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Genentech’s Avastin is unlikely to show therapeutic benefit in the current C-08 trial for adjuvant colorectal cancer, physicians said. This, the physicians agreed, is because metastases may still occur in the adjuvant colorectal cancer setting despite the drug’s inhibition of angiogenesis.
As the actual mechanism of Avastin remains unknown, physicians said the drug may work on pathways other than vascular endothelial growth factor (VEGF).
Avastin, an anti-angiogenic agent, acts by inhibiting angiogenesis, the formation of new blood vessels, which could potentially supply the tumor with nutrients needed to proliferate. It is a monoclonal antibody targeting VEGF, and is approved by the FDA for the treatment of metastatic colorectal cancer and other solid tumors.
Angiogenesis occurs most often as the body grows and develops; it is less frequent in adults. Angiogenesis also often occurs in patients with cancer, however, where it creates new, small blood vessels that nourish a tumor with the nutrients it needs to grow.
In the adjuvant setting, as opposed to the metastatic setting, patients do not have rooted tumors. However, they might have tumors circulating in their blood stream which are approximately 100 to 1000 cells in size. Some physicians believe that giving patients Avastin could potentially keep these tumors from finding solid ground and growing.
Yet circulating tumor cells in the adjuvant could also possibly derive the nutrients needed to grow and thrive through diffusion, according to some physicians interviewed by this news service. If this is the case, then the cancer might still survive and grow, they said.
The ongoing C-08 trial is studying the effect of a combination of Avastin and 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) on prolonging disease-free survival. The secondary aim of the study is to examine the effect of the combination on prolonging survival overall.
”Patients with Stage III colon cancer are at risk for metastases and our hope is that we can reduce the risk of cancer relapse and metastases,” according to a Genetech spokesperson. ”Similar to our approach with Herceptin, we hope we can improve disease-free survival for patients with colon cancer,” she said.
Dr Alberto Sobrero, the director of medical oncology at the San Martino Hospital in Genoa, Italy, said the scientific rationale behind Avastin’s use in the adjuvant setting is not very strong, and he considers it unlikely the drug’s anti-angiogenic effects will work in this setting. In the adjuvant setting, patients may have small tumor deposits which are the size of several thousand cells, Sobrero explained, and cells in micrometastases may be able to soak up nutrients from the environment by diffusion and may not need blood vessels to survive.
Dr Axel Grothey, a colon cancer expert at the Mayo Clinic College of Medicine in Rochester, Minnesota, said, “I don’t think that it is safe to be used in this setting. I have a hard time seeing how Avastin would work in the adjuvant setting. We see that it works in colorectal cancer, but the presumed mechanism of action doesn’t lend itself to believe that it works in the adjuvant.”
The presumed mechanism of action of Avastin is based on anti-angiogenesis. By preventing the development of blood vessels, it increases the chemotherapy delivery, the normalization of blood vessels, and lowers interstitial pressure. These factors, however, do not apply to micrometastases, said Grothey.
One physician who spoke on background, also added that Avastin’s actual mechanism of action remains unknown, and agreed it remains unknown whether it will work in the adjuvant setting. “If micrometastases land in an organ and set up root, then Avastin could prevent the micrometastases from taking root, but nobody is sure how,” he said. However, it is possible that the tumor cells could be supplied nutrition through the process of diffusion.
Sobrero explained that, if the above is the case, then treatment with Avastin will not keep the cancer at bay because blood vessels are not needed for tumor proliferation and survival.
The current cost for Avastin is USD 15,000 for two months, and the cost of adjuvant therapy will also be very prohibitive, one physician estimated. Another physician speculated that an approximate cost for Avastin in the adjuvant setting would be close to half a million dollars for a two-year period.
Dr Rodrigo Erlich, an assistant professor of medicine at Johns Hopkins School of Medicine said Avastin’s effect of increasing tumor leakage and decreasing tumor interstitial pressure will probably not be effective when the drug is used in the adjuvant setting. “In patients who have microscopic disease, decreasing tumor interstitial pressure is not relevant,” Erlich said.
Dr Jochem van der Voort van Zyp, resident in radiation oncology at the Leiden University Medical Center in the Netherlands also said that, because it is possible that micrometastases derive their nutrients from diffusion, Avastin would theoretically not work in the adjuvant setting.
Zyp said, however, that Avastin’s efficacy in the adjuvant colorectal cancer setting could depend on the grade and aggressiveness of the tumor. “It could work from half a year to a year, and then the patient progresses,” he said.
Yet the theory behind Avastin’s use is that these small micrometastatic cells stay alive for at least one year, said Sobrero. “If Avastin was efficacious and the drug’s inhibitory message was removed, then the tumor cells would grow again,” he said.
In the adjuvant setting, it is believed that Avastin would need to be administered for prolonged periods of time in order to be effective, said Dr Erlich, who said he believed that a study examining the difference between prolonged administration of Avastin and FOLFOX, compared to brief administration, should be conducted.
Ongoing trials testing Avastin’s use in the adjuvant colorectal setting are also administering the drug in combination with cytotoxic drugs. “I don’t think that patients should get cytotoxic drugs for a prolonged period of time, such as the drugs that are being given in the adjuvant setting,” said Dr Pasquale Comella, a physician and research scientist at the National Tumor Institute in Naples, Italy.
Dr Yubao Wang, a GI oncologist at the University of Texas Health Science Center said these drugs could prove very profitable in the adjuvant setting, but that he felt it will be very difficult for them to show benefit in that setting.
Patients in the adjuvant setting are healthier than in the metastatic setting, so the risk-benefit profile of this agent will also be a significant factor, he said.
Dr J. Leonard Lichtenfeld, deputy chief medical officer for the national office of the American Cancer Society, said if Avastin could markedly improve survival, then there will be more of a willingness from physicians to accept serious adverse reactions. The exact duration of treatment needed in adjuvant colorectal cancer, however, remains unknown, he said.
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