Over the past decade, there is increasing evidence that the majority of ovarian cancers arise in the fallopian tube and not primarily in the ovary.1–4 Consequently, in 2010 the British Columbia Ovarian Cancer Research Group launched an educational campaign about the potential benefit of “opportunistic salpingectomy” done concurrently with hysterectomy for benign gynecologic conditions or instead of tubal ligation for contraception. It was estimated that this practice could reduce ovarian cancer risk by 20–40% over the next 20 years.5 Salpingectomy is favorable to salpingo-oophorectomy at the time of hysterectomy for premenopausal women, because it avoids the downstream health risks associated with premature menopause after oophorectomy, including osteoporosis and coronary heart disease.6
On the other hand, there has been skepticism about the absolute benefit of opportunistic salpingectomy. Narod7 estimated that 10,000 salpingectomies would be required every year in British Columbia to reduce ovarian cancer incidence by 40% (to prevent 100/263 ovarian cancer cases per year). Herzog et al8 also questioned the economic effect of this practice. Furthermore, there are still no longitudinal clinical studies confirming that the fallopian tube is the origin of most ovarian cancers. A population-based cohort study is essential for establishing the long-term risks and benefits associated with this procedure despite taking many years to yield results. In the absence of these data, a decision analytic model could readily estimate the costs and benefits of opportunistic salpingectomy. Our objective was to conduct a cost-effectiveness analysis of opportunistic salpingectomy as an ovarian cancer prevention strategy in the general population.
MATERIALS AND METHODS
This study was exempt from research ethics board review, according to Article 2.2 of the Canadian Tri-Council Policy Statement on the Ethical Conduct for Research Involving Humans. We constructed two Markov Monte Carlo simulation models to estimate the average lifetime costs and benefits of opportunistic salpingectomy in a hypothetical cohort of premenopausal women requiring: 1) hysterectomy for benign conditions and 2) surgical sterilization.
In the first model, three strategies were compared: 1) hysterectomy alone, 2) hysterectomy with salpingectomy, and 3) hysterectomy with bilateral salpingo-oophorectomy (BSO). The benefit of each strategy was calculated in terms of average years of life expectancy gain, and average lifetime costs were estimated in Canadian dollars in the year 2014. Data on risks and benefits were derived from our own experience in British Columbia as well as other available literature. All direct and indirect costs associated with surgery and ovarian cancer treatment were estimated from the British Columbia Medical Services Plan, the Canadian Institute for Health Information, and the Ontario Cancer Registry.9–11 Opportunity costs were estimated from employment time lost based on average hourly wages for women from Statistics Canada.12 Average costs of health conditions attributable to premenopausal oophorectomy including coronary heart disease were estimated from the Canadian Institute for Health Information. The primary outcome measure was the incremental cost-effectiveness ratio), defined as the additional cost divided by the incremental benefit compared with an alternate strategy. A strategy was strongly dominated if it was more costly and less effective than another or cost-effective if it had an incremental cost-effectiveness ratio of $50,000–100,000 per year of life gained relative to an alternate strategy, a commonly accepted threshold for preventive health measures.13 As per the U.S. Panel on Cost-effectiveness in Health and Medicine, we adopted a societal perspective and discounted all costs and benefits at a rate of 3% per year.14
Women requiring hysterectomy for benign gynecologic conditions reside in one of four Markov health states: 1) well, 2) at risk, 3) ovarian cancer, or 4) dead. All of them begin in the at-risk state. Women diagnosed with ovarian cancer transition to the ovarian cancer state as governed by their surgical procedure. We assumed that women were comparable across strategies with respect to other risk factors for ovarian cancer such as obstetric history, family history, body mass index, and oral contraceptive use. In the ovarian cancer state, women may die of ovarian cancer or age-dependent competing mortalities according to Canadian Life Tables.15 If they survive ovarian cancer after 10 years, the likelihood of recurrence is sufficiently low such that they transition to the well state, where they are still subject to age-dependent mortality risks. This process continues in yearly cycles until they reach the dead state because of ovarian cancer or other causes. The average age at hysterectomy was 45 years, and these women were monitored over a time horizon of 40 years. We assumed a general population lifetime risk of ovarian cancer of 1.4%.16 Assuming that the majority of ovarian cancers in the population are high-grade serous carcinomas (70%) and that the majority of these (70%) arise in the fallopian tube,2,3,17 we assumed that opportunistic salpingectomy could decrease ovarian cancer risk by up to 50%.18 We assumed a 90% reduction in ovarian cancer risk with BSO6 and a 20% reduction with hysterectomy alone.19,20
Based on long-term follow-up data from the Nurses Health Study, women having concomitant BSO with hysterectomy before the age of 50 years without estrogen replacement therapy had higher risks of all-cause mortality from coronary heart disease, cardiovascular disease, and total cancers including lung and colorectal cancer. We assumed that premenopausal women who had BSO with hysterectomy were routinely prescribed estrogen replacement therapy after surgery, but that 20% discontinued this by 5 years.21 Deaths from coronary heart disease attributable to premature menopause from BSO were modeled like in the Nurses Health Study such that 80% of deaths occurred after 15 years from surgery.6
Although long-term follow-up data after salpingectomy are lacking, we assumed that women having this procedure did not become menopausal immediately based on postoperative anti-Müllerian hormone levels as a surrogate for ovarian function.22 The additional operative time required for salpingectomy was insignificant,23 and perioperative complications and length of hospitalization were not increased compared with hysterectomy alone.22–25 There is no available data on the rate of inadvertent oophorectomy at the time of salpingectomy. Based on the FinHyst prospective study, in which only “a few” unintended oophorectomies occurred during 3,600 abdominal and vaginal hysterectomies, we estimated a 1% risk of inadvertent oophorectomy during salpingectomy.26
Approximately 50,000 women have a hysterectomy every year in Canada, and assuming that 56% of these have ovarian preservation based on British Columbia data in 2011,23 28,000 would be eligible for elective salpingectomy. The Monte Carlo simulation was based on this cohort of 28,000 women and was repeated for 100 trials. We estimated the number of ovarian cancer cases associated with each strategy, adverse events attributable to BSO, and the number needed to treat to prevent one case of ovarian cancer (compared with hysterectomy alone).
In the second model, two strategies were compared: 1) tubal ligation and 2) salpingectomy. We assumed that the ovarian cancer risk reduction from tubal ligation was approximately 30%19,20,27,28 compared with 50% from salpingectomy (like in the first model). The average age at surgical sterilization was 35 years (10 years younger than in the hysterectomy model), and this cohort of women was monitored over a time horizon of 40 years. Cost inputs, Markov health states, assumptions relating to operative morbidity, and primary outcome measures were similar to the hysterectomy model.
Approximately 25,000 women in Canada will seek surgical sterilization every year, extrapolating from data in 2011.23 The Monte Carlo simulation was based on this cohort for 100 trials to estimate the number of ovarian cancer cases associated with each sterilization procedure and number needed to treat to prevent one ovarian cancer case.
The models were programmed using TreeAge Pro 2013 with multiple sensitivity analyses to account for uncertainty around various parameters such as costs of treatment (to approximate costs in the United States), age at surgery, and estimates of risk reduction attributable to salpingectomy. Selected data for the base case are provided in Table 1.
The average discounted costs, life expectancy, and incremental cost-effectiveness ratios for women undergoing hysterectomy and surgical sterilization are provided in Table 2.
Salpingectomy with hysterectomy was less costly ($11,044±$1.56) and more effective (21.12±0.02 years) than hysterectomy alone ($11,207±$29.81, 21.10±0.03 years) or with BSO ($12,627±$13.11, 20.94±0.03 years), respectively. Our results were stable over a wide range of parameters, including costs of treatment and estimates of risk reduction associated with salpingectomy. Age at hysterectomy had to exceed 50.87 years before hysterectomy with BSO became the dominant strategy (Fig. 1). The risk of inadvertent oophorectomy during salpingectomy had to exceed 2.0% for this procedure to be dominated by hysterectomy alone if none of the women used hormone therapy afterward (Fig. 2). Even when costs were varied within wide range of plausible estimates to approximate higher U.S. costs, hysterectomy with salpingectomy remained the dominant strategy (more effective and less costly than hysterectomy alone or with BSO).
The Monte Carlo simulation estimates that 270 women would be subsequently diagnosed with ovarian cancer after hysterectomy alone compared with 167 having opportunistic salpingectomy, representing a 38.1% (95% confidence interval [CI] 36.5–41.3%) reduction. For every 28,000 women having salpingectomy at the time of hysterectomy, there are 103 more women who avoid the diagnosis of ovarian cancer compared with hysterectomy alone (or 37 ovarian cancers prevented for every 10,000 women, translating into a number needed to treat of 273; 95% CI 246–289). If these women were to undergo concomitant BSO instead of salpingectomy, 32 would be diagnosed with ovarian cancer, representing an 88.1% (95% CI 86.2–90.6%) reduction compared with hysterectomy alone. If these women did not routinely use hormone therapy after surgery, there would be 934 deaths attributable to premenopausal BSO. These results are summarized in Table 3.
Salpingectomy for sterilization was slightly more costly ($9,720±$3.74 compared with $9,339±$26.74) but more effective (22.45±0.02 compared with 22.43±0.02 years of life expectancy) than tubal ligation with an incremental cost-effectiveness ratio of $27,278 per year of life gained. Our results were sensitive to estimates in the magnitude of ovarian cancer risk reduction from tubal ligation and salpingectomy. Salpingectomy had to reduce ovarian cancer risk by at least 25% more than tubal ligation. Figure 3 illustrates a two-way sensitivity analysis on ovarian cancer risk reduction of these two surgical strategies given a willingness-to-pay threshold of $50,000 per year of life gained. If tubal ligation reduces ovarian cancer risk by 30%, salpingectomy has to reduce ovarian cancer risk by at least 37.5% compared with the general population risk for this strategy to be cost-effective. We varied the costs of all surgical procedures (including facility, surgeon, and anesthesiologist fees) in sensitivity analyses to approximate outcomes in other Canadian jurisdictions as well as in the United States, and our results were stable to a wide range of plausible estimates. Only if the cost of salpingectomy exceeds that of tubal ligation by more than $1,000 is it no longer a cost-effective procedure.
The Monte Carlo simulation predicts that 234 women will be diagnosed with ovarian cancer after tubal ligation compared with 166 women after salpingectomy, representing a 29.2% (95% CI 28.0–31.4%) reduction compared with tubal ligation. For every 25,000 women having salpingectomy as sterilization, 68 more women will avoid the diagnosis of ovarian cancer, translating into a number needed to treat of 366 (95% CI 338–379) to prevent one case of ovarian cancer compared with tubal ligation. These results are summarized in Table 3.
Opportunistic salpingectomy has the potential to reduce the number of ovarian cancer cases compared with hysterectomy alone or tubal ligation, which in turn will reduce future health care costs associated with ovarian cancer treatment. Our model also predicted that salpingectomy was more effective and less costly than BSO with hysterectomy in premenopausal women. Although BSO yields a greater risk reduction in ovarian cancer, the absolute risk is low in the general population and is far outweighed by the risks of coronary heart disease and other cancers (eg, lung and colorectal cancer) attributable to premenopausal BSO. The magnitude of ovarian cancer risk reduction from salpingectomy is lower for surgical sterilization than it is with hysterectomy, because tubal ligation appears to reduce ovarian cancer risk to greater extent than hysterectomy,27 which reduces the relative benefit of salpingectomy.
The absolute benefit from opportunistic salpingectomy is arguably nominal with number needed to treat estimates of 273 and 366 to prevent one case of ovarian cancer with hysterectomy or as surgical sterilization, respectively. However, these estimates are comparable to the number needed to vaccinate against human papillomavirus of 324 to prevent one case of cervical cancer.29 The average life expectancy gain of 0.02 years (approximately 1 week) above hysterectomy alone or tubal ligation appears insignificant, but it represents a very large gain for those women who would have died prematurely as a result of ovarian cancer, offset by the lack of gain for the majority of women who were never going to be diagnosed with this malignancy. To put this into perspective, the average life expectancy gain with triennial cervical cancer screening is approximately 1 month for the general population compared with no screening.30–32 The additional benefit from triennial human papillomavirus testing starting at age 30 years beyond triennial conventional screening is an average life expectancy gain of 0.005 years (just under 2 days).30 Because the incidence rates of ovarian and cervical cancers are low in North America, the benefit of these risk-reducing interventions (opportunistic salpingectomy and screening, respectively) may seem negligible when averaged over the entire population. In the absence of an effective screening test for ovarian cancer,33,34 there are no alternatives for ovarian cancer risk reduction that can be offered with minimal morbidity and cost. The oral contraceptive pill reduces ovarian cancer risk by 50% if used for more than 5 years,35,36 which is comparable to that from opportunistic salpingectomy. However, oral contraceptive pills are associated with increased risks of breast and cervical cancer and thromboembolic events such that the cumulative risk is likely to be equivalent or greater than the decreased risk in ovarian cancer,35 which precludes the routine use of oral contraceptive pills for the primary prevention of ovarian cancer.
Although there has been increased uptake of opportunistic salpingectomy in British Columbia, 20% of hysterectomies in 2011 were still done without salpingectomy or BSO.23 Some of these may have been vaginal hysterectomies; however, successful removal of the ovaries and fallopian tubes can be accomplished in the majority of patients with normal-sized mobile adnexae,37–40 and therefore vaginal hysterectomy should not be a contraindication to attempting salpingectomy. In the same year, 66.7% of surgical sterilizations were tubal ligations instead of salpingectomies.23 Despite the marked increase in salpingectomy for sterilization (from 0.4% in 2008 to 33.3% in 2011), increasing this further may be the greater challenge. Surgical sterilization rates in women have declined41 because availability of the levonorgestrel intrauterine device.42 However, gynecologic patients represent only a subgroup of women requiring abdominal or pelvic surgery. Opportunistic salpingectomy could be done at the time of other surgical procedures (eg, appendectomy, cholecystectomy), thereby extending the risk-reducing potential even further to other women in the general population.
The advantage of this analysis is that it can readily estimate the costs and benefits of opportunistic salpingectomy in a large cohort of women requiring hysterectomy for benign conditions, or surgical sterilization, which would be difficult to obtain from a clinical trial or cohort study. The disadvantage is the uncertainty relating to the long-term effect on ovarian function and absolute reduction in ovarian cancer risk from salpingectomy. We did not incorporate utilities or health preferences to estimate quality-adjusted life-years of each strategy. Presumably the quality of life after this procedure is superior to oophorectomy in premenopausal women and likely no different from hysterectomy alone. Despite the possible risk of inadvertent oophorectomy at the time of salpingectomy, the likelihood of iatrogenic menopause as a result of salpingectomy may have been overestimated because bilateral oophorectomy should be exceedingly rare. Finally, we did not model costs associated with potential morbidity from salpingectomy, because these were not likely to be different from the alternatives (hysterectomy alone or tubal ligation)22–25 nor did we include costs of recurrent ovarian cancer given the wide variety of scenarios and treatment options. We did not model subsequent adnexal cysts, which would be more prevalent after hysterectomy alone,25 the increased risk of osteoporosis and other cancers after hysterectomy with BSO,6 or ectopic pregnancies after tubal ligation.43 However, inclusion of these would yield an even greater difference favoring salpingectomy in terms of lifetime effectiveness and costs.
Prospective evaluation of salpingectomy with hysterectomy or instead of tubal ligation is essential to determine the long-term effect on ovarian function as well as ovarian cancer incidence; however, these outcomes will remain unknown for another one or two decades. In the interim, opportunistic salpingectomy (electively with hysterectomy or instead of tubal ligation) appears to be safe and should be considered for women requiring these gynecologic procedures.
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