Previously treated patients with advanced colorectal cancer who received the anti-angiogenesis agent bevacizumab (Avastin) in combination with an oxaliplatin (Eloxatin)-based chemotherapy regimen lived longer than patients who received chemotherapy alone, researchers announced yesterday. The Data Monitoring Committee (DMC) overseeing the NCI-sponsored clinical trial in which the patients were enrolled, E3200, recommended that the results of a recent interim analysis be made public because the study had met its primary end point of demonstrating improved overall survival.

Patients in the trial who received the combination of bevacizumab and a chemotherapy regimen called FOLFOX4 (oxaliplatin, 5-fluorouracil, and leucovorin) had a median overall survival of 12.5 months compared with 10.7 months for patients treated with FOLFOX4 alone, a 17 percent improvement. Combination therapy patients had a 26 percent reduction in the risk of death compared with those who received chemotherapy alone.

"As this treatment was, at the very least, second line, this is a real and quite remarkable finding," says the study's lead investigator, Dr. Bruce Giantonio, of the University of Pennsylvania's Abramson Cancer Center. "These data - taken along with the advances seen with the introduction of irinotecan, oxaliplatin, bevacizumab, and cetuximab for treatment of colorectal cancer - suggest that the median survival for patients with metastatic disease will be 2 years or more."

The clinical trial, conducted by the Eastern Cooperative Oncology Group, included 829 patients enrolled between October 2001 and April 2003. Trial participants, all of whom previously had received a fluorouracil-based chemotherapy and irinotecan (Camptosar), were randomized to one of three treatment groups: the FOLFOX4 regimen plus bevacizumab, the FOLFOX4 regimen alone, or bevacizumab alone. On the DMC's recommendation, study investigators suspended randomization to the bevacizumab alone arm in March 2003 because early results suggested that patients in that group might have lower overall survival than patients in the other two arms.

Part of a new class of targeted therapies, bevacizumab binds to and inhibits vascular endothelial growth factor, which is thought to help tumors grow by providing a blood supply through the formation of new blood vessels. "The use of targeted therapies is a fundamental shift in the way we treat cancers," Dr. Giantonio notes, "and here we see evidence that even in more advanced, previously treated disease, such an approach carries benefit."

According to Dr. Meg Mooney, a senior investigator in the NCI Cancer Therapy Evaluation Program, laboratory and clinical research has pointed toward anti-angiogenesis as a logical route for treating colorectal cancer. As a result, she explains, the bevacizumab/ FOLFOX approach is now being tested in the adjuvant (post-surgical) setting for colon cancer "to see if we can increase the cure rate." NCI is currently sponsoring a trial led by the National Surgical Adjuvant Breast and Bowel Project, NSABP C-08, that is testing FOLFOX with or without bevacizumab in stage II and III colon cancer. That trial comes on the heels of the MOSAIC trial, published in June in the New England Journal of Medicine, which showed that use of FOLFOX increased 3-year disease-free survival in patients with stage III colon cancer, compared to standard therapy.