Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08

Abstract

Purpose: The National Surgical Adjuvant Breast and Bowel Project C-08 trial was designed to investigate the safety and efficacy of adding bevacizumab to modified FOLFOX6 (mFOLFOX6; ie, infusional/bolus fluorouracil, leucovorin, and oxaliplatin) for the adjuvant treatment of patients with stages II to III colon cancer.

Methods: Patients received mFOLFOX6 every 2 weeks for 26 weeks alone or modified as FOLFOX6 + bevacizumab (5 mg/kg every 2 weeks for 52 weeks [ie, experimental group]). The primary end point was disease-free survival (DFS).

Results: Among 2,672 analyzed patients, demographic factors were well balanced by treatment. With a median follow-up of 35.6 months, the addition of bevacizumab to mFOLFOX6 did not result in an overall significant increase in DFS (hazard ratio [HR], 0.89; 95% CI, 0.76 to 1.04; P = .15). The point estimates for 3-year DFS for the overall population were 77.4% and 75.5% for the experimental and control arms, respectively. For patients with stages II and III diseases, these same estimates were 87.4% and 84.7%, respectively, for stage II and 74.2% and 72.4%, respectively, for stage III. Exploratory analyses found that the effect of bevacizumab on DFS was different before and after a 15-month landmark (time-by-treatment interaction P value < .0001). Bevacizumab had a strong effect before the landmark (HR, 0.61; 95% CI, 0.48 to 0.78; P < .001) but no significant effect after (HR, 1.22; 95% CI, 0.98 to 1.52; P = .076).

Conclusion: Bevacizumab for 1 year with mFOLFOX6 does not significantly prolong DFS in stages II and III colon cancer. However, a significant but transient effect during bevacizumab exposure was observed in the experimental arm. We postulate that this observation reflects a biologic effect during bevacizumab exposure. Given the lack of improvement in DFS, the use of bevacizumab cannot be recommended for use in the adjuvant treatment of patients with colon cancer.

Fig 1.

CONSORT diagram. Bev, bevacizumab.

Fig 2.

Disease-free survival (DFS). Overall DFS for patients treated with mFF6 (mFOLFOX6) alone for 6 months or mFF6 for 6 months plus bevacizumab for 12 months (mFF6 + Bev). HR, hazard ratio.

Fig 3.

Disease-free survival (DFS) hazard rates. The DFS hazard rates over time are illustrated for patients treated with either mFF6 (mFOLFOX6) alone or mFF6 plus bevacizumab (mFF6 + Bev).

Fig 4.

Disease-free survival (DFS) log (hazard ratio, HR). The smooth estimates of the logarithm of the DFS HR over time along with the 95% simultaneous confidence intervals. Values less than zero favor the bevacizumab (Bev) -containing arm.

Fig 5.

Disease-free survival (DFS) time by treatment interaction. (A) DFS before the 15-month landmark. The DFS during this initial period strongly and significantly favored the bevacizumab (Bev) arm (hazard ratio [HR], 0.61). (B) DFS subsequent to the 15-month landmark. The difference between the curves during this time was not significant (HR, 1.22). The time-by-treatment interaction using the 15-month landmark is highly significant (P < .0001).

Fig A1.

Time to first diagnostic imaging. The time to first diagnostic imaging is illustrated for patients in the control arm who received 6 months of therapy (mFF6 [mFOLFOX6]; blue line) versus those on the experimental arm that contained bevacizumab (Bev; gold line), for which therapy was extended to 12 months. The shaded region represents the possible delay in time to first imaging experienced by patients in the Bev arm. HR, hazard ratio.

Fig A2.

Disease-free survival (DFS) adjusted for possible bias in time to imaging. Overall DFS for patients treated with mFF6 (mFOLFOX6) alone for 6 months or mFF6 for 6 months plus bevacizumab (mFF6 + Bev) for 12 months after correction for the potential bias in time to first imaging because of the differences in treatment duration. Unadjusted Bev results plotted for reference. HR, hazard ratio.

Fig A3.

(A-B) Disease-free survival (DFS) time by treatment interaction adjusted for possible bias in time to imaging. (A) DFS before the 15-month landmark. The DFS during this initial period strongly and significantly favored the bevacizumab arm (Bev; HR, 0.71). (B) DFS subsequent to the 15-month landmark. DFS during this time was not significantly different (HR, 1.12). The time-by-treatment interaction using the 15-month landmark was highly significant (P = .0066), confirming that the effect of Bev on DFS differs between epochs defined by the landmark.