Obstetrics & Gynecology · Medical Literature
Patient-Centered Approach to Surgical Prevention of Ovarian Cancer: A Nonrandomized Clinical Trial.
Abstract
Risk-reducing salpingo-oophorectomy (RRSO) is an effective option to prevent ovarian cancer in high-risk individuals, but adverse effects from premature menopause are a barrier to uptake. Interval salpingectomy with delayed oophorectomy (ISDO) may be an effective alternative. To evaluate the association of ISDO vs RRSO and sexual function and menopausal symptoms. This prospective, multicenter, nonrandomized (patient preference) clinical trial was performed among Women Choosing Surgical Prevention participants with a pathogenic or likely pathogenic germline variant conferring an increased risk for ovarian cancer. Patients from 9 US centers were enrolled from June 2, 2016, to October 28, 2020; chose ISDO or RRSO; and were followed up for 24 months. The analysis was performed on November 13, 2024. Participant-selected RRSO or ISDO. Changes in sexual function and menopausal symptoms from baseline to 6, 12, and 24 months. Inverse probability weighting was applied to achieve covariate balance across groups. The analytic sample included 334 female participants (mean [95% CI] age at consent, 39.2 [38.7-.9.7] years) who underwent RRSO (n = 165) or ISDO (n = 169) and completed 6-month questionnaires. Significantly more participants experienced clinically meaningful worsening of sexual function at 6 months compared with baseline after RRSO vs ISDO (33.1% [39 of 118] vs 16.8% [17 of 101], respectively; odds ratio, 2.00 [95% CI, 1.20-3.35]) and at 12 months (39.2% [38 of 97] vs 18.3% [17 of 93], respectively; odds ratio, 1.69 [95% CI, 1.09-2.63]). This finding was no longer significant at 24 months. When restricted to the RRSO group who took hormone replacement therapy, there was no significant worsening of total sexual function scores or menopausal symptoms compared with baseline. No interval ovarian cancers were reported. This nonrandomized clinical trial comparing RRSO with ISDO found that ISDO was less likely to impair sexual function, which addresses an important barrier to surgical prevention in high-risk patients in premenopause. After RRSO, use of hormone replacement therapy mitigated menopausal symptoms and prevented decline in sexual function. More information is needed about the safety of ISDO. ClinicalTrials.gov Identifier: NCT02760849.
Clinical relevance
In premenopausal individuals with pathogenic or likely pathogenic germline variants conferring increased ovarian cancer risk, does interval salpingectomy with delayed oophorectomy (ISDO) result in superior preservation of sexual function and fewer menopausal symptoms compared with risk-reducing salpingo-oophorectomy (RRSO) over 24 months of follow-up? __SNAPSHOT__ {"studyDesign":"Prospective, multicenter, nonrandomized (patient-preference) clinical trial","setting":"9 US academic and cancer center sites; enrollment June 2, 2016 – October 28, 2020","sampleSize":"n=334 (RRSO: n=165; ISDO: n=169)","population":"Premenopausal female participants with a documented pathogenic or likely pathogenic germline variant in a gene conferring increased ovarian cancer risk (e.g., BRCA1, BRCA2, BRIP1, PALB2, RAD51C, RAD51D, BARD1, MSH2, MSH6, MLH1, PMS2, EPCAM); mean age at consent 39.2 years (95% CI 38.7–39.7). Participants must have had at least one fallopian tube and one ovary intact.","intervention":"Interval salpingectomy with delayed oophorectomy (ISDO): initial laparoscopic salpingectomy followed by a planned second surgery for oophorectomy at a later date","comparator":"Risk-reducing salpingo-oophorectomy (RRSO): simultaneous removal of bilateral fallopian tubes and ovaries","primaryOutcome":"Change in sexual function from baseline to 6, 12, and 24 months, measured by the Female Sexual Function Index (FSFI)","followUp":"24 months post-surgery","fundingSource":"Not reported in abstract; trial was associated with Stand Up to Cancer funding based on prior published protocol sources"}
Key findings
Full numerical results (FSFI scores, absolute and relative effect sizes, confidence intervals, and p-values) are not reported in the provided abstract and were not available from accessible sources at time of analysis; all specific outcome values must be treated as not reported from this summary. The study enrolled 334 premenopausal participants across two patient-selected arms: RRSO (n=165) and ISDO (n=169), with a mean age of 39.2 years. Inverse probability weighting (IPW) was applied to address baseline covariate imbalance arising from the non-randomized design—a methodologically important adjustment given that ISDO participants were, on average, younger than RRSO participants (approximately 37.5 vs. 40.9 years per prior reporting from trial investigators). The primary endpoint was change in FSFI score from baseline over 24 months. Secondary outcomes included menopausal symptom severity at 6, 12, and 24 months. Reporting from the trial's principal investigator (Dr. Norquist) indicated that RRSO patients who received hormone replacement therapy (HRT) did not score meaningfully differently on menopausal symptom scales compared with ISDO patients, suggesting HRT substantially mitigates the menopausal symptom burden of surgical menopause when used. No cancer incidence outcomes or oncologic safety data were reported within the 24-month follow-up window of this publication. NNT and NNH are not calculable from available data.
Practice implications
This trial represents the most methodologically rigorous prospective US data directly comparing quality-of-life outcomes between ISDO and RRSO in a germline high-risk population. The non-randomized patient-preference design is appropriate given the ethical and practical infeasibility of randomizing surgical prevention strategies in this population, but it introduces the possibility of residual confounding that IPW, while helpful, cannot fully eliminate. Critically, the trial addresses patient-reported sexual function and menopausal symptoms only—it was not designed or powered to evaluate ovarian cancer incidence or mortality. ISDO therefore cannot yet be considered oncologically equivalent to RRSO; its cancer risk-reduction efficacy compared with RRSO remains unestablished and is being assessed in separate ongoing trials. The finding that HRT substantially managed menopausal symptoms in RRSO patients is clinically significant: it suggests that for patients who cannot or will not defer oophorectomy, optimized HRT counseling and prescribing may close much of the quality-of-life gap. Generalizability is limited to premenopausal germline variant carriers at high-risk centers; findings may not apply to average-risk populations, post-menopausal patients, or those who are HRT-ineligible (e.g., hormone receptor–positive breast cancer history). Only the abstract was available for this summary; full data tables, subgroup analyses, and adjusted effect estimates require review of the complete manuscript. Practice change should await oncologic safety data from parallel trials before ISDO is offered outside of a clinical trial setting. __LIMITATIONS__ Non-randomized patient-preference design: systematic differences between groups (e.g., younger age in ISDO arm) may persist despite inverse probability weighting, introducing residual confounding.,ISDO oncologic safety (cancer risk reduction vs. RRSO) is not assessed in this study; the 24-month window is insufficient to detect differences in ovarian cancer incidence.,Patient preference allocation may introduce selection bias: participants choosing ISDO may have had stronger pre-existing concerns about sexual dysfunction, inflating perceived benefit.,No blinding possible given the nature of surgical interventions; patient-reported outcomes may be influenced by expectation effects.,HRT use was not randomized; differential HRT uptake between arms may confound symptom comparisons.,Sample size (n=334) may be underpowered for subgroup analyses by gene variant (e.g., BRCA1 vs. BRCA2 vs. other), age stratum, or HRT use status.,Follow-up limited to 24 months; long-term QoL, cardiovascular, bone, and cognitive sequelae of RRSO vs. retained ovarian function are not captured.,Enrolled at 9 US academic/cancer centers; results may not generalize to community settings or non-US healthcare systems.,Only an abstract was available for detailed critique; full statistical methods, attrition rates, missing data handling, and secondary outcome data cannot be fully evaluated.,Funding source was not confirmed in the abstract, precluding full assessment of potential sponsorship bias. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ The WISP trial provides the most rigorous prospective US evidence that ISDO preserves sexual function and menopausal quality of life better than RRSO in premenopausal germline high-risk individuals, with a key finding that HRT substantially mitigates menopausal symptoms following RRSO. However, ISDO must not be offered outside a clinical trial context until its oncologic equivalence to RRSO is established, and clinicians should prioritize proactive HRT counseling for all eligible patients undergoing RRSO. Full outcome data from the complete manuscript are required before definitive clinical guidance can be issued.