A drug designed to cut off a tumor's blood supply, when paired with a chemotherapy combination, resulted in significant improvement in survival in patients with metastatic colorectal cancer, the first time in decades that survival times have been extended in patients with this devastating form of advanced cancer.
The results of the study, done at UCLA's Jonsson Cancer Center and several other sites nationwide, appear June 3, 2004 in the New England Journal of Medicine.
The study paired the angiogenesis inhibitor Avastin, approved by the U.S. Food and Drug Administration in February for use in colorectal cancer, with irinotecan, 5-fluorouracil and leucovorin. The combination therapy improved median survival in patients by nearly five months, reducing risk of death by more than 30 percent. It also improved response rates, duration of response and progression-free survival times, said Dr. Fairooz Kabbinavar, a Jonsson Cancer Center researcher and senior author of the study.
"To put this study in the right perspective, up until the year 2000, median survival in patients with advanced colorectal cancer was about 12 months," said Kabbinavar, an associate professor of hematology/oncology who has been working with Avastin for the last 10 to 12 years, both in the lab and in the clinic. "In just four short years, we're now looking at survivals in excess of two years. We've come a long way. Avastin has not only changed the way we treat colorectal cancer, but I believe it will become a part of cancer management for other tumors such as lung, breast and pancreatic cancers."
A tumor cannot grow bigger than a pinhead unless it establishes an independent blood supply through a process called angiogenesis. This process provides the tumor with the oxygen and nutrients it needs to grow and spread. Researchers have theorized that by stopping or cutting off the new blood supply, they can starve and, hopefully, kill the cancer. Researchers had hoped that Avastin - a monoclonal antibody that targets the Vascular Endothelial Growth Factor (VEGF), a dominant protein that promotes growth of blood vessels - would help the chemotherapy work more effectively, and vice-versa, providing what is called a synergistic effect. Kabbinavar said the study proved there is such an effect.
"This is an important milestone in cancer management in general and in colorectal cancer management in particular," Kabbinavar said. "Avastin is the first angiogenesis inhibitor to be approved by the FDA, and we found it has manageable toxicity. So patients not only live longer, but their quality of life is also maintained."
In the study, 813 patients with previously untreated advanced colorectal cancer were randomly assigned to two groups. In one group, 402 patients received irinotecan, 5-fluorouracil and leucovorin plus Avastin. The other 411 patients received the chemotherapy combination plus a placebo. The studied looked at overall survival, progression-free survival, the response rate, duration of the response, safety and quality of life.
Median survival, the time at which half of study patients are still alive, in the group getting Avastin with chemotherapy was 20.3 months compared to 15.6 months in those getting chemotherapy and a placebo, reducing risk of death by 34 percent. Progression-free survival, the time before the cancer continues to grow again, was10.6 months in the Avastin group compared to 6.2 months in the placebo group. Response rates in the Avastin group were 44.8 percent, compared to 34.8 percent in the placebo group. Response duration in the Avastin group was 10.4 months, compared to 7.1 months the group getting the placebo with chemotherapy.
"The addition of (Avastin) to 5-fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer," the study states.
After several disappointments with angiogenesis inhibitors, this study proves that targeting a tumor's blood supply is a viable treatment option, Kabbinavar said.
According to the American Cancer Society, colorectal cancer will strike more than 146,000 Americans this year alone, killing about 56,730. Overall, colon cancers are the third most common cancers in men and women, and the second leading cause of cancer death in the United States.
UCLA's Jonsson Comprehensive Cancer Center is composed of more than 240 cancer researchers and clinicians engaged in cancer research, prevention, detection, control and education. The center, one of the nation's largest comprehensive cancer centers, is dedicated to promoting cancer research and applying the results to clinical situations. In 2003, the Jonsson Cancer Center was named the best cancer center in the western United States by U.S. News & World Report, a ranking it has held for four consecutive years.
For more information on the Jonsson Cancer Center, visit our web site at http://www.cancer.mednet.ucla.edu.
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