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The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is the largest randomized clinical trial to evaluate screening’s impact on ovarian cancer mortality, assigning women to multimodal screening (MMS) with serum cancer antigen 125 (CA-125) interpreted using a risk algorithm. If the MMS screening method is eventually shown to reduce mortality and be cost-effective, then it may be accepted by the medical community as a feasible screening tool.To estimate the cost-effectiveness of an MMS screening program in the United States.A Markov simulation model was constructed using data from UKCTOCS to compare MMS with no screening in the United States. Screening would begin at the age of 50 years for women in the general population. Published estimates of the long-term effect of MMS screening on ovarian cancer mortality and the trial’s published hazard ratios were used to simulate mortality estimates up to 40 years from start of screening. Base-case costs included CA-125, ultrasound, and false-positive work-up results, in addition to a risk algorithm cost estimate of $100. The utility and costs of ovarian cancer treatment were incorporated into the model.Screening strategies varied by costs of the algorithm and treatment for advanced ovarian cancer, rates of screening compliance, ovarian cancer incidence, and extrapolation of ovarian cancer mortality.Costs, quality-adjusted life-years (QALYs), and mortality reduction of ovarian cancer screening.Multimodal screening is both more expensive and more effective in reducing ovarian cancer mortality over a lifetime than no screening. After accounting for uncertainty in the underlying parameters, screening women starting at age 50 years with MMS is cost-effective 70% of the time, when decision makers are willing to pay $150 000 per QALY. Screening reduced mortality by 15%, with an incremental cost-effectiveness ratio (ICER) ranging from $106 187 (95% CI, $97 496-$127 793) to $155 256 (95% CI, $150 369-$198 567).Ovarian cancer screening is potentially cost-effective in the United States depending on final significance of mortality reduction and cost of the CA-125 risk algorithm. These results are limited by uncertainty around the effect of screening on ovarian cancer mortality beyond the 11 years of UKCTOCS.