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Adding bevacizumab to oxaliplatin-based chemotherapy for metastatic colorectal cancer improved progression-free survival but did not extend overall survival, according to data from an open-label study.
Median overall survival was about 20 months in XELOX1/NO16966 trial, which was led by Dr. Leonard B. Saltz of Memorial Sloan-Kettering Cancer Center in New York.
A total of 1,400 patients were evenly randomized to the study's four arms: XELOX (oxaliplatin and capecitabine) plus placebo, XELOX plus bevacizumab, or FOLFOX4 (oxaliplatin, 5-fluorouracil, and leucovorin) with either placebo or bevacizumab.
Fifty-nine percent of the patients were men, and the median age was 60.5 years.
Response rates were the same among the four treatment arms. However, median progression-free survival was 10.4 months for bevacizumab plus XELOX or FOLFOX4, compared with 7.9 months in the no-bevacizumab arms.
The difference was significant (P = .0001). Times to treatment failure were 6.9 months in the bevacizumab arms and 6 months in the no-bevacizumab arms, which also was a significant difference (P =.0030).
Patients who were in the XELOX arms received either placebo or intravenous bevacizumab at 7.5 mg/kg over 30-90 minutes on day 1. They also received IV oxaliplatin 130 mg/m² over 2 hours on day 1, and capecitabine 1,000 mg/m² orally twice daily on days 1 through 4. This schedule was repeated every 3 weeks.
In the FOLFOX arms, bevacizumab or placebo was dosed at 5 mg/kg, oxaliplatin at 85 mg/m², folinic acid at 200 mg/m² IV over 2 hours on days 1 and 2, fluorouracil 400 mg/m² IV bolus on days 1 and 2, and fluorouracil 600 mg/m² IV by infusion over 22 hours on days 1 and 2.
The duration of treatment was similar in the bevacizumab and placebo arms, although only 29% of bevacizumab recipients and 44%-50% of placebo recipients were treated until disease progression, the authors said.
A higher proportion of patients discontinued therapy because of adverse events in the bevacizumab arms than in the placebo arms (31% vs. 21%).
Most treatment discontinuations were due to chemotherapy rather than to bevacizumab-related events, the investigators said.
The most common reasons for stopping treatment were neurotoxicity, gastrointestinal events, general disorders, and hematologic events.
The authors concluded that their analysis of "on treatment" vs. "general" progression-free survival suggests that continuation of bevacizumab until disease progression may be necessary to optimize the effect of the drug on progression-free survival.
"It would appear from this study that bevacizumab does add to the benefit of oxaliplatin-based regimens, but not as dramatically as it has in previously reported irinotecan studies," said Dr. Richard Goldberg in a discussion of the trial.
"Should chemotherapy plus bevacizumab be continued when oxaliplatin must be stopped? Yes, probably," recommended Dr. Goldberg, who is chief of the division of hematology-oncology at the University of North Carolina at Chapel Hill.
A troubling issue in this study is the fact that response rates were identical whether or not bevacizumab was added to the chemotherapy regimen, according to Dr. Goldberg.
That finding might indicate that first-line treatments are not being optimized, he concluded.
Saltz L. et al. Bevacizumab (Bev) in combination with XELOX or FOLFOX4: Updated efficacy results from XELOX-1/NO16966, a randomized phase III trial in first-line metastatic colorectal cancer. Abstract 4028.
Commentary |
This large, international phase III trial demonstrates that the addition of bevacizumab to oxaliplatin-based chemotherapy regimens significantly improves the rate of progression-free survival. Front-line therapy with an oxaliplatin-bevacizumab containing regimen is an acceptable combination, improving progression-free survival with acceptable safety. — Stuart M. Lichtman, M.D.
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