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Do We Have a New Standard of Care for Advanced Ovarian Cancer?
Abstract & Commentary
By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman serves as an uncompensated scientific advisor for and has received research funding from Genentech/Roche.
Synopsis: Bevacizumab, when added to standard chemotherapy and continued as maintenance therapy for women with advanced stage ovarian cancer, significantly improved progression-free survival, but at the expense of increased toxicity. Overall survival data are immature but unlikely to demonstrate a benefit.
Source: Burger RA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011;365:2473-2483.
Vascular endothelial growth factor (vegf) is a key factor in the normal and tumor microenvironment regulating angiogenesis. VEGF expression in tumor has been linked prognostically with poor survival characteristics in epithelial ovarian cancer, and targeting it, via several pharmaceutical strategies, has suggested clinical efficacy in this disease. Bevacizumab, a humanized monoclonal antibody-targeting VEGF ligand, has shown single-agent and combinatorial activity in women with recurrent tumors. The current trial, GOG-218, was a double-blind, placebo-controlled, Phase 3 study randomly assigning women with newly diagnosed stage III/IV epithelial ovarian cancer to receive one of three treatments after primary debulking surgery. All three arms included paclitaxel and carboplatin IV at standard doses for six every-3-week infusions. Arm I used a placebo during chemotherapy (starting on cycle 2) continuing throughout the intended maintenance period (to cycle 22). Arm II used bevacizumab (15 mg/kg) every 3 weeks with chemotherapy, but continued with placebo during maintenance to cycle 22. Arm III used bevacizumab (same dose) during chemotherapy and maintenance. The initial primary endpoint was overall survival (OS), but was changed to progression-free survival (PFS) during the trial due to concerns of investigators and patients regarding post-progression blinding. Overall, 1873 women were enrolled. The median PFS for the three arms were: 10.3 months (control group [Arm I]), 11.2 months (Arm II), and 14.1 months (Arm III). Relative to Arm I, the hazard ratio for progression or death in Arm II was 0.908 (95% confidence interval [CI], 0.795-1.040; P = 0.16), and 0.717 (95% CI, 0.625-0.824; P < 0.001) in Arm III. At the time of analysis, 76.3% of patients were alive, with no significant differences in OS among the three groups. Some toxicities, particularly those associated with bevacizumab, were higher in the arms receiving the agent such as: hypertension requiring medical therapy (Arm II: 16.5%, Arm III: 22.9%, vs Arm I: 7.2%, P < 0.05), and gastrointestinal-wall disruption requiring medical intervention (Arm II: 2.8%, Arm III: 2.6%, vs Arm I: 1.2%, P = NS). However, others, such as gastrointestinal perforation, thromboembolic disease, proteinuria, and wound disruption, were no different between the arms. The use of bevacizumab during and up to 10 months after carboplatin and paclitaxel chemotherapy prolongs the median PFS by about 4 months in patients with advanced epithelial ovarian cancer.
The importance of VEGF in ovarian cancer has been known for more than 2 decades and antedated the first indication of bevacizumab in cancer therapy. Elegantly described was its role in ascites formation, tumor edema and perfusion, tumor growth and proliferation, metastases, and progression.1 Since that time, and with the availability of multiple agents and strategies for targeting the VEGF:VEGFR axis and its downstream events, exploration in the clinic has been aggressively pursued.2 Early enthusiasm driving the conduct of several small prospective Phase 2 trials predominately in patients with recurrent disease produced remarkable clinical activity, particularly for bevacizumab. These provided the necessary backdrop for funding the large Phase 3 studies conducted now in both frontline (GOG-218 and ICON7) and in the recurrent setting (OCEANS, GOG-213, and AURELIA). In this issue of the New England Journal of Medicine, the two frontline trials were reported.3 The punch line from these two is similar and well known following their initial presentation at national and international meetings in 2010, both with updates in 2011. However, the results are thought-provoking, especially in light of the unprecedented and widely publicized FDA vs Genentech/Roche showdown last summer (with a final decision in late 2011) over the retraction of the FDA label of bevacizumab in metastatic breast cancer. At the core of that debate was modest gains for an intermediary endpoint, PFS, in the absence of gains in OS, and with an unfavorable toxicity profile.
The situation is remarkably similar to the data from the two newly published frontline ovarian trials. I've chosen to profile GOG-218 because this trial was conducted with regulatory intent and included several key controls and assessments lacking in ICON7. However, both trials raise a number of concerns about whether we can adapt these data for standard clinical care. The first is in the types of patients in whom the drug should be given. Ideally, a biomarker (blood, imaging, tumor) would help make that selection; however, it would appear that patients with the bulkiest disease might benefit the most. This may be because that cohort of patients is, in general, receiving bevacizumab until progression. The act of stopping bevacizumab at an arbitrary point before progression, as well as post progression bevacizumab use, probably explains the "catch-up" effect, which nullified the OS endpoint. The other issue, not addressed by either study, is whether administering bevacizumab only in the maintenance setting (and not with chemotherapy) could have delivered the same effect. The major issue for each of these trials relative to clinical care is how to balance interim gains, intended therapy, toxicity, and cost. The quality of life (QoL) survey performed in GOG-218 demonstrated no perceptible diminution despite the additional toxicity. However, it has been estimated that given these results, to be cost-effective, the magnitude of benefit for the bevacizumab arm (Arm III) would have to be three times greater than control (around 31 months) or be one-fourth the cost.4 And, if our strategy to maximize clinical efficacy is to administer bevacizumab, not for 22 cycles, but until progression, the cost would be even greater. One has to recall that about one-third of patients are cured with chemotherapy alone; in the absence of knowing who these individuals are, we are obligating them to a lifetime of therapy they never needed.
And so I raise the question, which titles this review, "Do we have a new standard of care?" The answer is not easy, but would be hard-pressed to support fully without FDA approval. It is reasonable, however, to consider it a standard in women with the most advanced disease (suboptimally debulked), but questions remain as to dose and duration, and when to administer the agent. Fortunately, two studies (one fully enrolled and one nearly fully enrolled) are poised to address some of these issues in the near future. Until then, there is opportunity to search for reliable biomarkers, other classes of agents to be looked at in combination with standard chemotherapy in this setting, and new strategies to use this clearly active and important biological therapeutic for our patients with ovarian cancer.