Health Technology Assessment

Gynaecological cancer surveillance for women with Lynch syndrome: systematic review and cost-effectiveness evaluation

Background 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. 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. Results 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. Limitations 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. Conclusions 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. Study registration This study is registered as PROSPERO CRD42020171098. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR129713) and is published in full in Health Technology Assessment; Vol. 28, No. 41. See the NIHR Funding and Awards website for further award information.

Hyperthermic intraoperative peritoneal chemotherapy and cytoreductive surgery for people with peritoneal metastases: a systematic review and cost-effectiveness analysis

Background We compared the relative benefits, harms and cost-effectiveness of hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery ± systemic chemotherapy versus cytoreductive surgery ± systemic chemotherapy or systemic chemotherapy alone in people with peritoneal metastases from colorectal, gastric or ovarian cancers by a systematic review, meta-analysis and model-based cost–utility analysis. Methods We searched MEDLINE, EMBASE, Cochrane Library and the Science Citation Index, ClinicalTrials.gov and WHO ICTRP trial registers until 14 April 2022. We included only randomised controlled trials addressing the research objectives. We used the Cochrane risk of bias tool version 2 to assess the risk of bias in randomised controlled trials. We used the random-effects model for data synthesis when applicable. For the cost-effectiveness analysis, we performed a model-based cost–utility analysis using methods recommended by The National Institute for Health and Care Excellence. Results The systematic review included a total of eight randomised controlled trials (seven randomised controlled trials, 955 participants included in the quantitative analysis). All comparisons other than those for stage III or greater epithelial ovarian cancer contained only one trial, indicating the paucity of randomised controlled trials that provided data. For colorectal cancer, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably results in little to no difference in all-cause mortality (60.6% vs. 60.6%; hazard ratio 1.00, 95% confidence interval 0.63 to 1.58) and may increase the serious adverse event proportions compared to cytoreductive surgery ± systemic chemotherapy (25.6% vs. 15.2%; risk ratio 1.69, 95% confidence interval 1.03 to 2.77). Hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably decreases all-cause mortality compared to fluorouracil-based systemic chemotherapy alone (40.8% vs. 60.8%; hazard ratio 0.55, 95% confidence interval 0.32 to 0.95). For gastric cancer, there is high uncertainty about the effects of hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy versus cytoreductive surgery + systemic chemotherapy or systemic chemotherapy alone on all-cause mortality. For stage III or greater epithelial ovarian cancer undergoing interval cytoreductive surgery, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably decreases all-cause mortality compared to cytoreductive surgery + systemic chemotherapy (46.3% vs. 57.4%; hazard ratio 0.73, 95% confidence interval 0.57 to 0.93). Hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy may not be cost-effective versus cytoreductive surgery + systemic chemotherapy for colorectal cancer but may be cost-effective for the remaining comparisons. Limitations We were unable to obtain individual participant data as planned. The limited number of randomised controlled trials for each comparison and the paucity of data on health-related quality of life mean that the recommendations may change as new evidence (from trials with a low risk of bias) emerges. Conclusions In people with peritoneal metastases from colorectal cancer with limited peritoneal metastases and who are likely to withstand major surgery, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy should not be used in routine clinical practice (strong recommendation). There is considerable uncertainty as to whether hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy or cytoreductive surgery + systemic chemotherapy should be offered to patients with gastric cancer and peritoneal metastases (no recommendation). Hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy should be offered routinely to women with stage III or greater epithelial ovarian cancer and metastases confined to the abdomen requiring and likely to withstand interval cytoreductive surgery after chemotherapy (strong recommendation). Future work More randomised controlled trials are necessary. Study registration This study is registered as PROSPERO CRD42019130504. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/135/02) and is published in full in Health Technology Assessment; Vol. 28, No. 51. See the NIHR Funding and Awards website for further award information.

Testing strategies for Lynch syndrome in people with endometrial cancer: systematic reviews and economic evaluation

BackgroundLynch syndrome is an inherited genetic condition that is associated with an increased risk of certain cancers. The National Institute for Health and Care Excellence has recommended that people with colorectal cancer are tested for Lynch syndrome. Routine testing for Lynch syndrome among people with endometrial cancer is not currently conducted.ObjectivesTo systematically review the evidence on the test accuracy of immunohistochemistry- and microsatellite instability-based strategies to detect Lynch syndrome among people who have endometrial cancer, and the clinical effectiveness and the cost-effectiveness of testing for Lynch syndrome among people who have been diagnosed with endometrial cancer.Data sourcesSearches were conducted in the following databases, from inception to August 2019 – MEDLINE ALL, EMBASE (both via Ovid), Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (both via Wiley Online Library), Database of Abstracts of Reviews of Effects, Health Technology Assessment Database (both via the Centre for Reviews and Dissemination), Science Citation Index, Conference Proceedings Citation Index – Science (both via Web of Science), PROSPERO international prospective register of systematic reviews (via the Centre for Reviews and Dissemination), NHS Economic Evaluation Database, Cost-Effectiveness Analysis Registry, EconPapers (Research Papers in Economics) and School of Health and Related Research Health Utilities Database. The references of included studies and relevant systematic reviews were also checked and experts on the team were consulted.Review methodsEligible studies included people with endometrial cancer who were tested for Lynch syndrome using immunohistochemistry- and/or microsatellite instability-based testing [with or without mutL homologue 1 (MLH1) promoter hypermethylation testing], with Lynch syndrome diagnosis being established though germline testing of normal (non-tumour) tissue for constitutional mutations in mismatch repair. The risk of bias in studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool, the Consolidated Health Economic Reporting Standards and the Philips’ checklist. Two reviewers independently conducted each stage of the review. A meta-analysis of test accuracy was not possible because of the number and heterogeneity of studies. A narrative summary of test accuracy results was provided, reporting test accuracy estimates and presenting forest plots. The economic model constituted a decision tree followed by Markov models for the impact of colorectal and endometrial surveillance, and aspirin prophylaxis with a lifetime time horizon.ResultsThe clinical effectiveness search identified 3308 studies; 38 studies of test accuracy were included. (No studies of clinical effectiveness of endometrial cancer surveillance met the inclusion criteria.) Four test accuracy studies compared microsatellite instability with immunohistochemistry. No clear difference in accuracy between immunohistochemistry and microsatellite instability was observed. There was some evidence that specificity of immunohistochemistry could be improved with the addition of methylation testing. There was high concordance between immunohistochemistry and microsatellite instability. The economic model indicated that all testing strategies, compared with no testing, were cost-effective at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year. Immunohistochemistry withMLH1promoter hypermethylation testing was the most cost-effective strategy, with an incremental cost-effectiveness ratio of £9420 per quality-adjusted life-year. The second most cost-effective strategy was immunohistochemistry testing alone, but incremental analysis produced an incremental cost-effectiveness ratio exceeding £130,000. Results were robust across all scenario analyses. Incremental cost-effectiveness ratios ranged from £5690 to £20,740; only removing the benefits of colorectal cancer surveillance produced an incremental cost-effectiveness ratio in excess of the £20,000 willingness-to-pay threshold. A sensitivity analysis identified the main cost drivers of the incremental cost-effectiveness ratio as percentage of relatives accepting counselling and prevalence of Lynch syndrome in the population. A probabilistic sensitivity analysis showed, at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year, a 0.93 probability that immunohistochemistry withMLH1promoter hypermethylation testing is cost-effective, compared with no testing.LimitationsThe systematic review excluded grey literature, studies written in non-English languages and studies for which the reference standard could not be established. Studies were included when Lynch syndrome was diagnosed by genetic confirmation of constitutional variants in the four mismatch repair genes (i.e.MLH1, mutS homologue 2, mutS homologue 6 and postmeiotic segregation increased 2). Variants of uncertain significance were reported as per the studies. There were limitations in the economic model around uncertainty in the model parameters and a lack of modelling of the potential harms of gynaecological surveillance and specific pathway modelling of genetic testing for somatic mismatch repair mutations.ConclusionThe economic model suggests that testing women with endometrial cancer for Lynch syndrome is cost-effective, but that results should be treated with caution because of uncertain model inputs.Future workRandomised controlled trials could provide evidence on the effect of earlier intervention on outcomes and the balance of benefits and harms of gynaecological cancer surveillance. Follow-up of negative cases through disease registers could be used to determine false negative cases.Study registrationThis study is registered as PROSPERO CRD42019147185.FundingThis project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full inHealth Technology Assessment; Vol. 25, No. 42. See the NIHR Journals Library website for further project information.

Identifying the best diagnostic test for ovarian cancer – synopsis of Refining Ovarian Cancer Test accuracy Scores (ROCkeTS) research

Background Ovarian cancer survival is stage-dependent: Stage I patients have 90% 5-year survival versus 15% for stage IV. Over 70% of patients worldwide are diagnosed at advanced stages. Ovarian cancer presents with non-specific symptoms (abdominal bloating, early satiety, discomfort/pain, bowel/urinary changes). Current National Institute for Health and Care Excellence guidelines recommend that symptomatic women presenting to primary care are tested with cancer antigen 125 and ultrasound, then referred to secondary care for further triage if these tests are abnormal. Current standard of care risk prediction model used to triage women in National Health Service secondary care is Risk of Malignancy Index 1 combining cancer antigen 125 and simple ultrasound features, which at 250 threshold has 70% sensitivity and 90% specificity. Newer models offer potential for improved sensitivity, earlier diagnosis and better survival outcomes. Objectives To evaluate diagnostic strategies for ovarian cancer in women with non-specific symptoms through systematic review, United Kingdom Collaborative Trial of Ovarian Cancer Screening data set analysis, prospective studies and health economic evaluation comparing Risk of Malignancy Index 1 against newer approaches including Risk of Ovarian Malignancy Algorithm, Ovarian-Adnexal Reporting and Data System and International Ovarian Tumour Analysis models, including International Ovarian Tumour Analysis Assessment of Different NEoplasias in the adneXa. Methods Four concurrent work packages: (1) Cochrane systematic review; (2) United Kingdom Collaborative Trial of Ovarian Cancer Screening data set model development; (3) prospective multicentre diagnostic accuracy study (ROCkeTS) with parallel pre/postmenopausal cohorts; and (4) cost–consequence analysis. Allied analyses investigated psychological impact and cancer outcomes from symptom-triggered pathways. ROCkeTS recruited 2453 women across 23 hospitals (2015–23) with symptoms, raised cancer antigen 125 and/or abnormal imaging. Women completed questionnaires, donated blood and underwent transvaginal ultrasound scored by International Ovarian Tumour Analysis terminology by certified National Health Service sonographers with quality assurance. Reference standard was histology for surgical cases or 12-month wellbeing ascertainment. Primary outcome: primary invasive ovarian cancer versus benign or normal. Results The Cochrane systematic review (58 studies, 30,121 patients and 9061 ovarian cancer cases) demonstrated that most published diagnostic test accuracy studies failed to differentiate between pre- and postmenopausal women, and all were conducted in high-prevalence settings, limiting applicability to routine practice. In the ROCkeTS prospective study in premenopausal women, in the initial cohort recruited prior to protocol change ( n  = 857), Risk of Malignancy Index 1 at threshold 250 showed poor sensitivity (42.6%, 95% confidence interval 28.3 to 57.8) but high specificity (96.5%, 95% confidence interval 94.7 to 97.8). All other tests improved sensitivity but dropped specificity. International Ovarian Tumour Analysis Assessment of Different NEoplasias in the adneXa at 10% threshold achieved significantly higher sensitivity (89.1%, 95% confidence interval 76.4 to 96.4), higher than all other tests with acceptable specificity (73.2%, 95% confidence interval 69.9 to 76.4). In the ROCkeTS prospective cohort study in postmenopausal women ( n  = 1242), Risk of Malignancy Index 1 at 250 demonstrated better performance (82.9%, 95% confidence interval 76.7 to 88.0), but International Ovarian Tumour Analysis Assessment of Different NEoplasias in the adneXa at 10% had the best sensitivity at 96.1% (95% confidence interval 92.2 to 98.4) compared to Risk of Malignancy Index 1 with the least drop of specificity. Risk of Ovarian Malignancy Algorithm at manufacturer recommended threshold and Ovarian-Adnexal Reporting and Data System did not improve on Risk of Malignancy Index 1 sensitivity in postmenopausal women. Cancer prevalence differed between premenopausal (5.7%) and postmenopausal (17%) cohorts. Early-stage cancer (I/II) were diagnosed in 60.2% of premenopausal and 41% of postmenopausal cohorts. Cancer diagnosis rates were very low (1.6%) in women under 40 years. High anxiety and distress were noted, particularly in younger women. One in four women with high-grade serous ovarian cancers were diagnosed at early stage (I/II). Complete cytoreduction was achieved in 61.3% of cases, with optimal cytoreduction (≤ 1 cm residual disease) in an additional 15.1%. Cost–consequence analysis demonstrated that a two-step strategy deployed at the same ultrasound sitting, initially triaging out benign looking tumours on ultrasound, then calculating ovarian cancer risk with International Ovarian Tumour Analysis Assessment of Different NEoplasias in the adneXa ultrasound model at 10% demonstrated the best balance across cost, diagnostic yield and cancer deaths compared to other diagnostic strategies. Limitations Cohort study required key changes to protocol and post-pandemic recruitment was slow. Conclusions International Ovarian Tumour Analysis Assessment of Different NEoplasias in the adneXa ultrasound at 10% threshold, delivered by trained National Health Service sonographers demonstrated superior diagnostic performance compared to Risk of Malignancy Index 1 and should be considered as new standard of care for suspected ovarian cancer in pre- and postmenopausal women. A two-step strategy using International Ovarian Tumour Analysis Assessment of Different NEoplasias in the adneXa offers optimal balance across cost, diagnostic yield and cancer death reduction. Implementation requires sonographer training investment and quality assurance. Future research International Ovarian Tumour Analysis Assessment of Different NEoplasias in the adneXa implementation in primary care/community settings, artificial intelligence-enabled quality assurance, reconfiguration of referral pathways in primary care to reduce unnecessary referrals in younger women and consequent harm are important research areas. Systematic symptom elicitation capitalising on routine health interactions to reach underserved communities warrants further research. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 13/13/01.