Authors' objectives: Lynch syndrome is an inherited condition which leads to an increased risk of colorectal, endometrial and ovarian cancer. Risk-reducing surgery is generally recommended to manage the risk of gynaecological cancer once childbearing is completed. The value of gynaecological colonoscopic surveillance as an interim measure or instead of risk-reducing surgery is uncertain. We aimed to determine whether gynaecological surveillance was effective and cost-effective in Lynch syndrome. Lynch syndrome is an inherited cancer predisposition syndrome, which leads to an increased lifetime risk for colorectal, endometrial and ovarian cancers. These cancers are typically observed at younger ages in people with Lynch syndrome than in the general population. Cancer risks depend somewhat on which deoxyribonucleic acid (DNA) mismatch repair gene is affected in the patient, with path_MLH1 and path_MSH2 genotypes generally having the highest penetrance, path_MSH6 having high penetrance for endometrial cancer but lower penetrance for colorectal and ovarian cancer, and path_PMS2 having lower penetrance still. Survival from colorectal and ovarian cancer among patients with Lynch syndrome tends to be better than survival among unselected patients, and this may also be true for endometrial cancer, but survival from endometrial cancer is already more favourable. When Lynch syndrome is diagnosed, measures are put in place to manage cancer risks. These measures typically include biennial colonoscopic surveillance from 25 years of age and the offer of risk-reducing gynaecological surgery (hysterectomy with bilateral salpingo-oophorectomy) after completion of childbearing and before the individual faces a significant risk of gynaecological cancer (surgery is generally recommended from 35 years). In addition, some patients may use aspirin as chemoprophylaxis and may have surveillance of other organs besides the colon. Gynaecological cancer surveillance is contentious. It is perceived that there is a lack of evidence to support widespread adoption of colonoscopic surveillance but also that there is insufficient evidence that it is ineffective so should not be offered to patients. Many women with Lynch syndrome do want gynaecological surveillance, and some resort to private healthcare if it is not provided by their local NHS hospital. Some women may wish to receive colonoscopic surveillance for a time before opting for risk-reducing surgery when they are older; some women may not ever want to undergo risk-reducing surgery, and some may be unsuitable for surgery.

Authors' results and conclusions: We found 30 studies in the review of clinical effectiveness, of which 20 were non-comparative (single-arm) studies. There were no high-quality studies providing precise outcome estimates at low risk of bias. There is some evidence that mortality rate is higher for surveillance than for risk-reducing surgery but mortality is also higher for no surveillance than for surveillance. Some asymptomatic cancers were detected through surveillance but some cancers were also missed. There was a wide range of pain experiences, including some individuals feeling no pain and some feeling severe pain. The use of pain relief (e.g. ibuprofen) was common, and some women underwent general anaesthetic for surveillance. Existing economic evaluations clearly found that risk-reducing surgery leads to the best lifetime health (measured using quality-adjusted life-years) and is cost-effective, while surveillance is not cost-effective in comparison. Our economic evaluation found that a strategy of surveillance alone or offering surveillance and risk-reducing surgery was cost-effective, except for path_PMS2 Lynch syndrome. Offering only risk-reducing surgery was less effective than offering surveillance with or without surgery. There is insufficient evidence to recommend for or against gynaecological cancer surveillance in Lynch syndrome on clinical grounds, but modelling suggests that surveillance could be cost-effective. Further research is needed but it must be rigorously designed and well reported to be of benefit. A total of 30 studies were included in the review, of which 20 were single-arm studies. Five studies compared colonoscopic surveillance with risk-reducing surgery, three compared time periods with different surveillance approaches and two compared surveillance with no intervention. There was a high likelihood of overlap between some studies. No studies provided high-quality evidence that is precise and at low risk of bias. The most significant contribution to the risk of bias in studies was failure to adequately consider and address confounding factors. Some studies adopted a diagnostic accuracy evaluation design and were generally reported too poorly to enable good assessment of the risk of bias or were found to be at high risk of bias. Mortality and survival Some evidence suggests that all-cause mortality rates are lower with surgery than with surveillance, and lower with surveillance than with no intervention. Some evidence suggests that endometrial cancer-specific mortality is lower with surveillance than with no intervention, but lower still with risk-reducing surgery. Endometrial cancer survival for cancers detected by surveillance was not significantly different from survival for occult cancers diagnosed upon risk-reducing surgery. A similar but even weaker pattern was observed for ovarian cancer. Three cost-effectiveness analyses were identified. All three studies were based on relatively simple decision analytical models. All studies included at least one surveillance arm and one risk-reducing surgery arm. Two studies included a ‘no intervention’ arm. Risk-reducing surgery was economically dominant (less costly and more effective than alternatives) in two studies and was highly cost-effective in the other. Surveillance was dominated by risk-reducing surgery in all analyses. If risk-reducing surgery strategies were removed, one study would find surveillance cost-effective versus no intervention, while the other study would find it not cost-effective (producing health benefits but at too great a cost). Fifty-eight studies were identified, with more than half relating to ovarian cancer. Only four studies related to gynaecological surveillance and only two studies related to risk-reducing surgery for Lynch syndrome. The studies relating to surveillance and risk-reducing surgery asked participants to value hypothetical disease states, while most of the other studies asked patients to describe or value their own health. Utility values tended to be lower for more advanced endometrial or ovarian cancer. The studies reporting utility values for gynaecological surveillance were either methodologically flawed or reported minimal detail of their methods. The studies reporting utility values for risk-reducing surgery in Lynch syndrome were similarly methodologically flawed. For benign gynaecological conditions, utility generally drops sharply following surgery for a recovery period, and eventually reaches a level higher than preoperative utility. This finding is not expected to be replicated in risk-reducing surgery, but some studies may be a useful proxy for the utility of risk-reducing surgery, particularly if they include premenopausal bilateral oophorectomy. Risk reduction strategies are predicted to be cost-effective compared with no intervention, except for path_PMS2 Lynch syndrome. For other genotypes, surveillance (alone or with risk-reducing surgery also offered) is expected to lead to more QALYs (and greater costs) than only offering risk-reducing surgery and to be cost-effective. For path_PMS2, risk-reducing surgery and surveillance led to significant cost increases, since there were minimal changes to cancer outcomes to offset these costs. Value of information calculations suggest that further research to obtain more precise parameter estimates would be very valuable. Further value of information analyses may help to prioritise research. Clinical effectiveness evidence for gynaecological cancer surveillance in Lynch syndrome is sparse and methodologically limited. There is some evidence that surveillance can prevent some deaths compared with no intervention, but there is also evidence that risk-reducing surgery prevents more deaths. Some asymptomatic cancers are detected by surveillance, but some cancers are also missed. Recipients of surveillance have a wide range of pain experiences. While existing publications have concluded that risk-reducing surgery is clearly cost-effective (generally leading to a substantial gain in QALYs while lowering or only slightly increasing costs) and that surveillance alone is not cost-effective if risk-reducing surgery is an option, we have found that surveillance can be a cost-effective way to manage the risk of gynaecological cancer. Further research is needed to reduce the uncertainty in model parameters, both to determine cost-effectiveness and to provide context to patients about the potential clinical value of risk-reducing strategies. Implications for health care People with Lynch syndrome should be informed that gynaecological cancer surveillance is not expected to reduce the risk of gynaecological cancer and cancer death to the same extent as risk-reducing surgery. There is some evidence that surveillance could be beneficial compared with no risk reduction (e.g. some asymptomatic cancers detected), but there is also evidence that some cancers are missed and that some individuals find surveillance severely painful. The prognosis from endometrial and ovarian cancer appears to be better for people with Lynch syndrome than for unselected patients. Gynaecological cancer surveillance is estimated to cost the NHS over £300 per year per patient, while risk-reducing surgery is estimated to cost over £6000.

Authors' recommendations: Researchers should consult with biostatisticians or epidemiologists or other methodological experts before conducting trials and publishing further in this area – the quality of current research falls below the level needed to inform decision-making. More in-depth value of information analyses should be conducted to identify which parameters or groups of parameters are most critical to research further. Health utilities should be directly elicited from individuals with Lynch syndrome to identify the potential effects of surveillance and risk-reducing surgery on health-related quality of life and QALYs; relatedly, it may be beneficial to consider whether willingness to pay is a better indication of the value of undergoing or avoiding surveillance.

Authors' methods: We conducted systematic reviews of the effectiveness and cost-effectiveness of gynaecological cancer surveillance in Lynch syndrome, as well as a systematic review of health utility values relating to cancer and gynaecological risk reduction. Study identification included bibliographic database searching and citation chasing (searches updated 3 August 2021). Screening and assessment of eligibility for inclusion were conducted by independent researchers. Outcomes were prespecified and were informed by clinical experts and patient involvement. Data extraction and quality appraisal were conducted and results were synthesised narratively. We also developed a whole-disease economic model for Lynch syndrome using discrete event simulation methodology, including natural history components for colorectal, endometrial and ovarian cancer, and we used this model to conduct a cost–utility analysis of gynaecological risk management strategies, including surveillance, risk-reducing surgery and doing nothing. Firm conclusions about clinical effectiveness could not be reached because of the lack of high-quality research. We did not assume that women would immediately take up risk-reducing surgery if offered, and it is possible that risk-reducing surgery would be more effective and cost-effective if it was taken up when offered. We conducted a systematic review in line with a preregistered protocol (PROSPERO CRD42020171098). Our study identification methods included bibliographical database searches, citation chasing and hand screening of conference proceedings and clinical trials registries. Searches were updated to 3 August 2021. Study selection was conducted independently by two reviewers. A broad range of outcomes were determined a priori and a broad range of study designs were considered eligible for inclusion, including non-comparative observational studies (e.g. cross-sectional studies and case series). Risk of bias was assessed using one or more of three checklists, according to the study design. Narrative synthesis was performed, supported by cross-tabulation. Studies were too methodologically heterogeneous and insufficiently numerous to justify quantitative synthesis (i.e. meta-analysis). Our study identification methods included bibliographical database searches and citation chasing. Study selection was conducted independently by two reviewers. Data extraction and quality appraisal were conducted and included the use of a set of bespoke quality appraisal questions. Narrative synthesis was conducted, supported by cross-tabulation. We sought utility values relating to endometrial cancer, ovarian cancer, gynaecological cancer surveillance and risk-reducing gynaecological surgery. We did not restrict the population to people with Lynch syndrome. In expectation that there would be insufficient data on risk-reducing gynaecological surgery, we also sought utility values relating to gynaecological surgery for benign gynaecological conditions. Our study identification methods included bibliographical database searches and citation chasing. Study selection was conducted independently by two reviewers. Data extraction and quality appraisal were conducted. Narrative synthesis was conducted, supported by cross-tabulation. We developed a whole-disease model using a discrete event simulation methodology. The model included natural history components for colorectal, endometrial and ovarian cancers that were calibrated to aggregate data from published studies, including the Prospective Lynch Syndrome Database. Clinical parameters (e.g. cancer survival) were estimated, where possible, from studies of Lynch syndrome populations. We used the model to conduct a cost–utility analysis of risk-reducing strategies for gynaecological cancer, including surveillance and risk-reducing surgery, and comparing these with a no intervention strategy. The economic evaluation was generally conducted in line with the National Institute for Health and Care Excellence (NICE) reference case and quality-adjusted life-years (QALYs) were the measure of health benefit.

Project Status: Completed

URL for project: https://www.journalslibrary.nihr.ac.uk/programmes/hta/NIHR129713

Year Published: 2024

URL for published report: https://www.journalslibrary.nihr.ac.uk/hta/VBXX6307

URL for additional information: English

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: United Kingdom

DOI: 10.3310/VBXX6307

Organisation Name: NIHR Health and Social Care Delivery Program

Contact Name: Rhiannon Miller

Contact Email: rhiannon.m@prepress-projects.co.uk