Bevacizumab Combined With Oxaliplatin-Based Chemotherapy Prolongs Survival for Previously Treated Patients With Advanced Colorectal Cancer
Preliminary results from a large, randomized clinical trial for patients with advanced colorectal cancer who had previously received
treatment show that those who received bevacizumab (Avastin) in combination with an oxaliplatin (Eloxatin) regimen known as FOLFOX4 lived
longer than patients who received FOLFOX4 alone.
The Data Monitoring Committee overseeing the trial (known as E3200)* recommended that the results of a recent interim analysis be made
public because the study had met its primary endpoint of demonstrating improved overall survival. Researchers found that the patients in the
trial who received bevacizumab in combination with FOLFOX4 (a regimen of oxaliplatin, 5-fluorouracil and leucovorin) had a median overall
survival of 12.5 months compared to patients treated with FOLFOX4 alone, who had a median overall survival of 10.7 months. This difference is
statistically significant and corresponds to a 17 percent improvement in median overall survival. There was a 26 percent reduction in the risk
of death (hazard ratio of 0.74) for patients in this study who received bevacizumab plus FOLFOX4 compared to those who received FOLFOX4
alone.
The clinical trial was sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, and conducted by a
network of researchers led by the Eastern Cooperative Oncology Group. Genentech, Inc., which manufactures bevacizumab, provided bevacizumab
for the trial under the Cooperative Research and Development Agreement (CRADA) with NCI for the clinical development of bevacizumab.
Sanofi-Synthelabo, a member of the Sanofi-Aventis Group and manufacturer of oxaliplatin, provided that drug for the trial under its CRADA with
NCI.
"These results are simply more good news for people with colorectal cancer," said Study Chair Bruce J. Giantonio, M.D., of the University of Pennsylvania's Abramson Cancer Center in Philadelphia. "We now know that bevacizumab added to second-line chemotherapy with FOLFOX4 improves survival. With these findings, we can now more confidently expect survival for people with advanced disease to be more than double what it was just a few years ago." According to Giantonio, preliminary results of the E3200 trial will be presented at the ASCO Gastrointestinal Cancers
Symposium to be held in Hollywood, Fla., on Jan.27-29, 2005.
"This trial highlights benefits of the public-private collaborations that NCI has spearheaded over the last several years," said James H.
Doroshow, M.D., director of NCI's Division of Cancer Treatment and Diagnosis and leader of NCI's Clinical Trials Working Group. "Working with
the biotechnology and pharmaceutical companies, NCI was able to coordinate the drug development of these two new agents (bevacizumab and
oxaliplatin) in combination and, through the dedication and commitment of the patients and physicians who participated in the study, provide an
important advance for patients."
A total of 829 patients were enrolled in the study between October 2001 and April 2003. Patients previously had received a
fluorouracil-based therapy and irinotecan (Camptosar), either alone or at the same time, for advanced disease or if their disease had relapsed
within six months of concluding adjuvant (post-surgical) treatment with these chemotherapy agents. Patients were randomized to one of three
treatment groups. One patient group received the standard FOLFOX4 treatment plus bevacizumab. The second group received the standard FOLFOX4
treatment only, and the third group received bevacizumab alone. In March 2003, the study investigators suspended randomization to the third
treatment arm, bevacizumab alone, on the recommendation of the Data Monitoring Committee when review of early results suggested that overall
survival for patients in that group might be lower than that of patients treated in the other two groups.
Treatment toxicities observed in this study were consistent with those side effects observed in other clinical trials in which bevacizumab
was combined with chemotherapy. Side effects included neuropathy (problems with nerve function) for FOLFOX4 and high blood pressure and
bleeding for bevacizumab.
Bevacizumab is designed to bind to and inhibit Vascular Endothelial Growth Factor (VEGF), a protein that plays a critical role in tumor
angiogenesis, the formation of new blood vessels to the tumor. Oxaliplatin is a novel platinum-based anticancer drug that destroys cancer
cells.
"The results of this study are very important for all those living with advanced colorectal cancer," said NCI Director Andrew C. von
Eschenbach, M.D. "They provide further confirmation that a biologic agent that targets a tumor's blood supply can prolong survival when
combined with chemotherapy, even for patients who have previously received therapy for advanced disease."
An estimated 106,370 people will be diagnosed with colon cancer and an estimated 40,570 people will be diagnosed with rectal cancer in the
United States in 2004. Colorectal cancer is the third most commonly diagnosed cancer in this country both in men and in women. An estimated
56,730 deaths from colorectal cancer will occur in 2004 in the United States, accounting for about 10 percent of all cancer deaths in the
nation.
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For more information about cancer, visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer
Information Service at 1-800-4 CANCER (1-800-422-6237).
* E3200: Phase III Trial of Bevacizumab, Oxaliplatin, Fluorouracil and Leucovorin Versus Oxaliplatin, Fluorouracil and Leucovorin Versus
Bevacizumab Alone in Previously Treated Patients With Advanced Colorectal Cancer.
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