当前位置: 首页 > 期刊 > 《新英格兰医药杂志》 > 2004年第16期 > 正文
编号:11306651
Bevacizumab in Colorectal Cancer
http://www.100md.com 《新英格兰医药杂志》
     To the Editor: The randomized study reported by Hurwitz and associates (June 3 issue)1 did not allow the crossover of patients with disease progression in the group that received placebo to treatment with bevacizumab. Although this strategy can enhance the probability of detecting a difference in survival between the study groups, it is inherently unethical to disallow access to the study drug on progression of disease in patients in the placebo group. The lack of crossover also fails to simulate the commonplace occurrence of crossover in the practice of medical oncology.

    Guru Sonpavde, M.D.

    Baylor College of Medicine

    Houston, TX 77030

    gurus@bcm.tmc.edu

    References

    Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-2342.

    To the Editor: Given the poor outcome of metastatic colorectal cancer, the results reported by Hurwitz et al. seem impressive, in that there was a 50 percent chance of survival at 20.3 months if bevacizumab was added to irinotecan, fluorouracil, and leucovorin (IFL), as compared with a 38 percent chance of survival with IFL alone. In order for one additional patient to be alive at 20.3 months of follow-up, eight patients would need to be treated with bevacizumab plus IFL, rather than with IFL alone. A similar result is reported for progression-free survival.

    The patients with signs of disease progression were given a second line of treatment. However, the authors did not report how many in each group required it and also did not adjust for it statistically. This was a cointervention, and the intention-to-treat principle does not apply here. Furthermore, the authors report more adverse events in the bevacizumab-plus-IFL group, without reporting how patients perceived them — for example, in terms of quality-adjusted life-years,1 though the quality of life was a secondary outcome measure. Finally, it appears to be worthwhile to conduct a cost–utility analysis nested within a double-blind, randomized, controlled trial.

    Waseem Sharieff, M.D.

    University of Toronto

    Toronto, ON M5G 1X8, Canada

    doc.sharieff@utoronto.ca

    References

    Meltzer MI. Introduction to health economics for physicians. Lancet 2001;358:993-998.

    The authors reply: The prohibition of crossover may be controversial in some settings, but we believe that Dr. Sonpavde's ethical concerns do not apply to our study and may be misleading. Although the survival benefit of adding bevacizumab to IFL chemotherapy is a gratifying advance for patients with metastatic colorectal cancer,1 this result was not known when our study was initiated. Cancer treatments that appear to be promising in early pilot or phase 2 studies often fail to demonstrate a benefit when rigorously tested in phase 3 trials.2 Even useful treatments may have value only in limited settings.3,4 By providing high-quality evidence to guide medical practice, well-conducted phase 3 trials serve the individual study patients and society by minimizing the number of both study subjects and general patients who are exposed to treatments that may involve additional cost, inconvenience, and toxicity without providing a benefit.

    Our study required informed consent, complied with all local and federal ethical and legal requirements, and was monitored by an independent data safety monitoring board, with stopping rules for both efficacy and toxicity. Once the data demonstrating a survival benefit were known, the study centers were notified of the results, and the treating physicians were given the option of offering patients randomly assigned to the control group access to bevacizumab. The value of bevacizumab in the second- or third-line setting for colorectal cancer is not known.

    In reply to Dr. Sharieff, the percentage of patients receiving any second-line therapy was reported in our article (approximately 50 percent), as was the percentage of patients receiving second-line oxaliplatin (approximately 25 percent). Formal quality-of-life data and pharmacoeconomic analyses for our study could not be reported in our initial manuscript because of space limitations. Given the improvement in all measures of clinical benefit, which was also seen across all clinical subgroups, the addition of bevacizumab to first-line chemotherapy would probably be acceptable for most patients in whom this therapy is indicated.

    Herbert I. Hurwitz, M.D.

    Duke University Medical Center

    Durham, NC 27710

    hurwi004@mc.duke.edu

    William Novotny, M.D.

    Genentech

    South San Francisco, CA 94080

    Fairooz Kabbinavar, M.D.

    University of California at Los Angeles

    Los Angeles, CA 90095-1361

    for the Bevacizumab Study Team

    References

    Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-2342.

    Fogarty M. Learning from angiogenesis trial failures. Scientist 2002;16:33-33.

    Saltz LB, Niedzwiecki D, Hollis D, et al. Irinotecan plus fluorouracil/leucovorin (IFL) versus fluorouracil/leucovorin alone (FL) in stage III colon cancer (intergroup trial CALGB C89803 [GenBank] ). Prog Proc Am Soc Clin Oncol 2004;22:246. abstract.

    Shepherd FA, Pereira J, Ciuleanu TE, et al. A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1st line or 2nd line chemotherapy: a National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial. Prog Proc Am Soc Clin Oncol 2004;22:Suppl:18. abstract.