Obstetrics & Gynecology:
Cost-Effectiveness Analysis of Endometrial Cancer Prevention Strategies for Obese Women
Kwon, Janice S. MD, MPH; Lu, Karen H. MD
From the Department of Gynecologic Oncology, M. D. Anderson Cancer Center, Houston, Texas.
Corresponding author: Janice S. Kwon, MD, MPH, Department of Gynecologic Oncology, M. D. Anderson Cancer Center, PO Box 301439, Unit 1362, Houston, Texas; e-mail: firstname.lastname@example.org.
Financial Disclosure The authors have no potential conflicts of interest to disclose.
OBJECTIVE: It is unknown whether obese women would benefit from oral contraceptives or screening as endometrial cancer prevention strategies. We estimated the net health benefits and cost-effectiveness of these strategies in a hypothetical cohort of obese women.
METHODS: A Markov decision-analytic model evaluated 4 strategies: 1) no prevention (reference strategy); 2) oral contraceptive pills (OCPs) for 5 years; 3) annual screening with endometrial biopsy from age 30; 4) biennial screening from age 30. Net health benefit was life expectancy and primary outcome was the incremental cost-effectiveness ratio. Baseline and transition probabilities were obtained from published literature and the Surveillance Epidemiology and End Results database, and costs were from the U.S. Department of Health and Human Services and Agency for Healthcare Research and Quality. Sensitivity analyses were performed for uncertainty around various measures.
RESULTS: Average life expectancy for all strategies ranged from 74.52 to 74.60 years. None of the strategies had an incremental cost-effectiveness ratio less than $50,000 per year of life saved relative to the next best strategy. Endometrial cancer risk in obese women had to be 13 times greater than the general population risk before OCPs were a cost-effective intervention.
CONCLUSION: Oral contraceptives and current screening methods are not cost-effective endometrial cancer prevention strategies for obese women. Risk factors such as morbid obesity and longstanding anovulation may define a subgroup at highest risk of endometrial cancer for whom OCPs may be a cost-effective strategy. Interventions that reduce endometrial cancer risk further or those with additional health benefits are needed in this population.
LEVEL OF EVIDENCE: III
Endometrial cancer is the most common gynecologic malignancy and the fourth most common malignancy among women in North America. More than 40,000 women will be diagnosed with endometrial cancer in the United States in 2008,1 and approximately 40% of these endometrial cancers will be attributed to obesity.2 Obese women have a risk of endometrial cancer that is three to 10 times higher than that in the general population.3–11
The oral contraceptive pill (OCP) decreases endometrial cancer risk by 50–80%.7,10,12–16 This protective effect seems to be greater with prolonged use, and it persists long after discontinuation. Therefore, the OCP may be a potential chemoprevention strategy for obese women if it reduces their risk of endometrial cancer. Screening for endometrial cancer by endometrial biopsy has not been proven to reduce incidence or mortality rates in the general population, but it has been recommended for individuals at high risk for endometrial cancer, such as those with Lynch syndrome.17,18 In the absence of a randomized trial, a cost-effectiveness analysis of a hypothetical cohort can estimate the costs and benefits of various strategies. We present a cost-effectiveness analysis of different endometrial cancer prevention strategies for obese women.
METHODS AND MATERIALS
The M. D. Anderson Cancer Center Institutional Review Board approved a protocol entitled “Prevalence of endometrial abnormalities among obese women,” from which this project was developed. We developed a Markov decision-analytic model with available data from the literature to estimate the outcomes of a cohort of obese women (body mass index [BMI] more than 30) at risk for endometrial cancer. We compared four strategies by determining the incremental cost-effectiveness ratio, defined as the additional cost of a specific strategy divided by its health benefit compared with the next best strategy. The numerator of the incremental cost-effectiveness ratio is the difference in average lifetime cost (U.S. dollars in the year 2006) and the denominator is the difference in average life expectancy (in years). A strategy that was more costly but more effective than an alternate strategy was considered cost-effective if its incremental cost-effectiveness ratio was below $50,000 per year of life gained, a willingness-to-pay threshold commonly used in cost-effectiveness analyses evaluating preventive health measures.19 In keeping with the recommendations of the U.S. Panel on Cost-effectiveness in Health and Medicine, we adopted a societal perspective and discounted all costs and health benefits at a rate of 3% per year.20 Discounting provides a present value for costs and effects that are incurred in the future. A discount rate of 3% means that the present value of a year of life gained next year is 3% less than the present value of the same year of life gained right now. We discounted future costs and health benefits to calculate incremental cost-effectiveness ratios and compare strategies at the present time. We performed sensitivity analyses to account for uncertainty around various measures.
The model was programmed using TreeAge Pro 2007 (TreeAge Software, Inc., Williamstown, MA). A hypothetical cohort of obese women enters the model at age 20, and each year they face age-dependent risks of endometrial cancer to age 80. The model consists of four health states that are mutually exclusive: 1) well; 2) at risk for endometrial cancer; 3) endometrial cancer; 4) dead. All women begin in the “at risk for endometrial cancer” state. They transition from one state to another according to baseline and transition probabilities defined in the model. If they are diagnosed with endometrial cancer but have not relapsed in 5 years, they are considered disease-free and transition to the “well” state. The process continues until all women in the cohort reach the “dead” state, which results from endometrial cancer or other age-related causes.
Four strategies are defined: 1) no prevention (reference strategy); 2) combined OCPs for 5 years starting at age 30; 3) annual screening (clinic visit and endometrial biopsy) from age 30; and 4) biennial screening from age 30. Age-specific incidence rates of endometrial cancer among the general population were obtained from Surveillance Epidemiology and End Results (SEER) data21 and converted into annual probabilities (p) by the formula p=1–e–rate.22 We estimated the risk of endometrial cancer in obese women and the risk reduction attributable to OCPs from previously reported population-based studies.3,4,13–15 We assumed that 5-year death rates from endometrial cancer among obese women were similar to general population rates according to SEER data.1 We estimated the additional number of adverse cardiovascular (CV) events including acute myocardial infarction (AMI), stroke, and venous thromboembolism attributable to OCPs based on available literature.23–28
For the base case, we assumed that 1) all women who enter the model are 20 years of age, obese with a BMI more than 30, and are at risk for endometrial cancer; 2) their lifetime risk of endometrial cancer is at least three times higher than in the general population as long as they remain obese; 3) the probability of abnormal bleeding with a diagnosis of endometrial cancer is 80%29,30; 4) sensitivity of endometrial biopsy is 0.91 and 0.996 in premenopausal and postmenopausal women, respectively, and specificity is 0.98 in both premenopausal and postmenopausal women31; 5) any abnormal screen leads to total abdominal hysterectomy, bilateral salpingo-oophorectomy, and staging; 6) in the absence of symptoms or in the event of a false-negative biopsy, the diagnosis of endometrial cancer is made the following year after repeat biopsy; 7) OCPs reduce endometrial cancer risk by up to 50% if used for 5 years, and there is some risk reduction up to 20 years after discontinuation12–16; 8) cardiovascular risks attributable to OCPs increase with age but return to baseline after discontinuation of OCPs23–28; 9) breast cancer risk is not increased with OCPs32–34; 10) women are comparable across strategies with respect to other risk factors for endometrial cancer (eg, parity and hormone replacement therapy), and mortality (eg, cardiovascular disease and diabetes). Sensitivity analyses were used to evaluate alternate assumptions to those used in the base case, including risks of endometrial cancer, age at start of OCPs, duration of use, and adverse cardiovascular events attributable to OCPs. Because of the uncertainty relating to quality of life associated with obesity and being at risk for endometrial cancer, our primary outcome measure was life expectancy. We conducted a Monte-Carlo simulation of 100,000 women in each strategy to estimate the total number of endometrial cancer cases, as well as excess adverse CV events attributable to OCPs.
Cost inputs included direct and indirect health care costs. Costs of screening were obtained from the Medicare payment schedule from the U.S. Department of Health and Human Services, using Health Care Financing Administration Common Procedure Codes.35 Direct health care costs of endometrial cancer surgery were obtained from the Agency for Healthcare Research and Quality report on hospital and ambulatory surgery care for women’s cancers.36,37 Wholesale costs of oral contraceptive pills were obtained from the 2006 Red Book.38 We did not include costs of adjuvant radiotherapy or chemotherapy, or costs of treatment for recurrent disease. Indirect health care costs included time and travel costs. Time costs according to the Bureau of Labor Statistics were based on the estimated total time allocated to each strategy.39 The time spent on screening was estimated at 0.5 days per screen, and time spent on surgery was estimated at 6 weeks. Estimates for travel costs were based on automobile expenditures for urban travel, using a national average fuel consumption index and gasoline costs in the year 2006.40 Selected data used for the base case are summarized in Tables 1 and 2.
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.
Figure 1 illustrates a sensitivity analysis on the relative risk of endometrial cancer in obese women, given a conventional willingness-to-pay threshold of $50,000 per year of life saved. Their risk had to be 13 times greater than the general population risk before OCPs became a cost-effective strategy.
Results of the Monte Carlo simulation are summarized in Table 4. Oral contraceptive pills prevented approximately 20% of endometrial cancer cases that would have occurred in the absence of any risk-reducing strategy. Annual screening prevented the highest number of endometrial cancer cases over a lifetime. The simulation estimated an additional 27 acute myocardial infarctions, 39 strokes, and 143 venous thromboembolic events attributable to OCPs.
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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