The NSABP C-08 study represents the first prospective, randomized investigation of the use of anti-VEGF therapy for the adjuvant treatment of any malignancy. Unfortunately, the addition of 1 year of bevacizumab to 6 months of modified FOLFOX6 chemotherapy in patients with stages II and III colon cancer did not significantly improve DFS. However, DFS appeared to be significantly improved with the addition of bevacizumab to modified FOLFOX6 during the 15-month period of bevacizumab exposure. This effect on DFS diminished over the subsequent follow-up, such that DFS was not significantly different between the two arms. The initial favorable DFS for the bevacizumab-treated group is supported by the hazard rates and ratios illustrated in and . The hazard rates shown in demonstrate an initial lower event rate in the bevacizumab arm followed by a rate that is equal to or greater than the rate observed in the control arm. This change in rate after bevacizumab exposure accounts for the loss of an initial favorable DFS associated with bevacizumab. Of interest is that the 3-year DFS for patients with stage III disease noted in this study with use of the mFOLFOX6 regimen is indistinguishable from the oxaliplatin arms of NSABP C-07 that used the FLOX regimen and the MOSAIC trial that used FOLFOX4.21
The effect on DFS associated with bevacizumab during exposure to this agent may be explained by several possible mechanisms. The observation may reflect a purely cytostatic effect that results from bevacizumab exposure with gradual abatement after therapy. This concept is consistent with the known mechanisms of action of bevacizumab and suggests that exposure results in growth arrest rather than cell death.5
It is also plausible that bevacizumab is masking the early appearance of recurrent disease by diminishing the excessive permeability associated with tumor vasculature detected by imaging studies. Whether the DFS curves will continue to merge over time or will remain modestly separated will be critical in determining whether there is any evidence for a cytotoxic effect associated with the use of bevacizumab in this adjuvant setting.
An alternative explanation for the observed DFS difference relates to the potential for bias in the timing of routine follow-up imaging, given that there was a 6-month difference in duration of therapy between the treatment arms and routine imaging after therapy, which was not prescribed by the protocol. Of patients who did not reach a DFS event during the study follow-up, we observed a statistical delay in the median time to imaging of 1.28 months in the bevacizumab arm compared with the control arm and an average delay of 1.09 months during the period between 6 and 22 months, during which the greatest potential for imaging bias appeared to occur. The bias-adjusted DFS curves resulted in little change from the unadjusted DFS curves. The DFS-by-time interaction remained significant, and the HR of the adjusted curves was 0.90 compared with 0.89 in the unadjusted DFS curves. Thus, the timing of scans after therapy completion does not explain the time-varying effect of bevacizumab on DFS.
Several recent publications using preclinical murine models have suggested that exposure to anti-VEGF therapy may result in the development of a more aggressive tumor phenotype with a greater propensity for growth and metastatic spread.16–20
Such an effect could account for an initial favorable impact of bevacizumab followed by its loss as a result of the evolution of a more aggressive cancer in the bevacizumab-exposed patients. Our investigation of patient survival after relapse as well as the organ distribution and number of metastatic sites at relapse revealed no differences between the groups. Thus, the development of a more aggressive cancer phenotype associated with bevacizumab exposure was not supported by our data. Although there are several possible explanations for the observed effect of bevacizumab on DFS, it appears most plausible that the observed transient effect on DFS associated with bevacizumab exposure represents a biologic effect.
One of the critical issues in this study design was the selection of 1 year of bevacizumab therapy, with 6 months of bevacizumab given as a single agent. The available data from the advanced disease colorectal setting suggests that bevacizumab has little discernable clinical benefit when used as a single agent. However, there is no data concerning the use of bevacizumab in the adjuvant treatment of any cancer either in combination with chemotherapy or as a single agent. Given this lack of relevant data coupled with its unknown mechanism of action in the adjuvant setting, we elected to use a 1-year total exposure on the basis of the NSABP clinical experience with trastuzumab therapy in the adjuvant breast setting. In breast cancer, the biologic therapy has direct cellular effects on the malignant cell population and thus represents an imperfect, but potentially useful, model. If other colon cancer adjuvant studies, such as the Phase III Randomized Study of Adjuvant Oxaliplatin, Leucovorin Calcium, and Fluorouracil (FOLFOX-4) Versus Bevacizumab and FOLFOX-4 Versus Bevacizumab, Oxaliplatin, and Capecitabine in Patients With High-Risk Stage II or Stage III Colon Cancer (AVANT) clinical trial,22
confirm our observation of significant suppression of tumor recurrence during bevacizumab exposure only, this would provide supporting evidence of a biologic effect of bevacizumab.
We did not observe a statistically significant benefit in overall DFS with the use of bevacizumab for 1 year. Therefore, this agent should not be used for the management of patients with colon cancer in the adjuvant setting at this time. However, we did find evidence to support a transient biologic effect of bevacizumab that will require verification from other ongoing and planned clinical investigations.
On the basis of the results of this investigation, which showed a lack of benefit associated with the use of bevacizumab for 1 year, bevacizumab should not be used for the management of patients with stages II and III colon cancer in the adjuvant setting.