Avastin fails to live up to expectations for extending survival in ovarian cancer

Cancer drug Avastin has been found to add about four months to the time it takes for the cancer to worsen for women with advanced cases of ovarian cancer says a new report. However it may not extend survival significantly.

Patients treated with Avastin in addition to chemotherapy had about 14 months before their advanced ovarian cancer progressed, compared to about 10 months for those in the study who were  treated with chemotherapy and a placebo or dummy.

An early analysis of the trial's results was presented in June 2010 at the meeting of the American Society of Clinical Oncology; the complete report from the trial appeared Wednesday in the journal New England Journal of Medicine.

This was the third clinical trial to show that adding Avastin to standard chemotherapy treatments extends the time before ovarian cancers progress, said Dr. Carol Aghajanian, chief of gynecologic medical oncology service at Memorial Sloan-Kettering Cancer Center in New York City. “This is good news for women with ovarian cancer,” said Aghajanian, who was not involved in the new study.

However, women treated with Avastin did not live any longer than other women in the study, according to the report. The European Commission approved Avastin as a treatment for ovarian cancer this month, but it is unclear whether the drug will be approved to treat this cancer in the United States, Aghajanian said. The Food and Drug Administration will be looking at the data.

The drug Bevacizumab, made by pharmaceutical company Genentech, is designed to inhibit the growth of blood vessels that feed a tumor. It is currently approved to treat certain types of colon, lung, kidney and brain cancers, while the FDA recently disallowed its use for breast cancer.

The Gynecologic Oncology Group (GOG) study, led by Dr. Robert Burger of Fox Chase Cancer Center in Philadelphia, looked at 1,873 ovarian cancer patients who had been assigned at random to three groups. Patients were treated at 336 medical centers in the United States, Canada, South Korea, and Japan. All had previously untreated, incompletely resectable, stage III or stage IV epithelial ovarian, primary peritoneal, or fallopian-tube cancer, for which they had undergone debulking surgery. One group received chemotherapy treatments along with a placebo; one received Avastin along with chemotherapy at the start of their treatment, then received only chemotherapy for the rest of their treatment; the third group received Avastin along with chemotherapy for the entirety of their treatment. The patients did not know which treatment they were receiving; neither did the doctors treating them.

The researchers measured the blood levels of a marker called CA-125 to determine whether the patients' cancers were progressing. CA-125 levels are a very early marker of worsening cancer, Aghajanian said. Levels of CA-125 begin to rise before a growing cancer is visible on a CT scan. “They used a very conservative method of measuring progression, so we can be certain that it's meaningful,” Aghajanian said.

The other phase III trial, the ICON7 (International Collaboration on Ovarian Neoplasms) study led by the U.K. Medical Research Council clinical trials unit, involved women with advanced-stage ovarian cancer but no visible residual disease, as well as some women with high-risk early-stage disease.

This trial examined the efficacy and safety of a lower dose of bevacizumab (7.5 mg/kg) for a shorter interval (5 or 6 cycles with chemotherapy, and up to 12 cycles afterward), said Dr. Timothy J. Perren of the Institute of Oncology at St. James’s University Hospital in Leeds, England, and his associates.

The 1,528 study subjects were treated at 263 medical centers in the United Kingdom, Germany, France, Canada, Australia, New Zealand, Denmark, Finland, Norway, Sweden, and Spain. They were randomly assigned to receive either standard carboplatin-plus-paclitaxel chemotherapy every 3 weeks for 6 cycles (764 patients), or the same chemotherapy plus concurrent 7.5 mg/kg bevacizumab, with the monoclonal antibody alone extended for 12 additional cycles (764 patients).

At the primary data analysis after a median follow-up of 19.4 months, the median progression-free survival was 19.0 months with the addition of bevacizumab, which was significantly longer than the 17.3-month progression-free survival with standard chemotherapy alone. Thus, the addition of bevacizumab prolonged progression-free survival by approximately 2 months. In addition, it increased the overall rate of treatment response by 19%, with a complete or partial remission rate of 67%, compared with 48% in the control group, Dr. Perren and his colleagues said

Whether Avastin could extend patients' lives is a tricky question to try to answer with studies, Aghajanian said. At the end of this trial, for example, the patients and their doctors were told whether they had received Avastin or the placebo treatment, and it was entirely possible that those who had been on the placebo then received Avastin she explained. Such a crossover in treatments after a study's conclusion would make it difficult to later determine whether patients who received a drug during a trial lived longer.

However, both study groups showed improved global quality of life on two EORTC (European Organization for Research and Treatment of Cancer) QoL questionnaires, and differences between the two groups were not clinically significant.

Avastin has been trialed in breast cancer. There are important differences between the studies of Avastin as a treatment for breast cancer and the studies of its use for ovarian cancer, Aghajanian said. In November the FDA revoked its approval of Avastin to treat breast cancer because studies showed that breast cancer patients treated with it did not live any longer, and faced significant risks of severe side effects such as small holes developing in the intestines. The drug had been cleared by the FDA in February 2008 under an “accelerated approval” process based on promising early studies, allowing Avastin to be used for breast cancer patients while Genentech did further research. “There was not a consistent benefit seen in the breast cancer studies,” Aghajanian said. By contrast, three studies of the drug's use in ovarian cancer showed a consistent benefit.

The rate of patients who developed gastrointestinal perforations was twice as high among those who received Avastin as among those who received a placebo, but the rate was still under 3 percent. Elevated blood pressure was seen in more patients who received Avastin throughout the study than in those who received the drug only at the beginning or not at all.

After talking with the Food and Drug Administration, “we do not believe the data will support approval” although no final decision has been made, said Charlotte Arnold, a spokeswoman for Genentech, part of the Swiss company Roche. Avastin can still be sold for some colon, lung, kidney and brain cancers.

Dr. Gary Lyman, a Duke University researcher who was on the FDA advisory panel that recommended revoking Avastin's approval for breast cancer, wrote in an email that he agreed with the company's decision not to seek approval for ovarian cancer. “The situation is very similar” to the results in breast cancer, and approval is unlikely unless a biological marker or test can show which patients might benefit, he wrote.

About 220,000 new cases of ovarian cancer are diagnosed each year around the world, and it causes 140,000 deaths. In the United States, the National Cancer Institute estimates 22,000 new cases and 15,000 deaths each year.

The GOG study was funded by the U.S. National Cancer Institute and Genentech. The ICON7 study was funded by Roche (parent company of Genentech) and the U.K. National Institute for Health Research, through the U.K. National Cancer Research Network. Dr. Burger, Dr. Perren, and their associates reported numerous ties to industry sources.

Dr. Ananya Mandal

Written by

Dr. Ananya Mandal

Dr. Ananya Mandal is a doctor by profession, lecturer by vocation and a medical writer by passion. She specialized in Clinical Pharmacology after her bachelor's (MBBS). For her, health communication is not just writing complicated reviews for professionals but making medical knowledge understandable and available to the general public as well.


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