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Journal of Clinical Oncology, Vol 26, No 28 (October 1), 2008: pp. 4693-4694 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.18.8060
Bevacizumab in Advanced Colorectal Cancer: A Challenge to the Current ParadigmDivison of Cancer Care and Epidemiology, Queen's University Cancer Research Institute, Kingston, Ontario, Canada To the Editor: It is with great interest that I read the articles by Cassidy et al1 and Saltz et al2 describing the results of the NO16966 clinical trial. The authors are to be congratulated for conducting this large, well-designed clinical trial to address critical issues in the contemporary management of advanced colorectal cancer (CRC). The first article clearly demonstrates that capecitabine may be substituted for infusional fluorouracil in a first-line oxaliplatin-based regimen. This provides a much less cumbersome therapeutic option and will likely change practice to the benefit of our patients. The second article reports the results of bevacizumab compared with placebo among patients receiving oxaliplatin-based chemotherapy. By demonstrating that there was no evidence of treatment interaction, the authors were able to conduct the pooled analysis of capecitabine and oxaliplatin and oxaliplatin, fluorouracil, and leucovorin with or without bevacizumab. Although the primary end point of improved progression-free survival (PFS) met statistical significance (hazard ratio, 0.83; 97.5% CI, 0.72 to 0.95; P = .0023), the absolute improvement in median PFS of 1.4 months is not clinically meaningful. Additionally, unlike previous randomized controlled trials (RCTs) that have evaluated bevacizumab in advanced CRC, NO16966 did not show any improvement in response rate or overall survival. As the authors note, only 5% of patients in the control arm received bevacizumab in subsequent lines of therapy, making it unlikely that the lack of survival benefit was confounded by crossover. If this was the first large RCT to address the role of bevacizumab in advanced CRC, I suspect the authors’ conclusions would be quite different. Though this trial was clearly negative and (in isolation) did not support the use of bevacizumab in this patient population, the authors present an alternative hypothesis to explain their results. Unlike previous trials, overall treatment duration of bevacizumab and placebo was similar (approximately 6 months) despite improved PFS in the experimental arm. The study protocol specified that treatment could continue until progressive disease, and thus it seems that investigators may have discontinued the study drug prematurely. The authors conclude that "treatment continuation until disease progression may be necessary to optimize the contribution of bevacizumab to therapy."2 I was disappointed that the authors do not postulate anywhere in the article that perhaps bevacizumab is not effective in a broad patient population treated with contemporary chemotherapy. It is important to put the results of this well-designed RCT in context by reviewing the pivotal evidence to date in support of bevacizumab. In 2004, Hurwitz et al3 reported that the addition of bevacizumab to irinotecan, fluorouracil, and leucovorin in the first-line setting was associated with a clinically important increase in median survival of 4.7 months. In 2007, Dr Giantonio et al4 demonstrated that bevacizumab improved median survival by 2.1 months when given with oxaliplatin, fluorouracil, and leucovorin in the second-line setting. Recently, two large international phase IV observational studies have found impressive results when bevacizumab is administered in the general population.5,6 Finally, a non-randomized comparison between the Three Regimens of Eloxatin Evaluation (TREE) –1 and TREE-2 cohorts also suggest benefit of bevacizumab in metastatic CRC.7 As clinicians, many of us were unsure how to interpret the data from Hurwitz et al, given that irinotecan, fluorouracil, and leucovorin is no longer standard treatment in CRC. Furthermore, the limitations of observational data and nonrandomized comparisons are well recognized. However, I believe that until the publication of NO16966, most gastrointestinal oncologists felt that bevacizumab had a clinically meaningful role in the management of patients with advanced CRC. The results presented by Saltz et al2 pose a considerable challenge to the current paradigm in management of advanced CRC. In many jurisdictions clinical practice has moved ahead of the evidence and bevacizumab has become standard of care in first-line management of advanced CRC. I believe that the results of NO16966 should introduce some element of uncertainty regarding the role of beavicizumab in this disease. Given the totality of the evidence, I do not propose that bevacizumab plays no role in the management of CRC. However, since the largest and most contemporary RCT has failed to demonstrate a clinically meaningful benefit to patients, I believe it would be inappropriate to accept that bevacizumab in combination when oxaliplatin-based chemotherapy is the standard of care in first-line management of metatastic CRC. Rather, this trial should encourage future studies to explore predictive biomarkers that may allow oncologists to treat patients who are likely to benefit from bevacizumab and avoid treating patients with an expensive and potentially toxic drug who are unlikely to benefit. As clinicians and investigators, we need to have an open dialogue about the true benefit of these novel anticancer therapies in the general population and distinguish results that are clinically significant from those that are only statistically significant. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Cassidy J, Clarke S, Diaz-Rubio E, et al: Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 26:2006-2012, 2008 2. Saltz LB, Clarke S, Diaz-Rubio E, et al: Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: A randomized phase III study. J Clin Oncol 26:2013-2019, 2008 3. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004 4. Giantonio BJ, Catalano PJ, Meropol NJ, et al: Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: Results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539-1544, 2007 5. Berry S, Cunninghanm D, Michael M, et al: Preliminary efficacy of bevacizumab with first-line FOLFOX, XELOX, FOLFIRI, and fluoropyrimidines in mCRC: First BEAT. Proc Gastrointestinal Cancers Symposium, January 25-27, 2008 (abst 350) 6. Kozloff M, Sugrue M, Berlin J, et al: Safety and effectiveness of bevacizumab and chemotherapy in elderly patients with metastatic colorectal cancer: Results from the BRiTE prospective cohort study. Proc Gastrointestinal Cancers Symposium, January 25-27, 2008 (abst 345) 7. Hochster HS, Hart LL, Ramanathan RK, et al: Regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: Results of the TREE study. J Clin Oncol 21:3523-3529, 2008
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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