The predicted impact and cost-effectiveness of systematic testing of people with incident colorectal cancer for Lynch syndrome.

OBJECTIVES: To evaluate the health impact and cost-effectiveness of systematic testing for Lynch syndrome (LS) in people with incident colorectal cancer (CRC) in Australia. DESIGN, SETTING, PARTICIPANTS: We investigated the impact of LS testing strategies in a micro-simulation model (Policy1-Lynch), explicitly modelling the cost of testing all patients diagnosed with incident CRC during 2017, with detailed modelling of outcomes for patients identified as LS carriers (probands) and their at-risk relatives throughout their lifetimes. For people with confirmed LS, we modelled ongoing colonoscopic surveillance. MAIN OUTCOME MEASURES: Cost-effectiveness of six universal tumour testing strategies (testing for DNA mismatch repair deficiencies) and of universal germline gene panel testing of patients with incident CRC; impact on cost-effectiveness of restricting testing by age at CRC diagnosis (all ages, under 50/60/70 years) and of colonoscopic surveillance interval (one, two years). RESULTS: The cost-effectiveness ratio of universal tumour testing strategies (annual colonoscopic surveillance, no testing age limit) compared with no testing ranged from $28 915 to $31 904/life-year saved (LYS) (indicative willingness-to-pay threshold: $30 000-$50 000/LYS). These strategies could avert 184-189 CRC deaths with an additional 30 597-31 084 colonoscopies over the lifetimes of 1000 patients with incident CRC with LS and 1420 confirmed LS carrier relatives (164-166 additional colonoscopies/death averted). The most cost-effective strategy was immunohistochemistry and BRAF V600E testing (incremental cost-effectiveness ratio [ICER], $28 915/LYS). Universal germline gene panel testing was not cost-effective compared with universal tumour testing strategies (ICER, $2.4 million/LYS). Immunohistochemistry and BRAF V600E testing was cost-effective at all age limits when paired with 2-yearly colonoscopic surveillance (ICER, $11 525-$32 153/LYS), and required 4778-15 860 additional colonoscopies to avert 46-181 CRC deaths (88-103 additional colonoscopies/death averted). CONCLUSIONS: Universal tumour testing strategies for guiding germline genetic testing of people with incident CRC for LS in Australia are likely to be cost-effective compared with no testing. Universal germline gene panel testing would not currently be cost-effective.

Economic Analysis of First-Line Treatment with Cetuximab or Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer in England.

BACKGROUND: Combination therapies with cetuximab (Erbitux®; Merck Serono UK Ltd) and panitumumab (Vectibix®; Amgen UK Ltd) are shown to be less effective in adults with metastatic colorectal cancer who have mutations in exons 2, 3 and 4 of KRAS and NRAS oncogenes from the rat sarcoma (RAS) family. OBJECTIVE: The objective of the study was to estimate the cost effectiveness of these drugs in patients with previously untreated RAS wild-type (i.e. non-mutated) metastatic colorectal cancer, not eligible for liver resection at baseline, from the UK National Health Service and Personal Social Services perspective. METHODS: We constructed a partitioned survival model to evaluate the long-term costs and benefits of cetuximab and panitumumab combined with either FOLFOX (folinic acid, fluorouracil and oxaliplatin) or FOLFIRI (folinic acid, fluorouracil and irinotecan) vs. FOLFOX or FOLFIRI alone. The economic analysis was based on three randomised controlled trials. Costs and quality-adjusted life-years were discounted at 3.5% per annum. RESULTS: Based on the evidence available, both drugs fulfil the National Institute for Health and Care Excellence's end-of-life criteria. In the analysis, assuming discount prices for the drugs from patient access schemes agreed by the drug manufacturers with the Department of Health, predicted mean incremental cost-effectiveness ratios for cetuximab + FOLFOX, panitumumab + FOLFOX and cetuximab + FOLFIRI compared with chemotherapy alone appeared cost-effective at the National Institute for Health and Care Excellence's threshold of £50,000 per quality-adjusted life-year gained, applicable to end-of-life treatments. CONCLUSION: Cetuximab and panitumumab were recommended by the National Institute for Health and Care Excellence for patients with previously untreated RAS wild-type metastatic colorectal cancer, not eligible for liver resection at baseline, for use within the National Health Service in England. Both treatments are available via the UK Cancer Drugs Fund.

A systematic review of test accuracy studies evaluating molecular micro-satellite instability testing for the detection of individuals with lynch syndrome.

BACKGROUND: A systematic review was conducted to assess the diagnostic test accuracy of polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing for identifying Lynch syndrome in patients with colorectal cancer (CRC). Unlike previous reviews, this was based on assessing MSI testing against best practice for the reference standard, and included CRC populations that were unselected, age-limited or high-risk for Lynch syndrome. METHODS: Single- and two-gate diagnostic test accuracy studies, or similar, were identified, assessed for inclusion, data extracted and quality appraised by two reviewers according to a pre-specified protocol. Sensitivity of MSI testing was estimated for all included studies. Specificity, likelihood ratios and predictive values were estimated for studies that were not based on high-risk samples. Narrative synthesis was conducted. RESULTS: Nine study samples were included. When MSI-Low results were considered to be negative, sensitivity estimates ranged from 67% (95% CI 47, 83) to 100% (95% CI 94, 100). Three studies contributed to estimates of both sensitivity and specificity, with specificity ranging from 61% (95% CI 57, 65), to 93% (95% CI 89, 95). Good sensitivity was achieved at the expense of specificity. When MSI-L was considered to be positive (effectively lowering the threshold for a positive index test result) sensitivity increased and specificity decreased. Between-study heterogeneity in both the MSI and reference standard testing, combined with the low number of studies contributing to both sensitivity and specificity estimates, precluded pooling by meta-analysis. CONCLUSIONS: MSI testing is an effective screening test for Lynch syndrome. However, there is significant uncertainty surrounding what balance of sensitivity and specificity will be achieved in clinical practice and how this relates to specific characteristics of the test (such as the panel of markers used or the thresholds used to denote a positive test).

Immunosuppressive agents in adult kidney transplantation in the National Health Service: a model-based economic evaluation.

BACKGROUND: Immunosuppression is required in kidney transplantation to prevent rejection and prolong graft survival. We conducted an economic evaluation to support England's National Institute for Health and Care Excellence in developing updated guidance on the use of immunosuppression, incorporating new immunosuppressive agents, and addressing changes in pricing and the evidence base. METHODS: A discrete-time state transition model was developed to simulate adult kidney transplant patients over their lifetime. A total of 16 different regimens were modelled to assess the cost-effectiveness of basiliximab and rabbit anti-thymocyte globulin (rabbit ATG) as induction agents (with no antibody induction as a comparator) and immediate-release tacrolimus, prolonged-release tacrolimus, mycophenolate mofetil, mycophenolate sodium, sirolimus, everolimus and belatacept as maintenance agents (with ciclosporin and azathioprine as comparators). Graft survival was extrapolated from acute rejection rates, graft function and post-transplant diabetes rates, all estimated at 12 months post-transplantation. National Health Service (NHS) and personal social services costs were included. Cost-effectiveness thresholds of £20 000 and £30 000 per quality-adjusted life year were used. RESULTS: Basiliximab was predicted to be more effective and less costly than rabbit ATG and induction without antibodies. Immediate-release tacrolimus and mycophenolate mofetil were cost-effective as maintenance therapies. Other therapies were either more expensive and less effective or would only be cost-effective if a threshold in excess of £100 000 per quality-adjusted life year were used. CONCLUSIONS: A regimen comprising induction with basiliximab, followed by maintenance therapy with immediate-release tacrolimus and mycophenolate mofetil, is likely to be effective for uncomplicated adult kidney transplant patients and a cost-effective use of NHS resources.

Molecular testing for Lynch syndrome in people with colorectal cancer: systematic reviews and economic evaluation.

BACKGROUND: Inherited mutations in deoxyribonucleic acid (DNA) mismatch repair (MMR) genes lead to an increased risk of colorectal cancer (CRC), gynaecological cancers and other cancers, known as Lynch syndrome (LS). Risk-reducing interventions can be offered to individuals with known LS-causing mutations. The mutations can be identified by comprehensive testing of the MMR genes, but this would be prohibitively expensive in the general population. Tumour-based tests - microsatellite instability (MSI) and MMR immunohistochemistry (IHC) - are used in CRC patients to identify individuals at high risk of LS for genetic testing. MLH1 (MutL homologue 1) promoter methylation and BRAF V600E testing can be conducted on tumour material to rule out certain sporadic cancers. OBJECTIVES: To investigate whether testing for LS in CRC patients using MSI or IHC (with or without MLH1 promoter methylation testing and BRAF V600E testing) is clinically effective (in terms of identifying Lynch syndrome and improving outcomes for patients) and represents a cost-effective use of NHS resources. REVIEW METHODS: Systematic reviews were conducted of the published literature on diagnostic test accuracy studies of MSI and/or IHC testing for LS, end-to-end studies of screening for LS in CRC patients and economic evaluations of screening for LS in CRC patients. A model-based economic evaluation was conducted to extrapolate long-term outcomes from the results of the diagnostic test accuracy review. The model was extended from a model previously developed by the authors. RESULTS: Ten studies were identified that evaluated the diagnostic test accuracy of MSI and/or IHC testing for identifying LS in CRC patients. For MSI testing, sensitivity ranged from 66.7% to 100.0% and specificity ranged from 61.1% to 92.5%. For IHC, sensitivity ranged from 80.8% to 100.0% and specificity ranged from 80.5% to 91.9%. When tumours showing low levels of MSI were treated as a positive result, the sensitivity of MSI testing increased but specificity fell. No end-to-end studies of screening for LS in CRC patients were identified. Nine economic evaluations of screening for LS in CRC were identified. None of the included studies fully matched the decision problem and hence a new economic evaluation was required. The base-case results in the economic evaluation suggest that screening for LS in CRC patients using IHC, BRAF V600E and MLH1 promoter methylation testing would be cost-effective at a threshold of £20,000 per quality-adjusted life-year (QALY). The incremental cost-effectiveness ratio for this strategy was £11,008 per QALY compared with no screening. Screening without tumour tests is not predicted to be cost-effective. LIMITATIONS: Most of the diagnostic test accuracy studies identified were rated as having a risk of bias or were conducted in unrepresentative samples. There was no direct evidence that screening improves long-term outcomes. No probabilistic sensitivity analysis was conducted. CONCLUSIONS: Systematic review evidence suggests that MSI- and IHC-based testing can be used to identify LS in CRC patients, although there was heterogeneity in the methods used in the studies identified and the results of the studies. There was no high-quality empirical evidence that screening improves long-term outcomes and so an evidence linkage approach using modelling was necessary. Key determinants of whether or not screening is cost-effective are the accuracy of tumour-based tests, CRC risk without surveillance, the number of relatives identified for cascade testing, colonoscopic surveillance effectiveness and the acceptance of genetic testing. Future work should investigate screening for more causes of hereditary CRC and screening for LS in endometrial cancer patients. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016033879. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The clinical effectiveness and cost-effectiveness of cetuximab (review of technology appraisal no. 176) and panitumumab (partial review of technology appraisal no. 240) for previously untreated metastatic colorectal cancer: a systematic review and economic evaluation.

BACKGROUND: Colorectal cancer is the fourth most commonly diagnosed cancer in the UK after breast, lung and prostate cancer. People with metastatic disease who are sufficiently fit are usually treated with active chemotherapy as first- or second-line therapy. Targeted agents are available, including the antiepidermal growth factor receptor (EGFR) agents cetuximab (Erbitux®, Merck Serono UK Ltd, Feltham, UK) and panitumumab (Vecitibix®, Amgen UK Ltd, Cambridge, UK). OBJECTIVE: To investigate the clinical effectiveness and cost-effectiveness of panitumumab in combination with chemotherapy and cetuximab in combination with chemotherapy for rat sarcoma (RAS) wild-type (WT) patients for the first-line treatment of metastatic colorectal cancer. DATA SOURCES: The assessment included a systematic review of clinical effectiveness and cost-effectiveness studies, a review and critique of manufacturer submissions, and a de novo cohort-based economic analysis. For the assessment of effectiveness, a literature search was conducted up to 27 April 2015 in a range of electronic databases, including MEDLINE, EMBASE and The Cochrane Library. REVIEW METHODS: Studies were included if they were randomised controlled trials (RCTs) or systematic reviews of RCTs of cetuximab or panitumumab in participants with previously untreated metastatic colorectal cancer with RAS WT status. All steps in the review were performed by one reviewer and checked independently by a second. Narrative synthesis and network meta-analyses (NMAs) were conducted for outcomes of interest. An economic model was developed focusing on first-line treatment and using a 30-year time horizon to capture costs and benefits. Costs and benefits were discounted at 3.5% per annum. Scenario analyses and probabilistic and univariate deterministic sensitivity analyses were performed. RESULTS: The searches identified 2811 titles and abstracts, of which five clinical trials were included. Additional data from these trials were provided by the manufacturers. No data were available for panitumumab plus irinotecan-based chemotherapy (folinic acid + 5-fluorouracil + irinotecan) (FOLFIRI) in previously untreated patients. Studies reported results for RAS WT subgroups. First-line treatment with anti-EGFR therapies in combination with chemotherapy appeared to have statistically significant benefits for patients who are RAS WT. For the independent economic evaluation, the base-case incremental cost-effectiveness ratio (ICER) for RAS WT patients for cetuximab plus oxaliplatin-based chemotherapy (folinic acid + 5-fluorouracil + oxaliplatin) (FOLFOX) compared with FOLFOX was £104,205 per quality-adjusted life-year (QALY) gained; for panitumumab plus FOLFOX compared with FOLFOX was £204,103 per QALY gained; and for cetuximab plus FOLFIRI compared with FOLFIRI was £122,554 per QALY gained. The ICERs were sensitive to treatment duration, progression-free survival, overall survival (resected patients only) and resection rates. LIMITATIONS: The trials included RAS WT populations only as subgroups. No evidence was available for panitumumab plus FOLFIRI. Two networks were used for the NMA and model, based on the different chemotherapies (FOLFOX and FOLFIRI), as insufficient evidence was available to the assessment group to connect these networks. CONCLUSIONS: Although cetuximab and panitumumab in combination with chemotherapy appear to be clinically beneficial for RAS WT patients compared with chemotherapy alone, they are likely to represent poor value for money when judged by cost-effectiveness criteria currently used in the UK. It would be useful to conduct a RCT in patients with RAS WT. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015016111. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model.

BACKGROUND: End-stage renal disease is a long-term irreversible decline in kidney function requiring renal replacement therapy: kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation, followed by immunosuppressive therapy (induction and maintenance therapy) to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES: To review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect(®), Novartis Pharmaceuticals UK Ltd) and rabbit anti-human thymocyte immunoglobulin (rATG) (Thymoglobulin(®), Sanofi) as induction therapy, and immediate-release tacrolimus (TAC) (Adoport(®), Sandoz; Capexion(®), Mylan; Modigraf(®), Astellas Pharma; Perixis(®), Accord Healthcare; Prograf(®), Astellas Pharma; Tacni(®), Teva; Vivadex(®), Dexcel Pharma), prolonged-release tacrolimus (Advagraf(®) Astellas Pharma), belatacept (BEL) (Nulojix(®), Bristol-Myers Squibb), mycophenolate mofetil (MMF) (Arzip(®), Zentiva; CellCept(®), Roche Products; Myfenax(®), Teva), mycophenolate sodium (MPS) (Myfortic(®), Novartis Pharmaceuticals UK Ltd), sirolimus (SRL) (Rapamune(®), Pfizer) and everolimus (EVL) (Certican(®), Novartis) as maintenance therapy in adult renal transplantation. METHODS: Clinical effectiveness searches were conducted until 18 November 2014 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science (via ISI), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted until 18 November 2014 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Database (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and the American Economic Association's electronic bibliography (via EconLit, EBSCOhost). Included studies were selected according to predefined methods and criteria. A random-effects model was used to analyse clinical effectiveness data (odds ratios for binary data and mean differences for continuous data). Network meta-analyses were undertaken within a Bayesian framework. A new discrete time-state transition economic model (semi-Markov) was developed, with acute rejection, graft function (GRF) and new-onset diabetes mellitus used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death. RESULTS: Eighty-nine randomised controlled trials (RCTs), of variable quality, were included. For induction therapy, no treatment appeared more effective than another in reducing graft loss or mortality. Compared with placebo/no induction, rATG and BAS appeared more effective in reducing biopsy-proven acute rejection (BPAR) and BAS appeared more effective at improving GRF. For maintenance therapy, no treatment was better for all outcomes and no treatment appeared most effective at reducing graft loss. BEL + MMF appeared more effective than TAC + MMF and SRL + MMF at reducing mortality. MMF + CSA (ciclosporin), TAC + MMF, SRL + TAC, TAC + AZA (azathioprine) and EVL + CSA appeared more effective than CSA + AZA and EVL + MPS at reducing BPAR. SRL + AZA, TAC + AZA, TAC + MMF and BEL + MMF appeared to improve GRF compared with CSA + AZA and MMF + CSA. In the base-case deterministic and probabilistic analyses, BAS, MMF and TAC were predicted to be cost-effective at £20,000 and £30,000 per quality-adjusted life-year (QALY). When comparing all regimens, only BAS + TAC + MMF was cost-effective at £20,000 and £30,000 per QALY. LIMITATIONS: For included trials, there was substantial methodological heterogeneity, few trials reported follow-up beyond 1 year, and there were insufficient data to perform subgroup analysis. Treatment discontinuation and switching were not modelled. FUTURE WORK: High-quality, better-reported, longer-term RCTs are needed. Ideally, these would be sufficiently powered for subgroup analysis and include health-related quality of life as an outcome. CONCLUSION: Only a regimen of BAS induction followed by maintenance with TAC and MMF is likely to be cost-effective at £20,000-30,000 per QALY. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014013189. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Immunosuppressive therapy for kidney transplantation in children and adolescents: systematic review and economic evaluation.

BACKGROUND: End-stage renal disease is a long-term irreversible decline in kidney function requiring kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation followed by induction and maintenance immunosuppressive therapy to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES: To systematically review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect,(®) Novartis Pharmaceuticals) and rabbit antihuman thymocyte immunoglobulin (Thymoglobuline,(®) Sanofi) as induction therapy and immediate-release tacrolimus [Adoport(®) (Sandoz); Capexion(®) (Mylan); Modigraf(®) (Astellas Pharma); Perixis(®) (Accord Healthcare); Prograf(®) (Astellas Pharma); Tacni(®) (Teva); Vivadex(®) (Dexcel Pharma)], prolonged-release tacrolimus (Advagraf,(®) Astellas Pharma); belatacept (BEL) (Nulojix,(®) Bristol-Myers Squibb), mycophenolate mofetil (MMF) [Arzip(®) (Zentiva), CellCept(®) (Roche Products), Myfenax(®) (Teva), generic MMF is manufactured by Accord Healthcare, Actavis, Arrow Pharmaceuticals, Dr Reddy's Laboratories, Mylan, Sandoz and Wockhardt], mycophenolate sodium, sirolimus (Rapamune,(®) Pfizer) and everolimus (Certican,(®) Novartis Pharmaceuticals) as maintenance therapy in children and adolescents undergoing renal transplantation. DATA SOURCES: Clinical effectiveness searches were conducted to 7 January 2015 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science [via Institute for Scientific Information (ISI)], Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (HTA) (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted to 15 January 2015 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Databases (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and EconLit (via EBSCOhost). REVIEW METHODS: Titles and abstracts were screened according to predefined inclusion criteria, as were full texts of identified studies. Included studies were extracted and quality appraised. Data were meta-analysed when appropriate. A new discrete time state transition economic model (semi-Markov) was developed; graft function, and incidences of acute rejection and new-onset diabetes mellitus were used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death. RESULTS: Three randomised controlled trials (RCTs) and four non-RCTs were included. The RCTs only evaluated BAS and tacrolimus (TAC). No statistically significant differences in key outcomes were found between BAS and placebo/no induction. Statistically significantly higher graft function (p < 0.01) and less biopsy-proven acute rejection (odds ratio 0.29, 95% confidence interval 0.15 to 0.57) was found between TAC and ciclosporin (CSA). Only one cost-effectiveness study was identified, which informed NICE guidance TA99. BAS [with TAC and azathioprine (AZA)] was predicted to be cost-effective at £20,000-30,000 per quality-adjusted life year (QALY) versus no induction (BAS was dominant). BAS (with CSA and MMF) was not predicted to be cost-effective at £20,000-30,000 per QALY versus no induction (BAS was dominated). TAC (with AZA) was predicted to be cost-effective at £20,000-30,000 per QALY versus CSA (TAC was dominant). A model based on adult evidence suggests that at a cost-effectiveness threshold of £20,000-30,000 per QALY, BAS and TAC are cost-effective in all considered combinations; MMF was also cost-effective with CSA but not TAC. LIMITATIONS: The RCT evidence is very limited; analyses comparing all interventions need to rely on adult evidence. CONCLUSIONS: TAC is likely to be cost-effective (vs. CSA, in combination with AZA) at £20,000-30,000 per QALY. Analysis based on one RCT found BAS to be dominant, but analysis based on another RCT found BAS to be dominated. BAS plus TAC and AZA was predicted to be cost-effective at £20,000-30,000 per QALY when all regimens were compared using extrapolated adult evidence. High-quality primary effectiveness research is needed. The UK Renal Registry could form the basis for a prospective primary study. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014013544. FUNDING: The National Institute for Health Research HTA programme.

The effectiveness and cost-effectiveness of erythropoiesis-stimulating agents (epoetin and darbepoetin) for treating cancer treatment-induced anaemia (including review of technology appraisal no. 142): a systematic review and economic model.

BACKGROUND: Anaemia is a common side effect of cancer treatments and can lead to a reduction in quality of life. Erythropoiesis-stimulating agents (ESAs) are licensed for use in conjunction with red blood cell transfusions to improve cancer treatment-induced anaemia (CIA). OBJECTIVE: To investigate the effectiveness and cost-effectiveness of ESAs in anaemia associated with cancer treatment (specifically chemotherapy). DATA SOURCES: The following databases were searched from 2004 to 2013: The Cochrane Library, MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Web of Science, Cumulative Index to Nursing and Allied Health Literature, British Nursing Index, Health Management Information Consortium, Current Controlled Trials and ClinicalTrials.gov. The US Food and Drug Administration and European Medicines Agency websites were also searched. Bibliographies of included papers were scrutinised for further potentially includable studies. REVIEW METHODS: The clinical effectiveness review followed principles published by the NHS Centre for Reviews and Dissemination. Randomised controlled trials (RCTs), or systematic reviews of RCTs, of ESAs (epoetin or darbepoetin) for treating people with CIA were eligible for inclusion in the review. Comparators were best supportive care, placebo or other ESAs. Anaemia- and malignancy-related outcomes, health-related quality of life (HRQoL) and adverse events (AEs) were evaluated. When appropriate, data were pooled using meta-analysis. An empirical health economic model was developed comparing ESA treatment with no ESA treatment. The model comprised two components: one evaluating short-term costs and quality-adjusted life-years (QALYs) (while patients are anaemic) and one evaluating long-term QALYs. Costs and benefits were discounted at 3.5% per annum. Probabilistic and univariate deterministic sensitivity analyses were performed. RESULTS: Of 1457 titles and abstracts screened, 23 studies assessing ESAs within their licensed indication (based on start dose administered) were included in the review. None of the RCTs were completely aligned with current European Union licenses. The results suggest a clinical benefit from ESAs for anaemia-related outcomes and an improvement in HRQoL scores. The impact of ESAs on AEs and survival remains highly uncertain, although point estimates are lower, confidence intervals are wide and not statistically significant. Base-case incremental cost-effectiveness ratios (ICERs) for ESA treatment compared with no ESA treatment ranged from £ 19,429 to £ 35,018 per QALY gained, but sensitivity and scenario analyses demonstrate considerable uncertainty in these ICERs, including the possibility of overall health disbenefit. All ICERs were sensitive to survival and cost. LIMITATIONS: The relative effectiveness of ESAs was not addressed; all ESAs were assumed to have equivalent efficacy. No studies were completely aligned with their European labelling beyond the starting dose evaluated. There is questionable generalisability given that the included trials were published >20 years ago and there have been many changes to chemotherapy as well as to the quality of supportive treatment. Trial quality was moderate or poor and there was considerable unexplained heterogeneity for a number of outcomes, particularly survival, and evidence of publication bias. Adjustments were not made to account for multiple testing. CONCLUSIONS: ESAs could be cost-effective when used closer to licence, but there is considerable uncertainty, mainly because of unknown impacts on overall survival. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013005812. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

A model-based assessment of the cost-utility of strategies to identify Lynch syndrome in early-onset colorectal cancer patients.

BACKGROUND: Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2. Individuals with Lynch syndrome have an increased risk of colorectal cancer, endometrial cancer, ovarian and other cancers. Lynch syndrome remains underdiagnosed in the UK. Reflex testing for Lynch syndrome in early-onset colorectal cancer patients is proposed as a method to identify more families affected by Lynch syndrome and offer surveillance to reduce cancer risks, although cost-effectiveness is viewed as a barrier to implementation. The objective of this project was to estimate the cost-utility of strategies to identify Lynch syndrome in individuals with early-onset colorectal cancer in the NHS. METHODS: A decision analytic model was developed which simulated diagnostic and long-term outcomes over a lifetime horizon for colorectal cancer patients with and without Lynch syndrome and for relatives of those patients. Nine diagnostic strategies were modelled which included microsatellite instability (MSI) testing, immunohistochemistry (IHC), BRAF mutation testing (methylation testing in a scenario analysis), diagnostic mutation testing and Amsterdam II criteria. Biennial colonoscopic surveillance was included for individuals diagnosed with Lynch syndrome and accepting surveillance. Prophylactic hysterectomy with bilateral salpingo-oophorectomy (H-BSO) was similarly included for women diagnosed with Lynch syndrome. Costs from NHS and Personal Social Services perspective and quality-adjusted life years (QALYs) were estimated and discounted at 3.5% per annum. RESULTS: All strategies included for the identification of Lynch syndrome were cost-effective versus no testing. The strategy with the greatest net health benefit was MSI followed by BRAF followed by diagnostic genetic testing, costing £5,491 per QALY gained over no testing. The effect of prophylactic H-BSO on health-related quality of life (HRQoL) is uncertain and could outweigh the health benefits of testing, resulting in overall QALY loss. CONCLUSIONS: Reflex testing for Lynch syndrome in early-onset colorectal cancer patients is predicted to be a cost-effective use of limited financial resources in England and Wales. Research is recommended into the cost-effectiveness of reflex testing for Lynch syndrome in other associated cancers and into the impact of prophylactic H-BSO on HRQoL.

A systematic review and economic evaluation of intraoperative tests [RD-100i one-step nucleic acid amplification (OSNA) system and Metasin test] for detecting sentinel lymph node metastases in breast cancer.

BACKGROUND: In breast cancer patients, sentinel lymph node biopsy is carried out at the same time as the removal of the primary tumour to postoperatively test with histopathology for regional metastases in the sentinel lymph node. Those patients with positive test results are then operated on 2-4 weeks after primary surgery to remove the lymph nodes from the axilla (axillary lymph node dissection, ALND). New molecular tests RD-100i [one-step nucleic acid amplification (OSNA); based on messenger RNA amplification to identify the cytokeratin-19 (CK19) gene marker] (Sysmex, Norderstedt, Germany) and Metasin (using the CK19 and mammaglobin gene markers) (Cellular Pathology, Princess Alexandra Hospital NHS Trust, Harlow, UK) are intended to provide an intraoperative diagnosis, thereby avoiding the need for postoperative histopathology and, in positive cases, a second operation for ALND. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of using OSNA and Metasin in the NHS in England for the intraoperative diagnosis of sentinel lymph nodes metastases, compared with postoperative histopathology, the current standard. DATA SOURCES: Electronic databases including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library and the Health Economic Evaluations Database as well as clinical trial registries, grey literature and conference proceedings were searched up to July 2012. REVIEW METHODS: A systematic review of the evidence was carried out using standard methods. Single-gate studies were used to estimate the accuracy of OSNA with histopathology as the reference standard. The cost-effectiveness analysis adapted an existing simulation model of the long-term costs and health implications of early breast cancer diagnostic outcomes. The model accounted for the costs of an extended first operation with intraoperative testing, the loss of health-related quality of life (disutility) from waiting for postoperative test results, disutility and costs of a second operation, and long-term costs and disutility from lymphoedema related to ALND, adjuvant therapy, locoregional recurrence and metastatic recurrence. RESULTS: A total of 724 references were identified in the searches, of which 17 studies assessing test accuracy were included in the review, 15 on OSNA and two on Metasin. Both Metasin studies were unpublished. OSNA sensitivity of 84.5% [95% confidence interval (CI) 74.7% to 91.0%] and specificity of 91.8% (95% CI 87.8% to 94.6%) for patient nodal status were estimated in a meta-analysis of five studies [unadjusted for tissue allocation bias (TAB)]. At these values and a 20% node-positive rate, OSNA resulted in lifetime discounted cost-savings of £498 and a quality-adjusted life-year (QALY) loss of 0.048 relative to histopathology, that is, £4324 saved per QALY lost. The most favourable plausible scenario for OSNA in terms of the node-positive rate (range 10-40%), diagnostic accuracy values (91.3% sensitivity and 94.2% specificity, from three reports that adjusted for TAB), the costs of histopathology, OSNA and second surgery, and long-term costs and utilities resulted in a maximum saving per QALY lost of £10,500; OSNA sensitivity and specificity would need to be ≥ 95% for this figure to be ≥ £20,000. LIMITATIONS: There is limited evidence on the diagnostic test accuracy of intraoperative tests. The quality of information on costs of resource utilisation during the diagnostic pathway is low and no evidence exists on the disutility of waiting for a second surgery. No comparative studies exist that report clinical outcomes of intraoperative diagnostic tests. These knowledge gaps have more influence on the decision than current uncertainty in the performance of postoperative histopathology in standard practice. CONCLUSIONS: One-step nucleic acid amplification is not cost-effective for the intraoperative diagnosis of sentinel lymph node metastases. OSNA is less accurate than histopathology and the consequent loss of health benefits in this patient group is not compensated for by health gains elsewhere in the health system that may be obtained with the cost-savings made. The evidence on Metasin is insufficient to evaluate its cost-effectiveness. STUDY REGISTRATION: This study is registered as PROSPERO CRD42012002889. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

A systematic review and economic evaluation of diagnostic strategies for Lynch syndrome.

BACKGROUND: Lynch syndrome (LS) is an inherited autosomal dominant disorder characterised by an increased risk of colorectal cancer (CRC) and other cancers, and caused by mutations in the deoxyribonucleic acid (DNA) mismatch repair genes. OBJECTIVE: To evaluate the accuracy and cost-effectiveness of strategies to identify LS in newly diagnosed early-onset CRC patients (aged < 50 years). Cascade testing of relatives is employed in all strategies for individuals in whom LS is identified. DATA SOURCES AND METHODS: Systematic reviews were conducted of the test accuracy of microsatellite instability (MSI) testing or immunohistochemistry (IHC) in individuals with CRC at risk of LS, and of economic evidence relating to diagnostic strategies for LS. Reviews were carried out in April 2012 (test accuracy); and in February 2012, repeated in February 2013 (economic evaluations). Databases searched included MEDLINE (1946 to April week 3, 2012), EMBASE (1980 to week 17, 2012) and Web of Science (inception to 30 April 2012), and risk of bias for test accuracy was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) quality appraisal tool. A de novo economic model of diagnostic strategies for LS was developed. RESULTS: Inconsistencies in study designs precluded pooling of diagnostic test accuracy results from a previous systematic review and nine subsequent primary studies. These were of mixed quality, with significant methodological concerns identified for most. IHC and MSI can both play a part in diagnosing LS but neither is gold standard. No UK studies evaluated the cost-effectiveness of diagnosing and managing LS, although studies from other countries generally found some strategies to be cost-effective compared with no testing. The de novo model demonstrated that all strategies were cost-effective compared with no testing at a threshold of £20,000 per quality-adjusted life-year (QALY), with the most cost-effective strategy utilising MSI and BRAF testing [incremental cost-effectiveness ratio (ICER) = £5491 per QALY]. The maximum health benefit to the population of interest would be obtained using universal germline testing, but this would not be a cost-effective use of NHS resources compared with the next best strategy. When the age limit was raised from 50 to 60 and 70 years, the ICERs compared with no testing increased but remained below £20,000 per QALY (except for universal germline testing with an age limit of 70 years). The total net health benefit increased with the age limit as more individuals with LS were identified. Uncertainty was evaluated through univariate sensitivity analyses, which suggested that the parameters substantially affecting cost-effectiveness: were the risk of CRC for individuals with LS; the average number of relatives identified per index patient; the effectiveness of colonoscopy in preventing metachronous CRC; the cost of colonoscopy; the duration of the psychological impact of genetic testing on health-related quality of life (HRQoL); and the impact of prophylactic hysterectomy and bilateral salpingo-oophorectomy on HRQoL (this had the potential to make all testing strategies more expensive and less effective than no testing). LIMITATIONS: The absence of high-quality data for the impact of prophylactic gynaecological surgery and the psychological impact of genetic testing on HRQoL is an acknowledged limitation. CONCLUSIONS: Results suggest that reflex testing for LS in newly diagnosed CRC patients aged < 50 years is cost-effective. Such testing may also be cost-effective in newly diagnosed CRC patients aged < 60 or < 70 years. Results are subject to uncertainty due to a number of parameters, for some of which good estimates were not identified. We recommend future research to estimate the cost-effectiveness of testing for LS in individuals with newly diagnosed endometrial or ovarian cancer, and the inclusion of aspirin chemoprevention. Further research is required to accurately estimate the impact of interventions on HRQoL. STUDY REGISTRATION: This study is registered as PROSPERO CRD42012002436. FUNDING: The National Institute for Health Research Health Technology Assessment programme.