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NSABP C-08: Bevacizumab plus standard therapy failed to improve DFS in early-stage colon cancer
2009 ASCO Annual Meeting
Results of the NSABP Protocol C-08 indicated that adding bevacizumab to standard adjuvant chemotherapy of FOLFOX6 did not improve DFS in patients with early-stage colon cancer.
“The hope was that because bevacizumab in metastatic colon cancer can prolong survival, by adding it to a regimen in early-stage colon cancer we could increase the rate of cure,” Norman Wolmark, MD, chairman of the department of human oncology at Alleghany General Hospital, said during a presentation at the 2009 ASCO Annual Meeting.
However, the trial failed to meet its primary endpoint.
Researchers enrolled 2,710 patients and randomly assigned them to six months chemotherapy with FOLFOX6 or six months FOLXFOX6 plus bevacizumab (Avastin, Genentech) plus an additional six months bevacizumab after chemotherapy had ended. The primary endpoint was DFS. Median follow-up was three years.
At three years, 77.4% of patients assigned bevacizumab were alive and free of disease compared with 75.5% of patients assigned standard chemotherapy. “There was an absolute difference of 2% in favor of bevacizumab at three years with an HR of 0.89 and a P value that was not statistically significant,” Wolmark said. “This was disappointing.”
At one year, bevacizumab had a “robust effect,” Wolmark said. There was a 40% reduction in the event rate (P=.0004) with bevacizumab. However, after one-year this effect disappeared.
“Clearly the addition of bevacizumab to standard chemotherapy did not result in an overall statistically significant prolongation in disease free survival and clearly the prespecified and hoped for endpoint of the trial, to increase the cure rate of early-stage colon cancer, was simply not met,” Wolmark said. “Having said that, it is clear that there was statistically significant transient benefit in DFS during the one year that bevacizumab was given.
“Clearly, strong consideration should be given to clinical trials that use bevacizumab for periods of time well beyond the one year that was used in NSABP Protocol C-08. We hope to start a trial in the not too distant future where we do use bevacizumab for a period of about two years,” he said. – by Leah Lawrence
This is a significant negative trial. Bevacizumab is now part of standard first-line chemotherapy in colon cancer. Studies in both first- and second-line chemotherapy showed improvements in response rate, time to progression and median survival. Particularly, in the older trials with IFL and second-line trials with FOLFOX, bevacizumab improved outcome. So there was a lot of hope that adding bevacizumab to adjuvant chemotherapy would have an impact based on promising results in metastatic disease. However, the trial did not meet the primary endpoint, which was to improve three-year DFS. It was about 75% in both arms. There was no significant difference, despite an early trend toward improved DFS within the first two years. The negative results indicate that bevacizumab should not be incorporated into adjuvant treatment and should be reserved only for use in metastatic disease.
The early trend toward improved DFS does not argue to treat all patients with bevacizumab to salvage some early failures, when there is may be no survival difference, is not justifiable. To propose to look at another trial in all patients extending the use of bevacizumab is not justifiable. If we can identify a subset of patients that may benefit, then that group could be targeted in another trial.
- David Ilson, MD
HemOnc Today Editorial Board member
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