Ros Wade

Background: General population cancer screening in the United Kingdom is limited to selected cancers. Blood-based multi-cancer early detection tests aim to detect potential cancer signals from multiple cancers in the blood. The use of a multi-cancer early detection test for population screening requires a high specificity and a reasonable sensitivity to detect early-stage disease so that the benefits of earlier diagnosis and treatment can be realised. Objective: To undertake a systematic literature review of the clinical effectiveness evidence on blood-based multi-cancer early detection tests for screening. Methods: Comprehensive searches of electronic databases (including MEDLINE and EMBASE) and trial registers were undertaken in September 2023 to identify published and unpublished studies of multi-cancer early detection tests. Test manufacturer websites and reference lists of included studies and pertinent reviews were checked for additional studies. The target population was individuals aged 50–79 years without clinical suspicion of cancer. Outcomes of interest included test accuracy, number and proportion of cancers detected (by site and stage), time to diagnostic resolution, mortality, potential harms, health-related quality of life, acceptability and satisfaction. The risk of bias was assessed using the quality assessment of diagnostic accuracy studies-2 checklist. Results were summarised using narrative synthesis. Stakeholders contributed to protocol development, report drafting and interpretation of review findings. Results: Over 8000 records were identified. Thirty-six studies met the inclusion criteria: 1 ongoing randomised controlled trial, 13 completed cohort studies, 17 completed case-control studies and 5 ongoing cohort or case-control studies. Individual tests claimed to detect from 3 to over 50 different types of cancer. Diagnostic accuracy of currently available multi-cancer early detection tests varied substantially: Galleri^® (GRAIL, Menlo Park, CA, USA) sensitivity 20.8–66.3%, specificity 98.4–99.5% (three studies); CancerSEEK (Exact Sciences, Madison, WI, USA) sensitivity 27.1–62.3%, specificity 98.9– 99.1% (two studies); SPOT-MAS™ (Gene Solutions, Ho Chi Minh City, Vietnam) sensitivity 72.4–100%, specificity 97.0–99.9% (two studies); Trucheck™ (Datar Cancer Genetics, Bayreuth, Germany) sensitivity 90.0%, specificity 96.4% (one study); Cancer Differentiation Analysis (AnPac Bio, Shanghai, China) sensitivity 40.0%, specificity 97.6% (one study). AICS^® (AminoIndex Cancer Screening; Ajinomoto, Tokyo, Japan) screens for individual cancers separately, so no overall test performance statistics are available. Where reported, sensitivity was lower for detecting earlier-stage cancers (stages I–II) compared with later-stage cancers (stages III–IV). Studies of seven other multi-cancer early detection tests at an unclear stage of development were also summarised. Limitations: Study selection was complex; it was often difficult to determine the stage of development of multi-cancer early detection tests. The evidence was limited; there were no completed randomised controlled trials and most included studies had a high overall risk of bias, primarily owing to limited follow-up of participants with negative test results. Only one study of Galleri recruited asymptomatic individuals aged over 50 in the United States of America; however, study results may not be representative of the United Kingdom's general screening population. No meaningful results were reported relating to patient-relevant outcomes, such as mortality, potential harms, health-related quality of life, acceptability or satisfaction. Conclusions: All currently available multi-cancer early-detection tests reported high specificity (> 96%). Sensitivity was highly variable and influenced by study design, population, reference standard test used and length of follow-up. Future work: Further research should report patient-relevant outcomes and consider patient and service impacts. Study registration: This study is registered as PROSPERO CRD42023467901. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR161758) and is published in full in Health Technology Assessment; Vol. 29, No. 2. See the NIHR Funding and Awards website for further award information.

Background: This work was undertaken to inform a National Institute for Health and Care Excellence guideline on the initial assessment of adults with suspected acute respiratory infection. Objective: To undertake a rapid evidence synthesis of systematic reviews and cost-effectiveness studies of signs, symptoms and early warning scores for the initial assessment of adults with suspected acute respiratory infection. Methods: MEDLINE, EMBASE and Cochrane Database of Systematic Reviews were searched for systematic reviews and MEDLINE, EMBASE, EconLit and National Health Service Economic Evaluation Database were searched for cost-effectiveness studies in May 2023. References of relevant studies were checked. Clinical outcomes of interest included escalation of care, antibiotic/antiviral use, time to resolution of symptoms, mortality and health-related quality of life. Risk of bias was assessed using the Risk of Bias in Systematic Reviews tool or the National Institute for Health and Care Excellence economic evaluations checklist. Results were summarised using narrative synthesis. Results: Nine systematic reviews and one cost-effectiveness study met eligibility criteria. Seven reviews assessed several early warning scores for patients with community- acquired pneumonia, one assessed early warning scores for nursing home-acquired pneumonia and one assessed individual signs/symptoms and the Centor score for patients with sore throat symptoms; all in face-to-face settings. Two good-quality reviews concluded that further research is needed to validate the CRB-65 in primary care/community settings. One also concluded that further research is needed on the Pneumonia Severity Index in community settings; however, the Pneumonia Severity Index requires data from tests not routinely conducted in community settings. One good-quality review concluded that National Early Warning Score appears to be useful in an emergency department/acute medical setting. One review (unclear quality) concluded that the Pneumonia Severity Index and CURB-65 appear useful in an emergency department setting. Two poor-quality reviews concluded that early warning scores can support clinical judgement and one poor-quality review found numerous problems with using early warning scores in a nursing home setting. A good-quality review concluded that individual signs and symptoms have a modest ability to diagnose streptococcal pharyngitis, and that the Centor score can enhance appropriate prescribing of antibiotics. The cost-effectiveness study assessed clinical scores and rapid antigen detection tests for sore throat, compared to delayed antibiotic prescribing. The study concluded that the clinical score is a cost-effective approach when compared to delayed prescribing and rapid antigen testing. Conclusions: Several early warning scores have been evaluated in adults with suspected acute respiratory infection, mainly the CRB-65, CURB-65 and Pneumonia Severity Index in patients with community-acquired pneumonia. The evidence was insufficient to determine what triage strategies avoid serious illness. Some early warning scores (CURB-65, Pneumonia Severity Index and National Early Warning Score) appear to be useful in an emergency department/acute medical setting; however, further research is required to validate the CRB-65 and Pneumonia Severity Index in primary care/community settings. The economic evidence indicated that clinical scores may be a cost-effective approach to triage patients compared with delayed prescribing. Future work and limitations: Only systematic reviews were eligible for inclusion in the synthesis of clinical evidence. There was a great deal of overlap in the primary studies included in the reviews, many of which had significant limitations. No studies were undertaken in remote settings (e.g. NHS 111). Only one cost-effectiveness study was identified, with limited applicability to the review question. Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR159945.

Background: Parkinson’s disease is a brain condition causing a progressive loss of co ordination and movement problems. Around 145,500 people have Parkinson’s disease in the United Kingdom. Levodopa is the most prescribed treatment for managing motor symptoms in the early stages. Patients should be monitored by a specialist every 6–12 months for disease progression and treatment of adverse effects. Wearable devices may provide a novel approach to management by directly monitoring patients for bradykinesia, dyskinesia, tremor and other symptoms. They are intended to be used alongside clinical judgement. Objectives: To determine the clinical and cost-effectiveness of five devices for monitoring Parkinson’s disease: Personal KinetiGraph, Kinesia 360, KinesiaU, PDMonitor and STAT-ON. Methods: We performed systematic reviews of all evidence on the five devices, outcomes included: diagnostic accuracy, impact on decision-making, clinical outcomes, patient and clinician opinions and economic outcomes. We searched MEDLINE and 12 other databases/trial registries to February 2022. Risk of bias was assessed. Narrative synthesis was used to summarise all identified evidence, as the evidence was insufficient for meta-analysis. One included trial provided individual-level data, which was re-analysed. A de novo decision-analytic model was developed to estimate the cost-effectiveness of Personal KinetiGraph and Kinesia 360 compared to standard of care in the UK NHS over a 5-year time horizon. The base-case analysis considered two alternative monitoring strategies: one-time use and routine use of the device. Results: Fifty-seven studies of Personal KinetiGraph, 15 of STAT-ON, 3 of Kinesia 360, 1 of KinesiaU and 1 of PDMonitor were included. There was some evidence to suggest that Personal KinetiGraph can accurately measure bradykinesia and dyskinesia, leading to treatment modification in some patients, and a possible improvement in clinical outcomes when measured using the Unified Parkinson’s Disease Rating Scale. The evidence for STAT-ON suggested it may be of value for diagnosing symptoms, but there is currently no evidence on its clinical impact. The evidence for Kinesia 360, KinesiaU and PDMonitor is insufficient to draw any conclusions on their value in clinical practice. The base-case results for Personal KinetiGraph compared to standard of care for one-time and routine use resulted in incremental cost-effectiveness ratios of £67,856 and £57,877 per quality-adjusted life-year gained, respectively, with a beneficial impact of the Personal KinetiGraph on Unified Parkinson’s Disease Rating Scale domains III and IV. The incremental cost-effectiveness ratio results for Kinesia 360 compared to standard of care for one-time and routine use were £38,828 and £67,203 per quality-adjusted life-year gained, respectively. Limitations: The evidence was limited in extent and often low quality. For all devices, except Personal KinetiGraph, there was little to no evidence on the clinical impact of the technology. Conclusions: Personal KinetiGraph could reasonably be used in practice to monitor patient symptoms and modify treatment where required. There is too little evidence on STAT-ON, Kinesia 360, KinesiaU or PDMonitor to be confident that they are clinically useful. The cost-effectiveness of remote monitoring appears to be largely unfavourable with incremental cost-effectiveness ratios in excess of £30,000 per quality-adjusted life-year across a range of alternative assumptions. The main driver of cost-effectiveness was the durability of improvements in patient symptoms. Study registration: This study is registered as PROSPERO CRD42022308597. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135437) and is published in full in Health Technology Assessment; Vol. 28, No. 30. See the NIHR Funding and Awards website for further award information.

Background General population cancer screening in the UK is limited to selected cancers. Blood-based multi-cancer early detection (MCED) tests aim to detect potential cancer signals from multiple cancers in the blood. The use of an MCED test for population screening requires a high specificity and a reasonable sensitivity to detect early-stage disease, so that the benefits of earlier diagnosis and treatment can be realised. Objective To undertake a systematic literature review of the clinical effectiveness evidence on blood-based MCED tests for screening. Methods Comprehensive searches of electronic databases (including MEDLINE and Embase) and trial registers were undertaken in September 2023 to identify published and unpublished studies of MCED tests. Test manufacturer websites and reference lists of included studies and pertinent reviews were checked for additional studies. The target population was individuals aged 50 to 79 years without clinical suspicion of cancer. Outcomes of interest included test accuracy, number and proportion of cancers detected (by site and stage), time to diagnostic resolution, mortality, potential harms, health-related quality of life (HRQoL), acceptability and satisfaction. Risk of bias was assessed using the QUADAS-2 checklist. Results were summarised using narrative synthesis. Stakeholders contributed to protocol development, report drafting, and interpretation of review findings. Results Over 8000 records were identified. Thirty-six studies met the inclusion criteria: one ongoing randomised controlled trial (RCT), 13 completed cohort studies, 17 completed case-control studies and five ongoing cohort or case-control studies. Individual tests claimed to detect from three to over 50 different types of cancer. Diagnostic accuracy of currently available MCED tests varied substantially: Galleri® (GRAIL) sensitivity 20.8% to 66.3%, specificity 98.4% to 99.5% (3 studies); CancerSEEK (Exact Sciences) sensitivity 27.1% to 62.3%, specificity 98.9% to 99.1% (2 studies); SPOT-MAS™ (Gene Solutions) sensitivity 72.4% to 100%, specificity 97.0% to 99.9% (2 studies); TruCheck™ (Datar Cancer Genetics) sensitivity 90.0%, specificity 96.4% (1 study); CDA (AnPac Bio) sensitivity 40.0%, specificity 97.6% (1 study). AICS® (Ajinomoto) screens for individual cancers separately, so no overall test performance statistics are available. Where reported, sensitivity was lower for detecting earlier stage cancers (Stage I-II) compared with later stage cancers (Stage III-IV). Studies of seven other MCED tests at an unclear stage of development were also summarised. Limitations Study selection was complex; it was often difficult to determine the stage of development of MCED tests. The evidence was limited; there were no completed RCTs and most included studies had a high overall risk of bias, primarily owing to limited follow-up of participants with negative test results. Only one study of Galleri recruited asymptomatic individuals aged over 50 in the USA, however, study results may not be representative of the UK general screening population. No meaningful results were reported relating to patient relevant outcomes, such as mortality, potential harms, HRQoL, acceptability or satisfaction. Conclusions All currently available MCED tests reported high specificity (>96%). Sensitivity was highly variable and influenced by study design, population, reference standard test used and length of follow-up. Future work Further research should report patient relevant outcome and consider patient and service impacts. PROSPERO registration number: CRD42023467901 Funding This project was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR161758) and will be published in full in the Health Technology Assessment Journal; Vol. XX, No. XX. See the NIHR Journals Library website for further project information. PLAIN LANGUAGE SUMMARY Cancer screening is only available for some cancers. New tests that look for signs of cancer in blood (blood-based multi-cancer early detection tests) are being developed; they aim to detect multiple different cancers at an early stage, when they are potentially more treatable. Taking account of stakeholder feedback, we reviewed all studies assessing the effectiveness of blood-based multi-cancer early detection tests for cancer screening. We thoroughly searched for relevant studies and found over 8000 records. We included 30 completed studies and six ongoing studies of 13 different tests. None of the studies were good quality, mainly because they didn’t properly check whether the test result might have been incorrect and participants with a negative test result actually had cancer. Most studies included participants who are different from the general UK population that would be likely to have this type test for cancer screening. None of the studies reported meaningful results for patient-relevant outcomes, such as death, potential harms, quality of life and acceptability. We found 14 completed studies assessing six tests that are currently available: Galleri® (GRAIL), CancerSEEK (Exact Sciences), SPOT-MAS™ (Gene Solutions), TruCheck™ (Datar Cancer Genetics), CDA (AnPac Bio) and AICS® (Ajinomoto). All of the tests were quite good at ruling out cancer, but their accuracy for finding cancer varied a lot, mostly because of differences in the study methods and characteristics of the included participants. The tests were better at finding more advanced cancers, which are potentially less curable than early cancers, so more research is needed to know whether tests would actually save lives. Better designed studies including participants similar to those who might get the test in the real world, and which report on patient-relevant outcomes and properly consider patient experience and impact on services, are needed. Several new studies are planned or underway. Background General population cancer screening in the UK is limited to selected cancers (cervical, breast, bowel and, for some high-risk individuals, lung). Most other cancers are detected after presentation of symptoms, when the disease tends to be at a more advanced stage and treatment options may be more limited. Blood-based multi-cancer early detection (MCED) tests aim to detect potential cancer signals (such as circulating cell-free deoxyribonucleic acid [cfDNA]) from multiple cancers in the blood. The use of an MCED test as a screening tool in a generally healthy, asymptomatic population, requires a high specificity and a reasonable sensitivity to detect early-stage disease, so that the benefits of earlier diagnosis and treatment can be realised. An MCED test embedded within a national population-based screening programme, in addition to existing cancer screening programmes, may increase the number of cancers diagnosed at an earlier stage. However, identification of cancers with no effective treatments, even at an early stage, may have no improvement on mortality or health-related quality of life (HRQoL). In addition, early screening of healthy people for such a wide range of cancers, and the expected lengthy time to diagnostic confirmation, may create anxiety and lead to unnecessary follow-up tests, when false positive test results occur. Objectives The aim of this project was to conduct a systematic review to assess the accuracy and clinical effectiveness, acceptability and feasibility of blood-based MCED tests for population-based screening. Methods Comprehensive searches of electronic databases (including MEDLINE and Embase) and trial registers were undertaken in September 2023. Test manufacturer websites and reference lists of included studies and pertinent reviews were checked for additional relevant studies. Published and unpublished prospective clinical trials and cohort studies of blood-based MCED tests for screening were sought. Studies assessing blood-based tests for assessing prognosis or therapeutic decision-making in patients with cancer were not eligible for inclusion. The target population was individuals aged 50 to 79 years without clinical suspicion of cancer and who had not been diagnosed with, or received treatment for, cancer within the last three years. As insufficient relevant studies were identified within the target population, studies that included patients known to have cancer (i.e., case-control studies) and studies that included individuals with a different age range were included. Outcomes of interest were test accuracy (including sensitivity, specificity, positive and negative predictive values), number and proportion of cancers detected (by site and stage), mortality, time to diagnostic resolution, incidental findings, additional tests and procedures, potential harms, HRQoL, acceptability and satisfaction. A standardised data extraction form was developed and piloted. Data on the intervention(s), participant characteristics, setting, study design, reference standard test(s) used, and relevant outcomes were extracted from included studies by one reviewer and independently checked by a second reviewer. Risk of bias and applicability were assessed using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies) checklist by one reviewer and independently checked by a second. Disagreements were resolved through discussion. Results were summarised using narrative synthesis. Stakeholders contributed to protocol development, report drafting, and interpretation of review findings. Results The electronic searches identified 8,069 records; 228 full texts were further reviewed. Eleven additional records were identified from searching MCED test manufacturer websites. Study selection was complex; it was often difficult to determine whether studies assessed technologies at an early stage of development, or the final or near-final version of the test. Thirty-six studies, evaluating thirteen MCED tests or technologies, met the review inclusion criteria: one ongoing randomised controlled trial (RCT), 13 completed cohort studies, 17 completed case-control studies, four ongoing cohort studies and one ongoing case-control study. Studies assessed the following MCED tests: Galleri® test (GRAIL, Menlo Park, California), CancerSEEK (Exact Sciences, Madison, Wisconsin), SPOT-MAS™ (Gene Solutions, Ho Chi Minh City, Vietnam), TruCheck™ (Datar Cancer Genetics, Beyreuth, Germany), CDA (Cancer Differentiation Analysis; AnPac Bio, Shanghai, China) and AICS® test (AminoIndex Cancer Screening; Ajinomoto, Tokyo, Japan). Other MCED technologies included in the review, that were at an unclear stage of development and did not appear to be available for use, were: Aristotle® (StageZero Life Sciences, Richmond, Ontario), CancerenD24 (manufacturer unknown), OncoSeek® (SeekIn Inc, San Diego, California), SeekInCare® (SeekIn Inc, San Diego, California), OverC™ (Burning Rock Biotech, Guangzhou, China), Carcimun-test (Carcimun Biotech, Garmisch-Partenkirchen, Germany) and SpecGastro test (manufacturer unknown). Technologies that appeared to be at a very early stage of development did not meet the inclusion criteria for the review. Individual MCED tests and technologies claimed to detect from three to over 50 different types of cancer. Owing to the differences in the number of cancer types detected, study design and populations, statistical pooling of results was not considered appropriate. Studies of MCED tests available for use The risk of bias assessment identified substantial concerns with the included studies. Case-control studies have a high risk of bias in the QUADAS-2 ‘patient selection’ domain. Almost all of the studies had a high risk of bias in the ‘flow and timing’ domain, however, this is difficult to avoid when the reference standard for positive test results involves invasive testing, as it is not practical or ethical to undertake such invasive tests in participants with a negative MCED (index) test result. Only one study was undertaken in the UK, although this was in individuals in whom cancer was suspected, so not reflective of the general cancer screening population. Cancer risk and the availability of general population cancer screening programmes differ worldwide, which will impact the applicability of results of the included studies to the UK. Ethnicity and socioeconomic status of included participants was not well reported in the included studies. There were also concerns about the applicability of the CancerSEEK test, which has since been modified (now called Cancerguard™) and is undergoing further assessment. The applicability of the SPOT-MAS, Trucheck, CDA and AICS tests assessed in the included studies was unclear. Outcomes relating to MCED test performance (i.e., test accuracy and number of cancers detected by site and/or stage) were reported in most studies. Overall test sensitivity and specificity are not directly comparable across different MCED tests, owing to the differences in the number of cancer types each test claims to detect. Diagnostic accuracy varied substantially (95% confidence interval [CI] shown in brackets): Galleri (3 studies) Sensitivity: 20.8% (14.0 to 29.2) to 66.3% (61.2 to 71.1) Specificity: 98.4% (98.1 to 98.8) to 99.5% (99.0 to 99.8) CancerSEEK (2 studies) Sensitivity: 27.1% (18.5 to 37.1) to 62.3% (59.3 to 65.3) Specificity: 98.9% (98.7 to 99.1) to 99.1% (98.5 to 99.8) SPOT-MAS (2 studies) Sensitivity: 72.4% (66.3 to 78.0) to 100% (54.1 to 100) Specificity: 97.0% (95.1 to 98.4) to 99.9% (99.6 to 100) TruCheck (1 study) Sensitivity: 90.0% (55.5 to 99.7) Specificity: 96.4% (95.9 to 96.8) CDA (1 study) Sensitivity: 40.0% (95% CI 12.2 to 73.8) Specificity: 97.6% (95% CI 96.8 to 98.2) AICS screens for individual cancers separately; sensitivity ranged from 16.7% (95% CI 3.0 to 56.4) for ovary/uterus cancer to 51.7% (95% CI 34.4 to 68.6) for gastric cancer. Sensitivity by cancer stage was only reported in some studies of Galleri and CancerSEEK. Sensitivity was considerably lower for detecting earlier stage cancers (Stage I-II) compared with later stage cancers (Stage III-IV). Amongst the Galleri studies, sensitivity for detecting Stage I-II cancer ranged from 27.5% (25.3 to 29.8) to 37.3% (29.8 to 45.4) and sensitivity for detecting Stage III-IV cancer ranged from 83.9% (81.7 to 85.9) to 89.7% (84.5 to 93.6). The CancerSEEK cohort study reported sensitivity for detecting Stage I-II cancer of 12.7% (95% CI 6.6 to 23.1) and sensitivity for detecting Stage III-IV cancer of 53.1% (95% CI 36.4 to 69.1). One study of Galleri found that sensitivity was higher in an ‘elevated risk’ cohort (23.4%, 95% CI 14.5 to 34.4) than a ‘non-elevated risk’ cohort (16.3%, 95% CI 6.8 to 30.7). Studies of Galleri, CancerSEEK, SPOT-MAS, CDA and AICS reported sensitivity by cancer site and found that it varied substantially, although the total number of participants diagnosed with certain types of cancer was low, so results are difficult to interpret. Screening programme availability: The sensitivity of the MCED tests to detect solid tumour cancers without a current screening programme in the UK was generally higher than the sensitivity to detect cancers with a current screening programme in the UK (breast, cervical and colorectal). However, this was not the case in one study of Galleri and the study of the CDA test, where sensitivity for detecting solid tumour cancers without a current screening programme was lower than for cancers with a current screening programme in the UK. Subgroup results by participant demographic characteristics: One study each of Galleri and CancerSEEK reported MCED test performance by pre-specified subgroups of interest (i.e., age, sex and ethnicity). For CancerSEEK, sensitivity was slightly lower for participants less than 50 years of age, compared to participants aged 50 or over, while for Galleri sensitivity was very similar across the age categories presented. The sensitivity of Galleri was highest for Hispanic participants (63%), and it was lowest (43%) for the small number of participants classified as ‘Other’ ethnicity in the study. Sensitivity of CancerSEEK ranged from 50% in participants with unknown ethnicities to 70.4% in Asian participants (and cancer was correctly detected by the CancerSEEK test in one Hispanic participant resulting in a sensitivity of 100%). One study using an earlier version of the Galleri test reported results by age and sex for a subset of study participants; cancer signal detection rate was similar in males and females and increased with age for both sexes, however, few details were given on the subset of participants analysed. Only one study of Galleri reported data for participants with a low socioeconomic status. Patient relevant outcomes Only limited results relating to patient relevant outcomes, such as mortality, potential harms, HRQoL, acceptability and satisfaction of individuals screened, were reported in some studies of Galleri, CancerSEEK and AICS. Studies of MCED technologies at an unclear stage of development The risk of bias assessment identified substantial concerns. Most studies were case-control studies so had a high risk of bias in the ‘patient selection’ domain of QUADAS-2. Most studies also had a high risk of bias in the ‘index test’ and/or ‘flow and timing’ domains. All studies were considered to have high or unclear concerns relating to the applicability of study participants, index tests and reference standard tests. Outcomes relating to MCED test performance were reported in most studies. OncoSeek reported the lowest overall sensitivity across all cancer types (47.4%), and CancerenD24 reported the lowest sensitivity in detecting bladder cancer (38.0%). By stage, OverC and SeekInCare reported a sensitivity of 35.4% and 50.3%, respectively, for stage I cancer. The highest sensitivity overall came from the Carcimun-test (88.8%), however, the exclusion of individuals with inflammation is noted as a disadvantage. The SpecGastro test was only developed to detect three types of gastrointestinal cancer (colorectal, gastric, and oesophageal). Stakeholder engagement At the protocol stage, stakeholders highlighted issues with the implementation of MCED tests, including resource use, impact on existing diagnostic services and wider care pathways, the need to balance benefits with potential risks, and consideration of factors likely to affect test uptake. Stakeholders also reinforced the importance of patient relevant outcomes. Stakeholders commenting on the draft report noted that important details about the potential benefits, harms, and possible unintended consequences of implementing MCED tests in the UK were poorly reported, limiting the relevance of the available evidence for policy decision-making. Other feedback fell into six broad areas: poor applicability and generalisability of available evidence; limitations of the current evidence base; the potential impact of MCED tests on existing screening, diagnostic and treatment pathways; opportunities to enhance services to improve outcomes; acceptability and potential impact on populations offered and/or receiving screening, and; targeting specific groups to support early identification and improve outcomes. Conclusions Limited evidence is available on the potential for early detection of treatable cancers, and the consequences of introducing screening with an...

Background: A wide range of ablative and non-surgical therapies are available for treating small hepatocellular carcinoma in patients with very early or early-stage disease and preserved liver function.Objective: To review and compare the effectiveness of all current ablative and non-surgical therapies for patients with small hepatocellular carcinoma (≤ 3 cm).Design: Systematic review and network meta-analysis.Data sources: Nine databases (March 2021), two trial registries (April 2021) and reference lists of relevant systematic reviews.Review methods: Eligible studies were randomised controlled trials of ablative and non-surgical therapies, versus any comparator, for small hepatocellular carcinoma. Randomised controlled trials were quality assessed using the Cochrane Risk of Bias 2 tool and mapped. The comparative effectiveness of therapies was assessed using network meta-analysis. A threshold analysis was used to identify which comparisons were sensitive to potential changes in the evidence. Where comparisons based on randomised controlled trial evidence were not robust or no randomised controlled trials were identified, a targeted systematic review of non-randomised, prospective comparative studies provided additional data for repeat network meta-analysis and threshold analysis. The feasibility of undertaking economic modelling was explored. A workshop with patients and clinicians was held to discuss the findings and identify key priorities for future research.Results: Thirty-seven randomised controlled trials (with over 3700 relevant patients) were included in the review. The majority were conducted in China or Japan and most had a high risk of bias or some risk of bias concerns. The results of the network meta-analysis were uncertain for most comparisons. There was evidence that percutaneous ethanol injection is inferior to radiofrequency ablation for overall survival (hazard ratio 1.45, 95% credible interval 1.16 to 1.82), progression-free survival (hazard ratio 1.36, 95% credible interval 1.11 to 1.67), overall recurrence (relative risk 1.19, 95% credible interval 1.02 to 1.39) and local recurrence (relative risk 1.80, 95% credible interval 1.19 to 2.71). Percutaneous acid injection was also inferior to radiofrequency ablation for progression-free survival (hazard ratio 1.63, 95% credible interval 1.05 to 2.51). Threshold analysis showed that further evidence could plausibly change the result for some comparisons. Fourteen eligible non-randomised studies were identified (n ≥ 2316); twelve had a high risk of bias so were not included in updated network meta-analyses. Additional non-randomised data, made available by a clinical advisor, were also included (n = 303). There remained a high level of uncertainty in treatment rankings after the network meta-analyses were updated. However, the updated analyses suggested that microwave ablation and resection are superior to percutaneous ethanol injection and percutaneous acid injection for some outcomes. Further research on stereotactic ablative radiotherapy was recommended at the workshop, although it is only appropriate for certain patient subgroups, limiting opportunities for adequately powered trials.Limitations: Many studies were small and of poor quality. No comparative studies were found for some therapies.Conclusions: The existing evidence base has limitations; the uptake of specific ablative therapies in the United Kingdom appears to be based more on technological advancements and ease of use than strong evidence of clinical effectiveness. However, there is evidence that percutaneous ethanol injection and percutaneous acid injection are inferior to radiofrequency ablation, microwave ablation and resection.Study registration: PROSPERO CRD42020221357.Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) programme (NIHR award ref: NIHR131224) and is published in full inHealth Technology Assessment; Vol. 27, No. 29. See the NIHR Funding and Awards website for further award information.

Introduction: Sudden onset severe headache is usually caused by a primary headache disorder but occasionally is secondary to a more serious problem, such as subarachnoid hemorrhage (SAH). Guidelines recommend non-contrast brain computed tomography (CT) followed by lumbar puncture (LP) to exclude SAH. However, guidelines pre-date the introduction of more sensitive modern CT scanners. A systematic review was undertaken to assess the clinical effectiveness of different care pathways for the management of headache in the Emergency Department.Methods: Eighteen databases (including MEDLINE and Embase) were searched to February 2020. Studies were quality assessed using criteria relevant to the study design; most studies were assessed using the QUADAS-2 tool for diagnostic accuracy studies. Where sufficient information was reported, diagnostic accuracy data were extracted into 2 × 2 tables to calculate sensitivity, specificity, false-positive and false-negative rates. Where possible, hierarchical bivariate meta-analysis was used to synthesize results, otherwise studies were synthesized narratively.Results: Fifty-one studies were included in the review. Eight studies assessing the accuracy of the Ottawa SAH clinical decision rule were pooled; sensitivity was 99.5 percent, specificity was 23.7 percent. The high false positive rate suggests that 76.3 percent SAH-negative patients would undergo further investigation unnecessarily. Four studies assessing the accuracy of CT within six hours of headache onset were pooled; sensitivity was 98.7 percent, specificity was 100 percent. CT sensitivity beyond six hours was considerably lower (≤90%; 2 studies). Three studies assessing LP following negative CT were pooled; sensitivity was 100 percent, specificity was 95.2 percent. LP-related adverse events were reported in 5.3–9.5 percent of patients.Conclusions: The evidence suggests that the Ottawa SAH Rule is not sufficiently accurate for ruling out SAH and does little to aid clinical decision making. Modern CT within six hours of headache onset (with images assessed by a neuroradiologist) is highly accurate, but sensitivity reduces considerably over time. The CT-LP pathway is highly sensitive for detecting SAH, although LP resulted in some false-positives and adverse events.

Introduction: Sudden onset severe headache is usually caused by a primary headache disorder but may be secondary to a more serious problem, such as subarachnoid hemorrhage (SAH). Very few patients who present to hospital with headache have suffered a SAH, but early identification is important to improve patient outcomes. A systematic review was undertaken to assess the clinical effectiveness of different care pathways for the management of headache, suspicious for SAH, in the Emergency Department. Capturing the perspective of patients was an important part of the research.Methods: The project team included a patient collaborator with experience of presenting to the Emergency Department with sudden onset severe headache. Three additional patients were recruited to our advisory group. The patient's perspective was collected at various points through the project including at team meetings, during protocol development and when interpreting the results of the systematic review and drawing conclusions.Results: Patients were reassured by the very high diagnostic accuracy of computed tomography (CT) for detecting SAH. Patients and clinicians emphasized the importance of shared decision making about whether to undergo additional tests to rule out SAH, after a negative CT result. When lumbar puncture was necessary, patients expressed a preference to have it on an ambulatory basis; further research on the safety and acceptability of ambulatory lumbar puncture was recommended.Conclusions: Patient input at the protocol development stage helped researchers understand the patient experience and highlighted important outcomes for assessment. Patient involvement added context to the review findings and highlighted the preferences of patients regarding the management of headache.

Background: Hepatocellular carcinoma is the most common type of primary liver cancer. Treatment choice is dependent on underlying liver dysfunction and cancer stage. Treatment options include conventional transarterial therapies for patients with intermediate-stage disease and systemic therapy [e.g. sorafenib (Nexavar^®; Bayer plc, Leverkusen, Germany)] for patients with advanced-stage disease. Selective internal radiation therapies deliver radiation to liver tumours via microspheres that are injected into the hepatic artery. There are three selective internal radiation therapies: TheraSphere™ [BTG Ltd, London, UK (now Boston Scientific, Marlborough, MA, USA)], SIR-Spheres^® (Sirtex Medical Ltd, Woburn, MA, USA) and QuiremSpheres^® (Quirem Medical BV, Deventer, the Netherlands). Objective: To assess the clinical effectiveness and cost-effectiveness of selective internal radiation therapies for treating patients with unresectable early-, intermediate- or advanced-stage hepatocellular carcinoma. Methods: A search was undertaken to identify clinical effectiveness literature relating to selective internal radiation therapies and relevant comparators for the treatment of hepatocellular carcinoma. Studies were critically appraised and summarised. The network of evidence was mapped to estimate the relative effectiveness of the different selective internal radiation therapies and comparator treatments. An economic analysis evaluated the cost-effectiveness. Results: Twenty studies were included in the clinical effectiveness review. Two large randomised controlled trials rated as having a low risk of bias [SARAH: Vilgrain V, Pereira H, Assenat E, Guiu B, Ilonca AD, Pageaux GP, et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled Phase 3 trial. Lancet Oncol 2017;18:1624–36; and SIRveNIB: Chow PKH, Gandhi M, Tan SB, Khin MW, Khasbazar A, Ong J, et al. SIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol 2018;36:1913–21] found no significant difference in overall survival or progression-free survival between SIR-Spheres and sorafenib (systemic therapy) in an advanced population, despite greater tumour response in the SIR-Spheres arm of both trials. There were some concerns regarding generalisability of the SARAH and SIRveNIB trials to UK practice. All other studies of SIR-Spheres, TheraSphere or QuiremSpheres were either rated as being at a high risk of bias or caused some concerns regarding bias. A network meta-analysis was conducted in adults with unresectable hepatocellular carcinoma who had Child–Pugh class A liver cirrhosis and were ineligible for conventional transarterial therapies. The analysis included the SARAH and SIRveNIB trials as well as a trial comparing lenvatinib (Kisplyx^®; Eisai Ltd, Tokyo, Japan) (systemic therapy) with sorafenib. There were no meaningful differences in overall survival between any of the treatments. The base-case economic analysis suggested that TheraSphere may be cost-saving relative to both SIR-Spheres and QuiremSpheres. However, incremental cost differences between TheraSphere and SIR-Spheres were small. In a fully incremental analysis, which included confidential Patient Access Scheme discounts, lenvatinib was the most cost-effective treatment and dominated all selective internal radiation therapies. In pairwise comparisons of sorafenib with each selective internal radiation therapy, sorafenib also dominated all selective internal radiation therapies. Limitations: The existing evidence cannot provide decision-makers with clear guidance on the comparative effectiveness of treatments in early- and intermediate-stage hepatocellular carcinoma or on the efficacy of TheraSphere or QuiremSpheres. Conclusions: In the advanced-stage hepatocellular carcinoma population, two large randomised trials have shown that SIR-Spheres have similar clinical effectiveness to sorafenib. None of the selective internal radiation therapies was cost-effective, being more costly and less effective than lenvatinib, both at list price and with Patient Access Scheme discounts. Future work: Future studies may wish to include early- and intermediate-stage hepatocellular carcinoma patients and the low tumour burden/albumin–bilirubin 1 subgroup of advanced-stage patients. Future high-quality studies evaluating alternative selective internal radiation therapies would be beneficial. Study registration: This study is registered as PROSPERO CRD42019128383. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 48. See the NIHR Journals Library website for further project information.

Background: Systematic reviews of medical devices are particularly challenging as the quality of evidence tends to be more limited than evidence on pharmaceutical products. This article describes the methods used to identify, select and critically appraise the best available evidence on selective internal radiation therapy devices for treating hepatocellular carcinoma, to inform a technology appraisal for the National Institute for Health and Care Excellence. Methods: A comprehensive search of ten medical databases and six grey literature sources was undertaken to identify studies of three devices (TheraSphere®, SIR-Spheres® and QuiremSpheres®) for treating hepatocellular carcinoma. The large evidence base was scoped before deciding what level of evidence to include for data extraction and critical appraisal. The methodological quality of the included studies was assessed using criteria relevant to each study design. Results: Electronic searches identified 4755 records; over 1000 met eligibility criteria after screening titles and abstracts. A hierarchical process was used to scope these records, prioritising comparative studies over non-comparative studies, where available. One hundred ninety-four full papers were ordered; 64 met the eligibility criteria. For each intervention, studies were prioritised by study design and applicability to current UK practice, resulting in 20 studies subjected to critical appraisal and data extraction. Only two trials had a low overall risk of bias. In view of the poor quality of the research evidence, our technology appraisal focused on the two higher quality trials, including a thorough critique of their reliability and generalisability to current UK practice. The 18 poorer quality studies were briefly summarised; many were very small and results were often contradictory. No definitive conclusions could be drawn from the poorer quality research evidence available. Conclusions: A systematic, pragmatic process was used to select and critically appraise the vast quantity of research evidence available in order to present the most reliable evidence on which to develop recommendations. Systematic review registration: PROSPERO CRD42019128383.