The average costs, life expectancy, and incremental cost-effectiveness ratios for each strategy are summarized in Table 3. Average life expectancy ranged from 74.52 years (reference strategy) to 74.60 years (annual screening). Discounted costs and life expectancy estimates were used to calculate incremental cost-effectiveness ratios and compare strategies. Life expectancy was expected to increase by only 0.0065 years (ie, 2 days) with OCPs for 5 years, at an incremental cost of $404,465 per year of life saved compared with the reference strategy. The incremental gains in life expectancy from biennial and annual screening were also inconsequential, resulting in highly unfavorable incremental cost-effectiveness ratios. These results were stable over a wide range of estimates. When OCPs were started at age 20, and when the duration of OCP use was increased to 10 years, there was no significant change in life expectancy, and the incremental cost-effectiveness ratios still remained well above $50,000 per year of life saved.
Obesity has been described as an epidemic, with a significant effect on health care costs and potential decline in life expectancy.45,46 Assuming that obesity still accounts for approximately 40% of all endometrial cancers, more than 16,000 cases of endometrial cancer will be attributed to obesity every year. Significant weight loss can occur with highly structured programs,47–49 but they may not provide long-term benefit.50 There are limited data on specific endometrial cancer prevention strategies for obese women if sustained weight loss cannot be achieved.
In our analysis, OCPs and screening for obese women reduced the overall number of endometrial cancer cases in a lifetime; however, the benefits of these interventions were inconsequential in terms of our primary outcome. The effect of an intervention (eg, OCPs to reduce endometrial cancer risk) is the gain in life expectancy averaged across the target population; therefore, the lower the disease-specific incidence and mortality, the smaller the incremental benefit of that intervention. Subsequently, the smaller the incremental benefit, the higher the incremental cost-effectiveness ratio. Cancer prevention strategies have proven to be cost-effective when the net health benefits are substantial, and this is most likely to occur when the baseline risks and mortality rates are high or when the magnitude of risk reduction approaches 100%, such as prophylactic mastectomy and oophorectomy for BRCA mutation carriers,51 or HPV vaccination for adolescents in the general population.52 As long as the overall risk and mortality of endometrial cancer in obese women remains relatively low and the extent of risk reduction by current prevention strategies is no greater than 50%, a cost-effective prevention strategy is unlikely for this specific population. The risk of endometrial cancer has to be 13 times the general population risk before OCPs yield an incremental cost-effectiveness ratio less than $50,000 per year of life saved. Most studies suggest a threefold relative risk of endometrial cancer among obese women,3,4,53 but it may be as high as 10-fold among women who are obese, diabetic, and inactive.5 Additional risk factors, such as morbid obesity (BMI more than 40) and a longstanding history of anovulation, may define a subgroup of women at highest risk of endometrial cancer for whom OCPs may be a cost-effective prevention strategy.
There are limited data on other risk-reducing interventions. The progestin-releasing intrauterine device (Mirena, Bayer HealthCare Pharmaceuticals, Morristown, NJ) can reverse early endometrial cancer in select cases54 and may be comparable to OCPs in reducing endometrial cancer risk. However, to maximize effectiveness for all obese women, the intervention should provide additional health benefits besides endometrial cancer risk reduction. Insulin-sensitizing drugs such as metformin can reverse polycystic ovarian syndrome,55 and they can also reduce fasting insulin levels, blood pressure, and low-density lipoprotein cholesterol.56–58 Aspirin can induce apoptosis in endometrial cancer cells,59 and it can also prevent occlusive vascular events.60 As a result, these drugs may not only decrease mortality attributable to endometrial cancer, but also to cardiovascular disease61,62 and therefore improve overall life expectancy to a greater extent than OCPs or screening alone. A combination of strategies such as OCPs with insulin-sensitizing drugs and/or aspirin may be the most effective intervention. If significant gains in life expectancy can be attained at reasonable cost, these chemopreventive strategies will likely be cost-effective for this population.
We did not model weight loss as a risk-reducing strategy because of limited empiric data supporting the magnitude and duration of benefit. Only about 15% of individuals are expected to have sustained weight loss with diet, group therapy, and/or behavior modification.63,64 According to a meta-analysis of randomized controlled trials of pharmacotherapy, mean weight loss is less than 5 kg.65 Even if weight loss outcomes from a clinical trial setting could be extrapolated to the general population, the extent of weight loss is unlikely to decrease endometrial cancer risk in obese women. Parker et al,66 from the Iowa Women’s Health study, reported that weight loss of 20 pounds was not associated with a reduction in endometrial cancer risk. Unless current obesity interventions are effective in restoring normal BMI, it is unlikely that they will have an effect on endometrial cancer risk.
Although the Monte Carlo simulation revealed that annual or biennial screening resulted in the lowest number of endometrial cancers in a lifetime, we assumed in our model that any abnormal screen would lead to surgery. This would include both true-positive (ie, diagnosis of cancer on screen and final pathology) and false-positive results (eg, complex atypical hyperplasia on screen but no cancer on final pathology). The lower the specificity of screening, the higher the rate of false positives, which leads to a higher rate of surgery and lower number of women at future risk for endometrial cancer. However, given the highly unfavorable incremental cost-effectiveness ratios associated with screening, this is not a cost-effective intervention.
There were a number of limitations of this analysis. First, we assumed that the extent of endometrial cancer risk reduction in obese women using OCPs was comparable to that in the general population, based on several large population-based and case-control studies that have all reported a significant risk reduction with prolonged use of OCPs, persisting for many years after discontinuation.4,6,7,9,10,13–16 However, Tao et al12 reported a nonsignificant odds ratio of 0.72 (95% confidence interval 0.46–1.15) for OCP use by obese women and 0.77 (95% confidence interval 0.53–1.11) after discontinuation, suggesting that the protective effect may be attenuated. Second, we may have overestimated the benefits of screening by assuming that all abnormal tests resulted in surgery, which would have decreased the lifetime risk of endometrial cancer. We did not model costs or effects of fertility-sparing treatment, which would have reduced rates of surgery and subsequently reduced the net benefits of screening. Finally, we assumed there were no contraindications to using OCPs, such as classic migraines or hypertension, but this may not be a realistic representation of obese women in the current U.S. population.
There has been tremendous publicity regarding cervical cancer prevention in the United States, yet endometrial cancer remains far more common than cervical cancer (40,100 and 11,070 cases in 2008, respectively).1,67 The cost of endometrial cancer treatment from a payer’s perspective is approximately $23,000 per case,36 excluding adjuvant therapy and patient opportunity costs (decreased work productivity during treatment), and this underscores the need for a cost-effective strategy to reduce the incidence of endometrial cancer. Clearly, the prevalence of obesity in our society must decrease, but the obvious endpoint of sustained weight reduction seems so difficult to achieve. In the interim, it may be possible to identify obese women at highest risk of endometrial cancer who would benefit from current preventive strategies. However, the longer the obesity epidemic continues, the more important it will be to establish prevention strategies that provide additional health benefits at acceptable cost to all women at risk within this population.
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