ORLANDO - A new analysis finds that bevacizumab was an independent risk factor for gastrointestinal adverse events in a pivotal phase III trial supporting addition of the antiangiogenic therapy to front-line chemotherapy for advanced ovarian cancer and related malignancies.
Adjuvant bevacizumab (Avastin) approximately doubled the risk of perforation, fistulae, necrosis, or hemorrhage in women with newly diagnosed epithelial ovarian, primary peritoneal, or fallopian tube cancers in the Gynecologic Oncology Group (GOG) 218 protocol (odds ratio, 2.15), Dr. Robert A. Burger reported at the annual meeting of the Society of Gynecologic Oncologists.
Dr. Robert A. Burger
A history of inflammatory bowel disease (IBD) or large-bowel resection at the time of primary surgery also significantly increased a woman’s chance of developing a GI event, he said; such a history does not rule out treatment with bevacizumab, but patients should be informed of their risk factors.
"The clinical impact of any of these [GI] events cannot be minimized, even though they are uncommon. When you get one, it can be disastrous," said Dr. Burger, director of the women’s cancer center and attending surgeon in gynecologic oncology at Fox Chase Cancer Center in Philadelphia.
At the plenary session during the 2010 annual meeting of the American Society of Clinical Oncology, Dr. Burger had reported that bevacizumab increased median progression-free survival by 3.8 months in the trial (that is, 14.1 months with the addition of bevacizumab to standard chemotherapy followed by maintenance bevacizumab vs. 10.3 months with standard chemotherapy and placebo).
Preliminary results from a second phase III trial – the ICON-7 study that was presented at the European Society of Clinical Oncology annual meeting this past fall – also showed an improvement: Median progression-free survival increased from 17.3 months with standard first-line chemotherapy to 19 months with the addition of bevacizumab.
Bevacizumab is not currently indicated for ovarian cancer, but Roche announced that it has applied for marketing approval in Europe and plans to apply in the United States this year. A study published March 7 in the Journal of Clinical Oncology concluded that adding bevacizumab to standard chemotherapy for advanced ovarian cancer is not cost effective (J. Clin. Oncol. 2011 March 7 [doi:10.1200/JCO.2010.32.1075]).
The GOG 218 trial randomized 1,873 women to three first-line treatment regimens. Participants had stage III or IV cancer, were treatment naive, and underwent tumor debulking prior to randomization.
Dr. David O'Malley
All participants received six cycles of platinum-taxane chemotherapy. Patients in arm 1 also received a placebo for cycles 2-22; patients in arm 2 also received bevacizumab (15 mg/kg) for cycles 2-6 and then placebo for cycles 7-22; and patients in arm 3 also received the same dose of bevacizumab for cycles 2-22.
In the new analysis, Dr. Burger and his associates assessed patient history for multiple factors, including GI disorders; chronic corticosteroid or NSAID use for any indication; small- or large-bowel resection at time of primary surgery or with anastomosis; cardiovascular disease; diabetes; smoking; and autoimmune disease. Complete history was available for 1,759 patients.
A total of 50 women (2.8%) experienced a grade 2 or greater GI adverse event, said Dr. Burger. These adverse events occurred in 1.7% (10 of 587) women who were treated only with standard therapies, compared with 3.4% of the two bevacizumab arms (20 of 587 women in arm 2, and 20 of 585 women in arm 3).
"Overall, 92% of GI adverse events occurred during the cytotoxic phase, most by cycle 4," Dr. Burger said.
IBD treatment, small-bowel resection, and large-bowel resection were each significantly associated with higher likelihood of a GI adverse event in univariate analyses. There were no associations with age, baseline performance status, stage, or residual disease after debulking surgery.
In a multivariate analysis, treatment of IBD (OR, 13.4) and large-bowel resection at time of primary surgery (OR, 2.05) remained significantly associated with GI adverse events, but small-bowel resection at time of primary surgery (OR, 1.95) was no longer significant. After controlling for these factors, researchers found that the risk of a GI adverse event more than doubled with receipt of bevacizumab (OR, 2.15) when both bevacizumab arms were combined, compared with placebo.
"This is an interesting and thought-provoking study. It addresses a very relevant question we all face with patients with advanced ovarian cancer," commented Dr. David O’Malley of the Ohio State University, Columbus, in an invited discussion of the study.
GI side effects are "still a relatively rare event, with only 50 GI adverse events identified," he noted, but he also cited a 2.5% overall incidence of fatal adverse events associated with bevacizumab that was reported in a recent meta-analysis (JAMA 2011:305:487-94).