Bevacizumab plus fluorouracil: the value of being part of a developing story.

The US Food and Drug Administration has recently approved bevacizumab for the first-line treatment of metastatic colorectal cancer in combination with any intravenous fluorouracil-based chemotherapy. This decision has generated much debate because this broad indication implies that the antiangiogenic effect of bevacizumab may be similar when added to any such chemotherapy, whereas this approval was mainly based on a single trial of this agent with the bolus regimen of irinotecan, fluorouracil, and leucovorin (IFL). The article by Kabbinavar et al in this issue of the Journal of Clinical Oncology adds to the debate on the use of bevacizumab in colorectal cancer. The study has several weaknesses; nevertheless, it conveys a series of important messages that, in turn, generate potentially important clinical implications. Among the weaknesses is the sample size, which is rather small due to an unrealistic and unjustified expectation of survival benefit (hazard ratio of 0.61). However, this was a phase II study, not a phase III trial, making the sample size more acceptable. The eligibility criteria were, at the same time, very broad to define the patients “unfit” for IFL (for example, a perfectly fit 66-year-old man with low tumor bulk was by definition “unfit” for IFL, and the same was true for a 40-year-old man with an Eastern Cooperative Oncology Group performance status of 1, but criteria were strict for the use of bevacizumab [see the exclusion criteria]). Yet, the accrual of these 200 selected patients required 60 centers over 2 years (1.6 patients per center per year), perhaps due to the broad acceptance of combination chemotherapy for most patients with metastatic colorectal cancer in the United States during the accrual period of the trial. The patient characteristics in this study do present worse features than those in the pivotal trial by Hurwitz et al, but despite the fact that they were considered unfit for IFL as first-line treatment, almost half were still fit for second-line chemotherapy with irinotecanor oxaliplatinbased combinations 6 months after enrollment (as the median duration of first-line therapy was 6 to 7 months). Thus, the external validity of the results of this study and its generalizability is limited. Finally, the advantage in overall survival (the primary end point of the study) for the experimental arm over the control arm, although remarkable in relative terms, was statistically insignificant; the times to quality of life deterioration were identical (3.1 v 3 months, respectively); and the bevacizumab-specific adverse effects accounted for a 16% higher frequency of grade 3 to 4 toxicity in the combined arm. Despite these weaknesses, the study is scientifically important and clinically relevant. In fact, when considered in the context of the available information on bevacizumab in colorectal cancer, it strengthens a series of concepts, thus helping the treating physician and regulatory and funding agencies. First, this study replicates the impressive relative increases in progression-free and overall survival observed in the pivotal study, providing further evidence that bevacizumab favorably affects the natural history of treated metastatic colorectal cancer. Both in the Hurwitz et al study and in this study, bevacizumab almost halved the rate of progression, and the relative increase in median survival was clinically relevant. Second, these relatively large effects in disease-free and overall survival could not have been predicted by an only 10% increment in response rate and the low complete response rates in both studies. Incidentally, no mention is made of the rate of secondary liver resections (expected to be low in elderly patients and contraindicated in two thirds of these patients having two or more metastatic sites), which is a weak, but relevant, surrogate of activity. These observations also apply to two additional studies: the third arm of the pivotal IFL plus bevacizumab study (that was closed after 100 patients were treated with fluorouracil, leucovorin, and bevacizumab); and a small phase II (35 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 16 JUNE 1 2005