Obstetrics & Gynecology:
Gynecologic Cancer Prevention in Lynch Syndrome/Hereditary Nonpolyposis Colorectal Cancer Families
Chen, Lee-may MD1; Yang, Kathleen Y. MD1; Little, Sarah E.2; Cheung, Michael K.1; Caughey, Aaron B. MD, PhD1
From the 1Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, California; and 2Department of Obstetrics & Gynecology, Stanford University, Stanford, California.
See related editorial on page 5.
Dr. Caughey is supported by the National Institute of Child Health and Human Development Grant HD01262 as a Women's Reproductive Health Research Scholar.
Presented at the 35th Meeting of the Western Association of Gynecologic Oncologists, Lake Tahoe, California. June 1–3, 2006.
Corresponding author: Lee-may Chen, MD, 1600 Divisadero Street 4th Floor, San Francisco, CA 94115-1702; e-mail: Lee-may.Chen@ucsfmedctr.org.
Financial Disclosure The authors have no potential conflicts of interest to disclose.
OBJECTIVE: Women from Lynch syndrome/hereditary nonpolyposis colorectal cancer (Lynch/HNPCC) families have an increased lifetime risk of developing endometrial and ovarian cancer. This study models a comparison of management strategies for women who carry a Lynch/HNPCC mutation.
METHODS: A decision analytic model with three arms was designed to compare annual gynecologic examinations with annual screening (ultrasonography, endometrial biopsy, CA 125) and with hysterectomy with bilateral salpingo-oophorectomy at age 30 years The existing literature was searched for studies on the accuracy of endometrial and ovarian cancer screening using endometrial biopsy, transvaginal ultrasonography, and serum CA 125. The Surveillance, Epidemiology and End Results database from 1988 to 2001 was used to estimate cancer mortality outcomes.
RESULTS: In the surgical arm, 0.0056% of women were diagnosed with ovarian cancer and 0.0060% of women with endometrial cancer. These numbers increased to 3.7% and 18.4% in women being screened, and 8.3% and 48.7% in women undergoing annual examinations, respectively. Surgical management led to the longest expected survival time at 79.98 years, followed by screening at 79.31 years, and annual examinations at 77.41 years. If starting at age 30 and discounting life years at 3%, surgery still leads to the greatest expected life years. When comparing prophylactic surgery with the screening option, one would need to perform 75 surgeries to save one woman's entire life. For cancer prevention, however, only 28 and 6 prophylactic surgeries would need to be performed to prevent one case of ovarian and endometrial cancer, respectively.
CONCLUSION: Risk-reducing hysterectomy and bilateral salpingo-oophorectomy may be considered in women with Lynch/HNPCC to prevent gynecologic cancers and their associated morbidities.
LEVEL OF EVIDENCE: III
Women who carry a Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC) germline mutation have a 40–60% lifetime risk of endometrial cancer and a 10–12% lifetime risk of ovarian cancer.1,2 The incidence of gynecologic cancers for women with Lynch/HNPCC syndrome is at least equal to if not greater than the risk of colorectal cancer. Autosomal dominant mutations in MLH1, MSH2, and MSH6 are all associated with a higher risk of endometrial cancer at a young age, and mutations in MSH2 are also associated with a higher risk of ovarian cancer.3–6 The clinical and pathologic features of Lynch/HNPCC-associated endometrial cancer suggest that the median age of incidence is in the fourth decade, with a trend toward earlier stage and grade; yet a quarter of these patients still present with high-risk features warranting adjuvant treatment.7 A comparison study of 50 women with Lynch/HNPCC-associated endometrial cancer and 100 sporadic controls matched for age and stage suggest a similar 5-year survival rate (88% compared with 82%, P=.59).8 Lynch/HNPCC-associated ovarian cancer seems to present at an earlier stage as well, many times in conjunction with synchronous endometrial cancer.9
The current consensus of expert opinion is to recommend that women in Lynch/HNPCC families undergo surveillance for gynecologic cancer, including annual endometrial biopsy, ultrasonography, and CA 125.10 Colorectal cancer screening in HNPCC has been shown to improve survival and be cost-effective, but this has not been well studied for endometrial and ovarian cancer.11,12 In BRCA1/BRCA2 mutation carriers, risk-reducing salpingo-oophorectomy has been shown to significantly decrease the incidence of ovarian cancer, and be cost-effective over surveillance in those affected women who have completed child bearing.13–15 Similarly, hysterectomy with bilateral salpingo-oophorectomy has been identified as a prevention strategy for women with HNPCC.16
Current clinical practice is to identify women from high-risk families for consideration of genetic testing. Commercially available testing is available for the MLH1 and MSH2 mutations only, but other women with Lynch/HNPCC are diagnosed on the basis of clinical family history only. In conjunction with cancer genetic counseling, high-risk women are offered surveillance and prophylactic surgery, but determining which strategy is most advantageous remains unproven. Our goal was to compare the options of annual examination alone, annual gynecologic cancer surveillance, and prophylactic surgery using decision analysis.
MATERIALS AND METHODS
A decision analytic model was developed with TreeAgePro 2004 software (TreeAge Software Inc, Williamstown, MA). Assumptions were that a cohort of women with Lynch/HNPCC-associated germline mutations would undertake one of three management strategies: 1) lifetime annual gynecologic examination only, 2) annual gynecologic surveillance including pelvic ultrasonography, endometrial biopsy, and serum CA 125 testing, or 3) prophylactic hysterectomy and bilateral salpingo-oophorectomy at age 30 years. (Figs. 1–3).
We assumed that women with an endometrial biopsy showing hyperplasia or carcinoma would proceed to hysterectomy and oophorectomy. If the ultrasonogram of the endometrial cavity appeared abnormal and the endometrial biopsy was normal, a dilation and curettage of the endometrium was performed. We also presumed that hormone replacement therapy was a reasonable option for most women after surgical menopause for management of symptoms.17 For women with BRCA1/BRCA2 mutations undergoing risk-reducing salpingo-oophorectomy, there are data to support hormone therapy based on quality of life issues.18 For patients with early endometrial cancer, there are data to support the relative safety of estrogen therapy after surgery.19 We assumed that a positive screen for ovarian cancer could come from two different scenarios: either an abnormal CA125 in addition to an abnormal ultrasonogram, or an abnormal ultrasonogram that persisted after 4 to 6 weeks.20,21 With a positive ovarian screen, a diagnostic surgery would be performed.
Probabilities were obtained through a review of the literature encompassing screening studies and outcomes of hereditary and sporadic ovarian and endometrial cancer. The Surveillance, Epidemiology and End Results database from 1988 to 2001 was used to estimate cancer mortality outcomes. Institutional review board approval from the Committee of Human Research at the University of California, San Francisco was obtained.
Estimates of cancer risk were taken from the cancer incidence in the population and relative cancer risks in Lynch/HNPCC.22–24 Based on clinical-pathologic reports of Lynch/HNPCC cancers, the distribution of stage in Lynch/HNPCC-associated endometrial cancer was assumed to be similar to population risk (Table 1).7,8 On the other hand, ovarian cancer was estimated to have a somewhat earlier diagnosis in Lynch/HNPCC.9
The estimates of the efficacy of surgery were taken from risk-reducing surgery experiences in BRCA1/BRCA2 patients as well as the extant literature in Lynch/HNPCC. We assumed that risk-reducing surgery decreases the incidence of advanced malignancy by 45% and would result in the diagnosis of endometrial and ovarian cancer at earlier stages (Table 2).16,25–27
Without any existing evidence to the contrary, we assumed that screen-detected endometrial cancer would have a similar stage distribution as endometrial cancer diagnosed at risk-reducing surgery.7,8 Although it is possible that screening could result in diagnosing ovarian cancer at an earlier stage in the setting of Lynch/HNPCC, the few data on ovarian cancer screening in BRCA1/BRCA2 patients does not support this.20,28 Thus, we deferred to the presenting ovarian cancer stage distribution in Lynch/HNPCC patients.9,29
A PubMed search was performed using the terms “ovarian cancer,” “endometrial cancer,” “screening,” “ultrasonography,” endometrial biopsy,” “CA 125, “efficacy,” “sensitivity,” and “specificity,” searching the literature for studies reporting on the accuracy of endometrial and ovarian cancer screening using endometrial biopsy, transvaginal ultrasonography, and serum CA 125 levels. The best studies that could be extrapolated to our study population were used to estimate probabilities for positive endometrial and ovarian cancer screening tests (Table 3).20,21,30,31
Survival data were taken from the Surveillance, Epidemiology and End Results database. Outcomes of Lynch/HNPCC-associated cancers were assumed to be equivalent to those of sporadic cancers. Surgical mortality was measured as the number of deaths within 30 days of surgical treatment (Table 4). For the model, surgical mortality for stage I and II disease was estimated separately from those patients with stage III and IV disease. Five- and 10-year survival was used in the model for patients diagnosed with cancer (Table 5). Ten-year survival was modeled for those patients who survived 5 years. For patients with synchronous endometrial and ovarian cancer, the worse survival of the two diseases was used in the model. We examined both total life expectancy as well as discounted life expectancy. When life expectancy is used to generate quality-adjusted life years, it is often done so using discounted life years. Discounting is a way to incorporate individual preferences toward time in the future. By and large, most individuals value future time less than time in the present. Thus, time in the future is commonly discounted using an annual exponential discount rate of 3%, which was applied to generated discounted life-expectancy.
To examine the robustness of our model, we conducted both univariable and multivariable sensitivity analyses. We varied all of the key inputs over theoretical ranges based on either the existing literature or from one half to two times their value. Further, we varied the age of the women in question from 30 to 70 years, to explore the effects of the different management strategies in different populations. Additionally, a Monte Carlo simulation with 10,000 trials was run to generate both an estimate of the proportion of time that the strategy which led to the best outcome did so and 95% confidence intervals around the difference in outcomes. The Monte Carlo simulation samples each of the probability distributions for the point estimates and applies them case-by-case 10,000 times to predict what would happen if each of the 10,000 women went through each of the management strategies.
With a theoretical cohort of 10,000 women in the surgical arm, only one woman each would be diagnosed with ovarian cancer and endometrial cancer at the time of prophylactic surgery (0.0056% and 0.0060%, respectively). In women being screened and subsequently undergoing surgery with a positive test, these numbers increased to 370 (3.7%) and 1,840 (18.4%), respectively. In women undergoing annual examination and being diagnosed with interval cancers, 830 (8.3%) women would be diagnosed with ovarian cancer and 4,870 (48.7%) would be diagnosed with endometrial cancer.
We found that surgical management led to the longest nondiscounted life expectancy at 79.98 years of age, followed by screening at 79.31, and annual examinations at 77.41. If starting at age 30 years and discounting life-years at 3%, surgery still leads to the greatest expected life years of 25.72, compared with 25.70 for screening, and 25.27 for annual examinations.
Sensitivity analysis suggests that prophylactic surgery is the best management modality as long as the false-positive rates of ovarian cancer screening (ultrasonography and CA 125) and endometrial biopsy were 3% or less. Sensitivity analysis by age of prophylactic surgery suggests that surgery is the most effective strategy at age 30 years, but is really quite similar to screening in effectiveness and continues to be superior to annual examination across the age continuum (Table 6). At age 70 years, the relative effectiveness of prophylactic surgery is diminished, because the overall risk of surgical morbidity and mortality increases. In the Monte Carlo simulation, the prophylactic surgery arm led to a greater life expectancy in 99.98% of the 10,000 trials run with 95% confidence intervals of 0.29 to 1.04 life-years improvement and 0.0135 to 0.209 discounted life-years improvement over the screening strategy.
Our results demonstrate that risk-reducing hysterectomy and bilateral salpingo-oophorectomy is an effective strategy in managing women with genetically increased risk of endometrial and ovarian cancer. Particularly, prophylactic surgery allows for a decrease in cancer-specific mortality and cancer treatment-related morbidity. Even though most endometrial cancers are curable through surgery and adjuvant treatment, a diagnosis of cancer still results in the anxiety and stigma of disease, in addition to the physical and fiscal costs of therapy, and finally the direct and indirect costs of long-term follow-up. A diagnosis of ovarian cancer is typically followed by staging or debulking surgery, chemotherapy, and life-long follow-up for possible cancer recurrence.
Based on this analysis, we recommend risk-reducing hysterectomy and bilateral salpingo-oophorectomy upon completion of child bearing in the third to fourth decades. Compared with annual examinations, prophylactic surgery at age 30 afforded a 2 1/2 year survival advantage. Even though the screening arm also seemed efficacious in reducing cancer mortality when compared with annual examinations alone, this resulted primarily from the large number of women with false-positive screening tests who then went on to have surgery. When comparing prophylactic surgery to the screening option, one would need to perform 75 surgeries to save one woman's entire life. For cancer prevention, however, only 28 and 6 prophylactic surgeries would need to be performed to prevent one case of ovarian and endometrial cancer, respectively.
In a retrospective case-control study of 61 women undergoing prophylactic hysterectomy (including 47 women undergoing bilateral salpingo-oophorectomy) for Lynch/HNPCC mutation carriers, Schmeler et al16 found that there were no occurrences of endometrial, ovarian, tubal, or peritoneal cancer in the surgery group, whereas the incidence of endometrial and ovarian cancer were 33% and 5%, respectively, in the control group, with a median follow-up time of more than 7 years. This study was limited by its selective retrospective nature—many women underwent prophylactic surgery before genetic testing, and a survival comparison was not performed.
In practice, the role of screening for Lynch/HNPCC-associated endometrial cancer requires more study. Two groups have reported their experience to date. Both of these studies included women with Lynch/HNPCC defined by both mutation status as well clinical criteria. Dove-Edwin et al32 followed 269 women with annual or biennial ultrasonography for 826 women-years at risk—no endometrial cancers were detected by screening, whereas there were two interval cancers diagnosed during the study period. Rijcken followed 41 women with annual examination, ultrasonography, and CA 125 for 197 women-years at risk—17 of 179 ultrasonograms prompted endometrial sampling, three cases of atypical endometrial hyperplasia were identified, and one interval endometrial cancer was missed.33 There were no abnormal CA 125 levels and no interval ovarian cancers in this study population. Even when ovarian cancer occurs at a higher prevalence, such as in BRCA1/BRCA2 mutation carriers, screening for familial ovarian cancer has not proven effective yet to detect early disease affecting prognosis.28 Our study was designed to look at Lynch/HNPCC mutation carriers, but because Lynch/HNPCC is a clinical syndrome with a variation of cancer risks, we believe that our results may apply to women with clinically defined Lynch/HNPCC as well. Not until distinctive endometrial and ovarian cancer risks have been ascribed to particular mutations will we be able to further the current model clinically. However, it is clear that with the risks of cancer we used in our model, prophylactic surgery led to the longest life expectancy.
Decision analysis allows for the study of complex, high-stakes decisions that involve uncertainty both regarding the risk of various interventions as well as uncertainty over the exact probabilities of various outcomes. The limitations of this study share those of other models, which can be limited in scope and miss clinical intangibles. One simplification that was necessary due to a complete lack of available data in the existing literature was our use of life-years rather than the quality-adjusted life-years. Thus, the morbidity related to cancer diagnosis and treatment is not incorporated into this model beyond the recognition of the different numbers of women who would be diagnosed with endometrial and ovarian cancer in the three treatment arms. Because the numbers of women diagnosed with cancer are much lower in the risk-reducing surgery arm, the inclusion of morbidity would only make our surgical arm relatively better. On the other hand, hysterectomy limits a woman's option for future child bearing, and oophorectomy results in early menopause. There are significant effects on fertility and quality of life that remain unanswered with this model. Some women may have remorse if they elect surgery for what proves to be a false-positive finding on screening, whereas others may find relief in decreasing their lifetime cancer risk. Exploration of women's preferences with respect to cancer diagnosis and the morbidity of treatment should be a priority for those interested in facilitating better choices by these women.
Additionally, our model does not account for the morbidity of false-positive screening tests. In fact, a false-positive screening test may actually improve outcomes in the surveillance arm, because it leads to surgery. Given the advantage that the surgery arm has on cancer mortality, it is likely that the advantages of the surveillance arm over annual examinations are derived from the fact that even false-positive screening tests lead to surgery enough of the time that fewer women are at risk to contract and die from cancer. This is further supported by the findings of our sensitivity analysis that demonstrated that with lower false-positive rates of the screening tests, outcomes in the screening arm actually worsened. For the time being, it seems that surveillance, unfortunately, is not as beneficial as risk-reducing surgery for cancer prevention. However, as more biomarkers and proteomic technology are able to be harnessed for ovarian cancer screening, the benefits of the surveillance arm may incrementally improve.
Our model incorporates the body of literature for Lynch/HNPCC-associated gynecologic cancers, but the number of women who have been studied remains small. Some of the cancer stage outcomes for risk-reducing surgery are extrapolated from the BRCA1/BRCA2 population, where the prevalence of disease is higher than in Lynch/HNPCC—the net effect is a potential overestimation of the benefits of the surveillance arm of the study, which would only make the overall advantage of the surgical arm greater. We rely on two large screening trials of CA 125 and ultrasonography to inform our ovarian cancer screening arm, thus our model is still limited by the effectiveness of screening. The risks of colorectal cancer and their effect on gynecologic cancer outcomes were deemed to be similar between groups of patients. By virtue that patients with Lynch/HNPCC have an increased risk of many cancers, overall life expectancy may be lower than our estimates, but the incremental life years lost still show an advantage toward the surgical arm.
Despite these limitations, we have demonstrated the potential advantage regarding prevention of endometrial and ovarian cancer through risk-reducing surgery for women with Lynch/HNPCC syndrome. Although there also seems to be a benefit regarding life expectancy with this approach, 75 prophylactic surgeries would be needed to prevent one death. In women who have completed child bearing, these benefits support the decision to proceed with prophylactic surgery. However, in women who still desire fertility, the decision is more difficult. The information from this study will be useful in patient counseling regarding the potential benefits, risks, outcomes, and morbidities related to the available approaches of prophylactic surgery, serial screening, and clinical evaluation alone. For such women, the results from this study can be used to give specific risks of the various outcomes that individuals can incorporate along with their personal preferences into a decision that includes their desire to maintain the option of child bearing. Because personal preferences are also important in decision making, future studies of Lynch/HNPCC women should focus on an understanding of the preferences and costs of outcomes related to prevention, screening, diagnosis, and treatment of hereditary ovarian and endometrial cancer.
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