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Big costs for little gain in ovarian cancer.

The results of the GOG 218 (Gynecologic Oncology Group) study were reported in abstract form at the 46th Annual Meeting of the American Society of Clinical Oncology in June 2010. In this threearm randomized phase III study, women with advanced epithelial ovarian cancer (stage III or IV, after maximal attempt at surgical debulking) were assigned to treatment with paclitaxel plus carboplatin followed by placebo (PC), paclitaxel plus carboplatin plus bevacizumab followed by placebo (PCB), or paclitaxel plus carboplatin plus bevacizumab followed by bevacizumab maintenance (PCB-B). Bevacizumab or placebo was administered at 15 mg/kg every 3 weeks, with the first five cycles administered concurrently with cycles two to six of chemotherapy and an additional 17 cycles delivered as single-agent maintenance treatment. Progression-free survival (PFS) was 10.3 months in the PC arm; 11.2 months, PCB; and 14.1 months, PCB-B. The 3.8-month improvement in PFS came at the cost (in terms of patient inconvenience and toxicity) of women receiving treatment every 3 weeks for an additional 51 weeks beyond the standard duration, a 23% risk for developing grade 2 hypertension, 10% risk for grades 3 to 4 hypertension, and 2.3% risk for grade 3 or worse GI perforation, hemorrhage, or fistula formation. At present, there seems to be no difference in overall survival among the treatment arms, although data are not yet mature. In this issue of Journal of Clinical Oncology, Cohn et al report on the potential cost effectiveness of adding bevacizumab to first-line treatment of advanced epithelial ovarian cancer. Here, cost refers only to the additional monetary expenditure incurred by adding bevacizumab to standard paclitaxel/carboplatin treatment. The authors provide a simplified cost-effectiveness analysis using standard methodology. No actual cost data were collected in GOG 218. The authors use estimates of drug costs using Medicare reimbursement rates. The model does not include any indirect costs (patient out-ofpocket expenses, time lost from work for 51 weeks of maintenance treatment, and so on). The only costs of toxicity that are included are the estimated costs for management of intestinal perforation. Specifically, the model does not include the costs of management of grade 2 or worse hypertension or other chemotherapyor bevacizumabassociated morbidities. Including direct and indirect costs of managing hypertension would only increase the size of the numerator and worsen the cost-effectiveness ratio. Results of the model reported by Cohn et al show that PCB-B costs $78.3 million ($1,305,000 per patient) and has an incremental cost-effectiveness ratio (compared with referent PC) of $401,088 per progression-free year of life saved. It should be noted that most costeffectiveness analyses model the costs of improvements in overall survival or quality-adjusted overall survival (true effectiveness) and compare the results with a traditional bar for what may be considered cost effective: $50,000 per year of life saved or, more recently, $100,000 per year of life saved. The choice by Cohn et al to model PFS was presumably a practical one; they simply did not have any mature overall-survival data to model. However, it is worth considering the implications of this choice. In basic terms, when we provide health care to patients (in frank terms, when we buy chemotherapy or pain medications or vaccinations against measles), there should be a gain in the patient experience (ie, longer life, relief of suffering, or prevention of widespread morbid disease among children). Modeling PFS presumes that those 3.8 months of progression-free time yield a tangible improvement in the patient experience. This may not be the case. The use of cancer antigen 125 and periodic computed tomography imaging means that most recurrences in ovarian cancer are found while patients are asymptomatic. It is not a given that remaining radiographically progression free for an extra 3.8 months would improve a patient’s quality of life. It is rather unlikely that it would translate into a quality-adjusted improvement in overall survival. If GOG 218 shows that PCB-B yields no improvement in overall survival, then the cost effectiveness of PCB-B will be even farther from the bar of acceptability. Sensitivity analyses constitute a standard part of costeffectiveness analyses, permitting researchers to vary the assumptions in the model to determine the weight and size of the drivers of cost and necessary magnitude of benefit that would be required to approach the acceptable cost-effectiveness bar. Only when PFS with PCB-B was hypothetically extended to 32.1 months (observed PFS in GOG 218 was 14.1 months) did the incremental cost-effectiveness ratio approach $100,000 per progression-free year of life saved. The data for bevacizumab in ovarian cancer to date would suggest that PFS of 32.1 months is unlikely to be achieved. Even among better-risk patients with optimally debulked stage III ovarian cancer treated with intraperitoneal-based platinum/taxane therapy, median PFS is just 24 months. Although the denominator of the cost-effectiveness ratio (PFS or overall survival) may not be something that can plausibly be prolonged beyond what is observed in GOG 218, the numerator (drug costs) is a potentially alterable parameter. Cohn et al test differing bevacizumab prices to determine how low the cost would need to be to JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S