A systematic review of early phase studies for children and young people with relapsed and refractory rhabdomyosarcoma: The REFoRMS-SR project.

Rhabdomyosarcoma is the commonest soft tissue sarcoma in children. Around one-third of children with rhabdomyosarcoma experience relapse or have refractory disease, which is associated with a poor prognosis. This systematic review of early phase studies in pediatric relapsed/refractory rhabdomyosarcoma was conducted to inform future research and provide accurate information to families and clinicians making difficult treatment choices. Nine databases and five trial registries were searched in June 2021. Early phase studies of interventions for disease control in patients under 18 years old with relapsed/refractory rhabdomyosarcoma were eligible. No language/geographic restrictions were applied. Studies conducted after 2000 were included. Survival outcomes, response rates, quality of life and adverse event data were extracted. Screening, data extraction and quality assessment (Downs and Black Checklist) were conducted by two researchers. Owing to heterogeneity in the included studies, narrative synthesis was conducted. Of 16,965 records screened, 129 published studies including over 1100 relapsed/refractory rhabdomyosarcoma patients were eligible. Most studies evaluated systemic therapies. Where reported, 70% of studies reported a median progression-free survival ≤6 months. Objective response rate was 21.6%. Adverse events were mostly hematological. One-hundred and seven trial registry records of 99 studies were also eligible, 63 of which report they are currently recruiting. Study quality was limited by poor and inconsistent reporting. Outcomes for children with relapsed/refractory rhabdomyosarcoma who enroll on early phase studies are poor. Improving reporting quality and consistency would facilitate the synthesis of early phase studies in relapsed/refractory rhabdomyosarcoma (PROSPERO registration: CRD42021266254).

Anti-Vascular Endothelial Growth Factor Drugs Compared With Panretinal Photocoagulation for the Treatment of Proliferative Diabetic Retinopathy: A Cost-Effectiveness Analysis.

OBJECTIVES: This study aimed to evaluate the cost-effectiveness of anti-vascular endothelial growth factor drugs (anti-VEGFs) compared with panretinal photocoagulation (PRP) for treating proliferative diabetic retinopathy (PDR) in the United Kingdom. METHODS: A discrete event simulation model was developed, informed by individual participant data meta-analysis. The model captures treatment effects on best corrected visual acuity in both eyes, and the occurrence of diabetic macular edema and vitreous hemorrhage. The model also estimates the value of undertaking further research to resolve decision uncertainty. RESULTS: Anti-VEGFs are unlikely to generate clinically meaningful benefits over PRP. The model predicted anti-VEGFs be more costly and similarly effective as PRP, generating 0.029 fewer quality-adjusted life-years at an additional cost of £3688, with a net health benefit of -0.214 at a £20 000 willingness-to-pay threshold. Scenario analysis results suggest that only under very select conditions may anti-VEGFs offer potential for cost-effective treatment of PDR. The consequences of loss to follow-up were an important driver of model outcomes. CONCLUSIONS: Anti-VEGFs are unlikely to be a cost-effective treatment for early PDR compared with PRP. Anti-VEGFs are generally associated with higher costs and similar health outcomes across various scenarios. Although anti-VEGFs were associated with lower diabetic macular edema rates, the number of cases avoided is insufficient to offset the additional treatment costs. Key uncertainties relate to the long-term comparative effectiveness of anti-VEGFs, particularly considering the real-world rates and consequences of treatment nonadherence. Further research on long-term visual acuity and rates of vision-threatening complications may be beneficial in resolving uncertainties.

A systematic review of combined surgery and brachytherapy approaches for children and young people with relapsed and refractory rhabdomyosarcoma (Local-REFoRMS).

Approximately one third of children with rhabdomyosarcoma relapse or have refractory disease. Treatment approaches include a combination of systemic therapies and local therapies, directed at tumour site(s). This review was conducted to evaluate the effectiveness and safety of the combination of surgery and brachytherapy as local therapy for treating children and young people with relapsed/refractory rhabdomyosarcoma. This review identified studies based on a previous systematic review looking at the treatments for children and young people under 18 years old with relapsed/refractory rhabdomyosarcoma. Studies conducted after 2000 were included. Survival outcomes, relapse rates, adverse events and functional outcomes were extracted. From 16,965 records identified in the baseline systematic review, 205 included the words 'AMORE' or 'brachytherapy', and were screened for eligibility in this substudy. Thirteen studies met the inclusion criteria for Local-REFoRMS, including over 55 relapsed and refractory rhabdomyosarcoma patients. Most studies were retrospective cohort studies conducted within Europe. Most patients had embryonal disease within the head and neck or bladder/prostate regions, and received local therapy for first relapse. Approximately one quarter of patients relapsed following surgery and brachytherapy, with local relapses occurring more than metastatic relapse. Adverse events and functional outcomes were infrequently reported, but related to the site of surgery and brachytherapy. Study quality was limited by inconsistent reporting and potential selection bias. Outcomes following surgery and brachytherapy for a selected group of relapsed and refractory rhabdomyosarcoma show reasonable benefits, but reporting was often unclear and based on small sample sizes.

Finding full texts in bulk: a comparison of EndNote 20 versus Zotero 6 using the University of York's subscriptions.

Objective: To understand the performance of EndNote 20 and Zotero 6's full text retrieval features. Methods: Using the University of York's subscriptions, we tested and compared EndNote and Zotero's full text retrieval. 1,000 records from four evidence synthesis projects were tested for the number of: full texts retrieved; available full texts retrieved; unique full texts (found by one program only); and differences in versions of full texts for the same record. We also tested the time taken and accuracy of retrieved full texts. One dataset was tested multiple times to confirm if the number of full texts retrieved was consistent. We also investigated the available full texts missed by EndNote or Zotero by: reference type; whether full texts were available open access or via subscription; and the content provider. Results: EndNote retrieved 47% of available full texts versus 52% by Zotero. Zotero was faster by 2 minutes 15 seconds. Each program found unique full texts. There were differences in full text versions retrieved between programs. For both programs, 99% of the retrieved full texts were accurate. Zotero was less consistent in the number of full texts it retrieved. Conclusion: EndNote and Zotero do not find all available full texts. Users should not assume full texts are correct; are the version of record; or that records without full texts cannot be retrieved manually. Repeating the full text retrieval process multiple times could yield additional full texts. Users with access to EndNote and Zotero could use both for full text retrieval.

Methods of assessing value for money of UK-based early childhood public health interventions: a systematic literature review.

INTRODUCTION: Economic evaluation has an important role to play in the demonstration of value for money of early childhood public health interventions; however, concerns have been raised regarding their consistent application and relevance to commissioners. This systematic review of the literature therefore aims to collate the breadth of the existing economic evaluation evidence of these interventions and to identify the approaches adopted in the assessment of value. SOURCE OF DATA: Recently published literature in Medline, EMBASE, EconLit, Health Management Information Consortium, Cochrane CENTRAL, Cochrane Database of Systematic Reviews, Health Technology Assessment, NHS EED and Web of Science. AREAS OF AGREEMENT: The importance of the early childhood period on future health and well-being as well as the potential to impact health inequalities making for a strong narrative case for expenditure in early childhood public health. AREAS OF CONTROVERSY: The most appropriate approaches to evaluating value for money of such preventative interventions relevant for UK decision-makers given the evident challenges. GROWING POINTS: The presented review considered inconsistencies across methodological approaches used to demonstrate value for money. The results showed a mixed picture in terms of demonstrating value for money. AREAS TIMELY FOR DEVELOPING RESEARCH: Future resource allocations decisions regarding early childhood public health interventions may benefit from consistency in the evaluative frameworks and health outcomes captured, as well as consistency in approaches to incorporating non-health costs and outcomes, incorporating equity concerns and the use of appropriate time horizons.

Librarians and information specialists as methodological peer-reviewers: a case-study of the International Journal of Health Governance.

BACKGROUND: Objectives of this study were to analyze the impact of including librarians and information specialist as methodological peer-reviewers. We sought to determine if and how librarians' comments differed from subject peer-reviewers'; whether there were differences in the implementation of their recommendations; how this impacted editorial decision-making; and the perceived utility of librarian peer-review by librarians and authors. METHODS: We used a mixed method approach, conducting a qualitative analysis of reviewer reports, author replies and editors' decisions of submissions to the International Journal of Health Governance. Our content analysis categorized 16 thematic areas, so that methodological and subject peer-reviewers' comments, decisions and rejection rates could be compared. Categories were based on the standard areas covered in peer-review (e.g., title, originality, etc.) as well as additional in-depth categories relating to the methodology (e.g., search strategy, reporting guidelines, etc.). We developed and used criteria to judge reviewers' perspectives and code their comments. We conducted two online multiple-choice surveys which were qualitatively analyzed: one of methodological peer-reviewers' perceptions of peer-reviewing, the other of published authors' views on the suggested revisions. RESULTS: Methodological peer-reviewers assessed 13 literature reviews submitted between September 2020 and March 2023. 55 reviewer reports were collected: 25 from methodological peer-reviewers, 30 from subject peer-reviewers (mean: 4.2 reviews per manuscript). Methodological peer-reviewers made more comments on methodologies, with authors more likely to implement their changes (52 of 65 changes, vs. 51 of 82 by subject peer-reviewers); they were also more likely to reject submissions (seven vs. four times, respectively). Where there were differences in recommendations to editors, journal editors were more likely to follow methodological peer-reviewers (nine vs. three times, respectively). The survey of published authors (87.5% response rate) revealed four of seven found comments on methodologies helpful. Librarians' survey responses (66.5% response rate) revealed those who conducted peer-reviews felt they improved quality of publications. CONCLUSIONS: Librarians can enhance evidence synthesis publications by ensuring methodologies have been conducted and reported appropriately. Their recommendations helped authors revise submissions and facilitated editorial decision-making. Further research could determine if sharing reviews with subject peer-reviewers and journal editors could benefit them in better understanding of evidence synthesis methodologies.

Communicating cardiovascular risk: Systematic review of qualitative evidence.

INTRODUCTION: Cardiovascular risk prediction models are widely used to help individuals understand risk and make decisions. METHODS: Systematic review of qualitative evidence. We searched MEDLINE, Embase, PsycINFO and CINAHL. We included English-language qualitative studies on the communication of cardiovascular risk. We assessed study quality using Hawker et al.'s tool and synthesised data thematically. RESULTS: Thirty-seven studies were included. Many patients think that risk scores are of limited practical value. Other sources of information feed into informal estimates of risk, which may lead patients to reject the results of clinical risk assessment when the two conflict. Clinicians identify a number of barriers to risk communication, including patients' limited understanding of risk and excessive anxiety. They use a range of strategies for adapting risk communication. Both clinicians and individuals express specific preferences for risk communication formats. DISCUSSION: Ways of communicating risk that provide some comparison or reference point seem more promising. The broader context of communication around risk may be more important than the risk scoring instrument. Risk communication interventions, in practice, may be more about appeals to emotion than a rationalistic model of decision-making.

Defensive healthcare practice: systematic review of qualitative evidence.

OBJECTIVE: To synthesise qualitative evidence on clinicians' views and experiences of defensive practice. DESIGN: Systematic review of qualitative data. DATA SOURCES: MEDLINE, Embase, PsycINFO, AMED, Maternity and Infant Care, CINAHL, ASSIA, Sociological Abstracts, Proquest Dissertations & Theses and PROSPERO were searched from 2000 to October 2023. ELIGIBILITY CRITERIA: We included English-language studies of clinicians which reported qualitative data on the impact of litigation or complaints on clinical practice. DATA EXTRACTION AND SYNTHESIS: We coded findings data line by line using a grounded theory approach. We assessed quality using Hawker et al's tool and synthesised data thematically. RESULTS: 17 studies were included. Participants identify a range of clinical decisions which may be defensively motivated, relating to diagnosis and documentation as well as to treatment. Defensive practice often relates to a diffuse sense of risk rather than the direct threat of litigation and may overlap with other motivations, such as perceived pressure from patients or the desire to avoid harm. Defensive practice is seen to be harmful in many ways, but again, these perceptions may gain force from broader narratives of mistrust and disempowerment, as much as from the risk of litigation. CONCLUSIONS: The idea of defensive practice, as enacted, is more complex than some theoretical accounts suggest and may often function to express broader concerns about the work of clinical care. The qualitative evidence calls into question the view of defensive practice as a key mediator linking litigation risk to inappropriate treatment and excess costs.

Initial assessment and management of adults with suspected acute respiratory infection: a rapid evidence synthesis of reviews and cost-effectiveness studies.

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.

Acute respiratory infections, such as cold and flu, are common and can be caused by viruses or bacteria. People with symptoms of acute respiratory infection often go to their general practitioner, who may advise them to stay at home (with or without antibiotics or antivirals) or might refer them to hospital if the infection is serious. Doctors assess the patient's symptoms or may use a tool called an 'early warning score' to judge whether the infection is serious. A systematic review is a research method where all relevant studies assessing a specific question are found and summarised. We aimed to summarise all systematic reviews and cost-effectiveness studies that assessed signs, symptoms and 'early warning scores' in adults with suspected acute respiratory infections in the community (i.e. not hospitalised patients). We found nine systematic reviews and one cost-effectiveness study. Several different early warning scores for acute respiratory infection have been assessed in systematic reviews. Seven of the reviews assessed early warning scores in patients with community-acquired pneumonia. Good-quality reviews concluded that further research is needed to see how useful the 'CRB-65' and 'Pneumonia Severity Index' early warning scores are for assessing pneumonia severity in the community. Another good-quality review concluded that the 'National Early Warning Score' early warning score appears to be useful in an emergency department setting. A good-quality review found that individual symptoms are not very reliable for diagnosing pharyngitis caused by streptococcal bacteria in patients with sore throat; the review also found that the 'Centor score' can help doctors decide whether to prescribe antibiotics for pharyngitis. The cost-effectiveness study assessed clinical scores and rapid antigen detection tests (which test for substances that increase in our blood when we have certain infections) in patients with sore throat, and found that clinical scores may be cost-effective compared to delaying prescribing antibiotics.

Collaborative care for common mental disorders in low- and middle-income countries: A systematic review and meta-analysis.

BACKGROUND: Low- and middle-income countries (LMICs) face high burden of common mental disorders (CMDs). Most of the evidence for the Collaborative Care (CC) model effectiveness comes from high-income countries (HICs) and may not generalise to LMICs. A systematic review was conducted to assess effectiveness of CC for CMDs in LMICs. METHODS: We searched eight-databases, two trial registries (2011-November 2023). Randomised controlled trials (RCTs) of adults (≥18 years) with depression/anxiety diagnosis, reporting remission/change in symptom severity were eligible. Random effects meta-analyses were conducted for: short-(0-6 months), medium-(7-12 months), long-(13-24 months), and very long-term (≥25 months) follow-up. Quality was assessed with Cochrane RoB2 tool. PROSPERO registration: CRD42022380407. RESULTS: Searches identified 7494 studies, 12 trials involving 13,531 participants were included; nine had low-risk of bias. CC was more effective than usual care for depression: dichotomous outcomes (short-term, 7 studies, relative risk (RR) 1.39, 95%CI 1.31, 1.48; medium-term, 6 studies, RR 1.35, 95%CI 1.28, 1.43); and continuous outcomes (short-term, 8 studies, standardised mean difference (SMD) -0.51, 95%CI -0.80, -0.23; medium-term, 8 studies, SMD -0.59, 95%CI -1.00, -0.17). CC was found to be effective at long-term (one study), but not at very long-term. Improvement in anxiety outcomes with CC (2 studies, 340 participants) reported up to 12-months; improvements in quality-of-life were not statistically significant (3 studies, 796 participants, SMD 0.62, 95%CI -0.10, 1.34). LIMITATIONS: Pooled estimates showed high heterogeneity. CONCLUSIONS: In LMICs, CC was more effective than usual care for improving depression outcomes at short and medium-term follow-up. A similar improvement was found for anxiety outcomes, but evidence is limited.

Devices for remote continuous monitoring of people with Parkinson's disease: a systematic review and cost-effectiveness analysis.

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.

Parkinson's disease is a brain condition causing loss of co-ordination and movement problems. Levodopa is the most prescribed treatment for early disease. Patients should be seen by a specialist every 6­12 months to assess their treatment needs. Wearable devices (like smart watches) may aid management by directly monitoring patients for disease symptoms including tremor and slowness of movement (bradykinesia), or side effects of treatment like involuntary movement (dyskinesia). This assessment considered the clinical and economic value of five wearable devices: Personal KinetiGraph, STAT-ON, Kinesia 360, KinesiaU and PDMonitor. We searched medical databases to find all studies of the five devices. We assessed the quality of these studies and reviewed their results. We found 77 studies of the devices. 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 symptoms. The evidence for STAT-ON suggested it may be of value for diagnosing symptoms, but there is currently no evidence on its clinical value. There was insufficient evidence for Kinesia 360, KinesiaU and PDMonitor to draw any conclusions. An economic analysis was conducted to investigate whether using any of these technologies is economically viable. The economic analysis found that the quality-of-life benefits generated by remote monitoring devices were small relative to the additional costs of implementing them in the NHS. As such, none of the remote monitoring devices were good value for money when compared with the current standard of care.

The effectiveness of ablative and non-surgical therapies for early hepatocellular carcinoma: Systematic review and network meta-analysis of randomised controlled trials.

BACKGROUND & AIMS: Non-surgical therapies are frequently used for patients with early or very early hepatocellular carcinoma (HCC). The aim of this systematic review and network meta-analysis (NMA) was to evaluate and compare the effectiveness of ablative and non-surgical therapies for patients with small HCC. METHODS: Nine databases were searched (March 2021) along with clinical trial registries. Randomised controlled trials (RCTs) of any ablative or non-surgical therapy versus any comparator in patients with HCC ≤3 cm were eligible. Risk of bias (RoB) was assessed using the Cochrane RoB 2 tool. The effectiveness of therapies was compared using NMA. Threshold analysis was undertaken to identify which NMA results had less robust evidence. RESULTS: Thirty-seven eligible RCTs were included (including over 3700 patients). Most were from China (n = 17) or Japan (n = 7). Sample sizes ranged from 30 to 308 patients. The majority had a high RoB or some RoB concerns. No RCTs were identified for some therapies and no RCTs reported quality of life outcomes. The results of the NMA and treatment effectiveness rankings were very uncertain. However, the evidence demonstrated that percutaneous ethanol injection was worse than radiofrequency ablation for overall survival (hazard ratio [HR]: 1.45, 95% credible interval [CrI]: 1.16-1.82), progression-free survival (HR: 1.36, 95% CrI: 1.11-1.67), overall recurrence (relative risk [RR]: 1.19, 95% CrI: 1.02-1.39) and local recurrence (RR: 1.80, 95% CrI: 1.19-2.71). The threshold analysis suggested that robust evidence was lacking for some comparisons. CONCLUSIONS: It is unclear which treatment is most effective for patients with small HCC because of limitations in the evidence base. It is also not known how these treatments would impact on quality of life. Further high quality RCTs are needed to provide robust evidence but may be difficult to undertake.

Ablative and non-surgical therapies for early and very early hepatocellular carcinoma: a systematic review and network meta-analysis.

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 in Health Technology Assessment; Vol. 27, No. 29. See the NIHR Funding and Awards website for further award information.

Hepatocellular carcinoma is the most common type of primary liver cancer. There are a range of different treatments available for patients with early hepatocellular carcinoma. We looked for clinical trials in patients with small tumours (up to 3 cm) that compared different treatments. We brought together and analysed the results of these trials to see which treatments were most effective in terms of survival, progression, side effects and quality of life. Overall, the evidence has limitations; many trials had few patients and were of poor quality. Most were from China or Japan, where the common causes of liver disease and treatments available differ from those in the United Kingdom. The results of our analyses were very uncertain so we cannot be sure which treatment is the best overall. We did find that three treatments ­ radiofrequency ablation, microwave ablation and surgery ­ were generally more effective than percutaneous ethanol injection and percutaneous acid injection. There was not enough evidence to be certain which treatment was better when radiofrequency ablation was compared with laser ablation, microwave ablation, proton beam therapy or surgery. We found only poor-quality, non-randomised trials on high-intensity focused ultrasound, cryoablation and irreversible electroporation. There was very little evidence on treatments that combined radiofrequency ablation with other therapies. We found no studies that compared electrochemotherapy, histotripsy, stereotactic ablative radiotherapy or wider radiotherapy techniques with other treatments. Only two studies reported data on quality of life or patient satisfaction. We discussed the findings with patients and clinical experts. Stereotactic ablative radiotherapy was highlighted as a treatment that requires further research; however, it is only appropriate for certain subgroups of patients. Feasibility studies could inform future clinical trials by exploring issues such as whether patients are willing to take part in a trial or find the treatments acceptable.