers. Increasingly, the economic burden of health care in general, and high-quality cancer care in particular, will be less and less affordable for an increasing number of Americans unless steps are taken to curb current trends. The American Society of Clinical Oncology (ASCO) is committed to improving cancer prevention, diagnosis, and treatment and eliminating disparities in cancer care through support of evidence-based and cost-effective practices. To address this goal, ASCO established a Cost of Care Task Force, which has developed this Guidance Statement on the Cost of Cancer Care. This Guidance Statement provides a concise overview of the economic issues facing stakeholders in the cancer community. It also recommends that the following steps be taken to address immediate needs: recognition that patient-physician discussions regarding the cost of care are an important component of high-quality care; the design of educational and support tools for oncology providers to promote effective communication about costs with patients; and the development of resources to help educate patients about the high cost of cancer care to help guide their decision making regarding treatment options. Looking to the future, this Guidance Statement also recommends that ASCO develop policy positions to address the underlying factors contributing to the increased cost of cancer care. Doing so will require a clear understanding of the factors that drive these costs, as well as potential modifications to the current cancer care system to ensure that all Americans have access to high-quality, cost-effective care.

Thymidine Phosphorylase Expression Is Associated With Response to Capecitabine Plus Irinotecan in Patients With Metastatic Colorectal Cancer

PURPOSEnTo evaluate the clinical activity and toxicity of capecitabine plus irinotecan as first-line therapy for patients with metastatic colorectal cancer (mCRC), and to describe the association of expression of thymidine phosphorylase (TP), thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) with antitumor activity.nnnPATIENTS AND METHODSnPatients with previously untreated mCRC received irinotecan days 1 and 8 intravenously, and capecitabine days 2 to 15 orally in 21-day cycles. Doses were irinotecan 125 mg/m2 and capecitabine 1,000 mg/m2 bid (n = 15; cohort 1), or irinotecan 100 mg/m2 and capecitabine 900 mg/m2 bid (n = 52; cohort 2). Tissues from primary and metastatic sites were assessed for TP, TS, and DPD gene and protein expression.nnnRESULTSnAn unacceptable level of GI toxicity in the first 15 patients led to a protocol modification in starting doses. The response rate was 45% (30 of 67 patients). Overall survival was associated with TP expression assessed by immunohistochemistry in both primary tumors (P = .045) and metastases (P = .001). Objective tumor response was associated with TP expression in primary tumors (odds ratio, 4.77; 95% CI, 1.25 to 18.18), with a similar trend in metastases (odds ratio, 8.67; 95% CI, 0.95 to 79.1). TP gene expression in primary tumors was also associated with response.nnnCONCLUSIONnThese data indicate that capecitabine plus irinotecan is an active regimen against mCRC. The biomarker analysis (including metastatic tissue) was feasible in a multicenter setting, and provides preliminary evidence that TP expression may be a predictive marker for response.

The National Cancer Institute–American Society of Clinical Oncology Cancer Trial Accrual Symposium: Summary and Recommendations

INTRODUCTIONnMany challenges to clinical trial accrual exist, resulting in studies with inadequate enrollment and potentially delaying answers to important scientific and clinical questions.nnnMETHODSnThe National Cancer Institute (NCI) and the American Society of Clinical Oncology (ASCO) cosponsored the Cancer Trial Accrual Symposium: Science and Solutions on April 29-30, 2010 to examine the state of accrual science related to patient/community, physician/provider, and site/organizational influences, and identify new interventions to facilitate clinical trial enrollment. The symposium featured breakout sessions, plenary sessions, and a poster session including 100 abstracts. Among the 358 attendees were clinical investigators, researchers of accrual strategies, research administrators, nurses, research coordinators, patient advocates, and educators. A bibliography of the accrual literature in these three major areas was provided to participants in advance of the meeting. After the symposium, the literature in these areas was revisited to determine if the symposium recommendations remained relevant within the context of the current literature.nnnRESULTSnFew rigorously conducted studies have tested interventions to address challenges to clinical trials accrual. Attendees developed recommendations for improving accrual and identified priority areas for future accrual research at the patient/community, physician/provider, and site/organizational levels. Current literature continues to support the symposium recommendations.nnnCONCLUSIONSnA combination of approaches addressing both the multifactorial nature of accrual challenges and the characteristics of the target population may be needed to improve accrual to cancer clinical trials. Recommendations for best practices and for future research developed from the symposium are provided.

Cost Implications of New Treatments for Advanced Colorectal Cancer

Since 1996, 6 new drugs have been introduced for the treatment of metastatic colorectal cancer. Although they are promising, these drugs frequently are given in the palliative and are much more expensive than older treatments. The objective of the current study was to measure the cost implications of treatment with sequential regimens that include chemotherapy and/or monoclonal antibodies.

ASCO Addresses the Rising Cost of Cancer Care

Cancer prevention and treatment strategies are improving population health. Current and future progress is clearly dependent on the translation of basic understanding of cancer to patient care. Cancer clinicians can be justifiably proud of the role they assume in delivering better treatment to patients. It is equally fair to say that there is far more to be done, and future improvements in cancer care will have to emerge in a rapidly changing financial environment. The cost of health care (including cancer care) in the United States is growing more rapidly than the overall economy and currently consumes 16% of the gross domestic product.1 n nThe rising cost of cancer care affects many stakeholders who play roles in a complex health care system. Our patients are the most vulnerable, because they often experience uneven insurance coverage leading to financial strain or even ruin. Other key groups include pharmaceutical and device manufacturers that bring innovation to the clinic and ultimately must pass on research, development, and marketing costs to the consumer; providers of cancer care, who dispense expensive drugs and diagnostics; and the insurance industry, faced with the increasing cost of care and high demand for the newest technologies. Increasingly, the economic burden of health care in general—and high-quality cancer care in particular—will be less and less affordable for many Americans unless steps are taken to curb dangerous trends in health care spending. n n nThe ASCO Cost of Care Task Force has developed a guidance statement on the cost of cancer care, stressing: n n nPatient-physician discussions on costs n n nProvider support tools for communication about costs n n nEducational resources for patients n n n nRead the full statement in Journal of Clinical Oncology. n nMeropol NJ, Schrag D, Smith TJ, et al: American Society of Clinical Oncology Guidance Statement: The cost of cancer care. J Clin Oncol doi.10.1200/JCO.2009.23.1183 [epub ahead of print on July 6, 2009] n n nASCO is committed to improving cancer prevention, diagnosis, and treatment and eliminating disparities in cancer care through support of evidence-based and cost-effective practices. To address this goal, ASCO established the Cost of Care Task Force, which has considered many of the implications of rising costs and recently developed a guidance statement on the cost of cancer care.2 The guidance statement provides a concise overview of the economic issues facing stakeholders in the cancer community. It also recommends the following steps be taken to address immediate needs: n n nRecognize that patient-physician discussions regarding cost of care are an important component of high-quality care. The physician must have a keen grasp of available evidence in support of the various treatment recommendations made to patients and be prepared to integrate their clinical effectiveness, toxicities, and relative costs to assist patients in making optimal decisions. n n nDesign educational and support tools for oncology providers to promote effective communication with patients about cost. The initial educational efforts of ASCO in this regard were reflected at the 2009 ASCO Annual Meeting, at which five sessions were devoted to this issue; an educational curriculum for cancer clinicians is in preparation. n n nDevelop resources to help educate patients about the high cost of cancer care to help guide their decision making regarding treatment options. ASCO has developed an online educational resource for patients to assist them and their families in raising this issue with their providers. Patients must understand direct and indirect costs of their care and the clinical effectiveness and cost implications of the therapies proposed. n n n nCancer care in the United States is delivered in the setting of a health care system that is not integrated. As a result, the components of the system (ie, providers, insurers, and pharmaceutical and device manufacturers) do not function in coordinated ways that would facilitate the greatest benefit for the largest number of people at the lowest cost. Because improving the well-being of cancer patients and facilitating the highest levels of practice and professionalism among cancer clinicians are central to its mission, ASCO is committed to contributing to the national discussion on how best to provide high-quality cancer care to all patients with and at risk for cancer. Doing so will require a clear understanding of the factors that drive cancer care costs as well as potential modifications to the current system to ensure that these goals are met. Research is needed in patient-physician communication to optimize information exchange and preference-sensitive decision making. In addition, we need to learn more about the comparative effectiveness of oncology therapies (eg, drugs, radiation, and surgical approaches) and diagnostics. Ultimately, we need to better understand the value of particular cancer treatments and how different stakeholders approach such judgments. These data are needed to inform the decisions of individual patients, their physicians, and society at large. n nWith the publication of its guidance statement, the ASCO Task Force on the Cost of Cancer Care is poised to probe these issues more deeply by understanding the drivers of increasing costs, their impact, and approaches to modulating them in an effort to ensure continued progress against cancer and universal access to high-quality care.

Let's Focus on Value

Cancer diagnosis and treatment is expensive, and the price tag is increasing at a rapid rate. However, the cost of cancer care is a small percentage of overall health care expenditures in the United States, and oncologists are unlikely to single-handedly bankrupt the economy. Why then, is there so much angst over the cost of cancer care? After all, is not society’s willingness to pay for new health care innovation merely a reflection of our insatiable thirst for (and a driver of) such innovation in a market-based economy?