The results of a large, multicenter trial showed that the addition of bevacizumab to adjuvant chemotherapy failed to improve disease-free survival (DFS) compared with chemotherapy alone. In fact, DFS headed in the wrong direction when bevacizumab, an angiogenesis inhibitor, was added to either of 2 different adjuvant chemotherapy regimens, reported Aimery de Gramont, MD. The hazard increased by 7% with 1 chemotherapy regimen and by 17% with the other, as compared with the FOLFOX (folinic acid/fluorouracil/ oxaliplatin) chemotherapy regimen alone.
"The chemotherapy-alone arm was favored numerically," noted de Gramont, an oncologist at Hopital Sainte-Antoine in Paris, France. "A preliminary analysis of overall survival [OS] suggests a potential detriment of adding bevacizumab to adjuvant chemotherapy."
He said, "The effect of bevacizumab treatment was not constant over time. A transient favorable effect was observed within 1 year. The treatment effect became unfavorable after 1 year."
De Gramont pointed out that bevacizumab is the third to show benefit in advanced colorectal cancer, yet it subsequently misses the mark as adjuvant therapy, joining irinotecan and cetuximab. All 3 drugs inhibit vascular endothelial growth factor (VEGF), but whether that is a coincidence or a biologically important issue has not been determined.
The rationale for evaluating bevacizumab as adjuvant therapy in colorectal cancer has support from evidence linking VEGF and angiogenesis to tumor growth and from trials showing improvement in DFS in the metastatic setting. Moreover, a study coordinated by the National Surgical Adjuvant Breast and Bowel Project (NSABP) showed a DFS benefit of adjuvant bevacizumab for the first 15 months of follow-up, but the difference was not statistically significant thereafter.
De Gramont reported on a trial involving 3451 patients with stage II/III colorectal cancer who were randomized to postoperative FOLFOX chemotherapy alone, FOLFOX plus bevacizumab, or XELOX chemotherapy plus bevacizumab for 6 months. Patients in both bevacizumab arms then received bevacizumab maintenance therapy for an additional 6 months. The primary endpoint was DFS, and de Gramont reported findings from a subgroup of 2867 patients with stage III cancer and a minimum follow-up of 3 years. The analysis showed that patients randomized to FOLFOX plus bevacizumab had a hazard ratio (HR) of 1.17 compared with FOLFOX alone. The XELOX/ bevacizumab arm had an HR of 1.07 versus the control arm. Neither difference was statistically significant.
A preliminary analysis of OS added to the evidence of a potential increase in the HR for patients who received the angiogenesis inhibitor. The FOLFOX/bevacizumab arm had a 1.31 survival hazard, and the confidence intervals did not overlap (HR, 1.03-1.67). The XELOX/bevacizumab regimen was associated with a 27% increase in the HR, which just missed statistical significance (HR, 0.99-1.62).
"I emphasize that the data on overall survival are immature, but they do suggest a potential detriment at this point," said de Gramont.
Johanna C. Bendell, MD, of the Sarah Cannon Cancer Research Institute in Nashville, Tennessee, was one of the invited discussants at the Gastrointestinal Cancers Symposium. She pointed out that results of the NSABP trial and the results reported by de Gramont differed in several respects. In the NSABP study, adjuvant bevacizumab conferred a consistent numerical benefit for DFS throughout follow-up, although the difference did not achieve statistical significance. In contrast, de Gramont's report showed that DFS favored chemotherapy alone after the first 15 months of follow-up.
Bendell suggested that the DFS detriment at 2 years and beyond might reflect a rebound effect after discontinuation of bevacizumab. The preliminary analysis of OS also suggests a possible rebound effect. She also noted that substantially more patients in the chemotherapyalone arm received bevacizumab after recurrence than did patients in the other 2 arms (35% vs 16% and 20%), which might have influenced survival.
________________________________________________________de Gramont A, Van Cutsem E, Tabernero J, et al. AVANT: Results from a randomized, three-arm multinational phase III study to investigate bevacizumab with either XELOX or FOLFOX4 versus FOLFOX4 alone as adjuvant treatment for colon cancer. Paper presented at: 2011 Gastrointestinal Cancers Symposium; January 2011; San Francisco, CA.Published in Oncology & Biotech News. February 2011.