Emily South

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.

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.

Background: Scoping reviews and evidence maps are forms of evidence synthesis that aim to map the available literature on a topic and are well-suited to visual presentation of results. A range of data visualisation methods and interactive data visualisation tools exist that may make scoping reviews more useful to knowledge users. The aim of this study was to explore the use of data visualisation in a sample of recent scoping reviews and evidence maps on health topics, with a particular focus on interactive data visualisation. Methods: Ovid MEDLINE ALL was searched for recent scoping reviews and evidence maps (June 2020-May 2021), and a sample of 300 papers that met basic selection criteria was taken. Data were extracted on the aim of each review and the use of data visualisation, including types of data visualisation used, variables presented and the use of interactivity. Descriptive data analysis was undertaken of the 238 reviews that aimed to map evidence. Results: Of the 238 scoping reviews or evidence maps in our analysis, around one-third (37.8%) included some form of data visualisation. Thirty-five different types of data visualisation were used across this sample, although most data visualisations identified were simple bar charts (standard, stacked or multi-set), pie charts or cross-tabulations (60.8%). Most data visualisations presented a single variable (64.4%) or two variables (26.1%). Almost a third of the reviews that used data visualisation did not use any colour (28.9%). Only two reviews presented interactive data visualisation, and few reported the software used to create visualisations. Conclusions: Data visualisation is currently underused by scoping review authors. In particular, there is potential for much greater use of more innovative forms of data visualisation and interactive data visualisation. Where more innovative data visualisation is used, scoping reviews have made use of a wide range of different methods. Increased use of these more engaging visualisations may make scoping reviews more useful for a range of stakeholders.

Background: Lifestyle risk behaviours are key risk factors for non-communicable diseases. Some disadvantaged groups face particularly poor health outcomes, which may be exacerbated by high prevalence of risk behaviours. The aim of this scoping review was to identify and bring together evidence from systematic reviews on reducing risk behaviours in these groups and highlight where there is insufficient evidence to inform policy. Methods: MEDLINE and Embase were searched up to October 2020 for English language reviews, with supplementary searching in Epistemonikos and Health Systems Evidence. Systematic reviews reporting behavioural outcomes of interventions targeting smoking, alcohol use, diet or physical inactivity in nine disadvantaged groups were eligible. Reviews of population-level policies reporting differential effects for these groups and qualitative reviews of barriers or facilitators to change were included. Literature was mapped based on the group and behaviour targeted. Results: Ninety-two systematic reviews were included. The majority (n = 68) focused on low income or socio-economic status. Fewer reviews were identified that included prisoners (n = 14), deprived areas (n = 12), homeless people (n = 10), people with learning disabilities (n = 9), unemployed people (n = 3) and refugees or asylum seekers (n = 2). We identified no reviews on care leavers or Gypsies, Travellers or Roma. In total only 11 reviews targeted alcohol use. There were some gaps for specific group and behaviour combinations and no intervention reviews on refugees. Conclusions: A number of gaps were identified, highlighting where new syntheses or primary studies could add value. For example, reviews on interventions in refugees, Gypsies, Travellers and Roma, and care leavers could be useful for policy-making. Other useful contributions might include an overview of the perceptions of disadvantaged groups allowing common barriers to behaviour change to be identified as well as factors unique to specific groups. Key messages: Nearly 100 systematic reviews focused on reducing risk behaviours in disadvantaged groups; they addressed different combinations of behaviours and groups. Gaps in the literature were identified where new syntheses could make a useful contribution to developing programmes and policies.

Background Lifestyle risk behaviours are associated with an increased risk of non-communicable disease and mortality. There are socio-economic inequalities in these behaviours, with some behaviours being more prevalent in particular groups, such as prisoners, homeless people and Gyspies, Travellers and Roma. The aim of this scoping review was to identify and bring together existing evidence from systematic reviews on reducing risk behaviours in disadvantaged groups and highlight where there is insufficient evidence to inform policy. Methods MEDLINE and Embase were searched up to October 2020 for English language reviews, with supplementary searching in Epistemonikos and Health Systems Evidence. Systematic reviews reporting behavioural outcomes of interventions targeting smoking, excessive alcohol use, unhealthy diet or physical inactivity in low income or socio-economic status (SES), unemployed people, homeless people, care leavers, prisoners, refugees or asylum seekers, Travellers, Gypsies or Roma, people with learning disabilities or deprived areas or communities were eligible. Reviews of population-level policies reporting differential effects for disadvantaged groups and qualitative reviews exploring barriers or facilitators to behaviour change were also included. The literature was mapped based on the group and behaviour targeted. Results In total 9,336 records were screened, 262 full texts retrieved and 92 systematic reviews included. The majority of reviews included studies of people with low income or SES (n=68), with diet and low income the most frequently addressed combination. There were fourteen reviews on prisoners, 12 on deprived areas, ten on homeless people and nine on people with learning disabilities. Only three reviews included unemployed people and two included refugees or asylum seekers (both focusing on barriers and facilitators to healthy eating). No reviews were identified on care leavers or Gypsies, Travellers and Roma. In total there were 11 reviews targeting alcohol use. Sixteen qualitative reviews explored participants’ perceptions of barriers and facilitators to changing their behaviour. Conclusion A large number of systematic reviews were identified but we found some evidence gaps where new syntheses or primary studies may be needed to guide policy, for example on care leavers, Gypsies, Travellers and Roma and refugees and asylum seekers. Other useful contributions might include an overview bringing together different interventions in low-income populations and an overview of the perceptions of disadvantaged groups about behaviour change, allowing common barriers to be identified as well as factors that are unique to specific groups.

Background: Responsibility for public health in England transferred from the National Health Service to local authorities in 2013, representing a different decision-making environment. Systematic reviews are considered the gold standard of evidence for clinical decision-making but little is known about their use in local government public health. This study aimed to explore the extent to which public health decision-makers in local authorities engage with systematic reviews and how they do so. Methods: Semi-structured interviews were conducted with senior public health practitioners (n = 14) in Yorkshire and the Humber local authorities. Sampling was purposive and involved contacting Directors of Public Health directly and snowballing through key contacts. Face-to-face or telephone interviews were digitally recorded, transcribed verbatim and analysed using the Framework Method. Results: Public health practitioners described using systematic reviews directly in decision-making and engaging with them more widely in a range of ways, often through a personal commitment to professional development. They saw themselves as having a role to advocate for the use of rigorous evidence, including systematic reviews, in the wider local authority. Systematic reviews were highly valued in principle and public health practitioners had relevant skills to find and appraise them. However, the extent of use varied by individual and local authority and was limited by the complexity of decision-making and various barriers. Barriers included that there were a limited number of systematic reviews available on certain public health topics, such as the wider determinants of health, and that the narrow focus of reviews was not reflective of complex public health decisions facing local authorities. Reviews were used alongside a range of other evidence types, including grey literature. The source of evidence was often considered an indicator of quality, with specific organisations, such as Public Health England, NICE and Cochrane, particularly trusted. Conclusions: Research use varies and should be considered within the specific decision-making and political context. There is a need for systematic reviews to be more reflective of the decisions facing local authority public health teams.

Background: Although many treatments exist for phantom limb pain (PLP), the evidence supporting them is limited and there are no guidelines for PLP management. Brain and spinal cord neurostimulation therapies are targeted at patients with chronic PLP but have yet to be systematically reviewed. Objective: To determine which types of brain and spinal stimulation therapy appear to be the best for treating chronic PLP. Design: Systematic reviews of effectiveness and epidemiology studies, and a survey of NHS practice. Population: All patients with PLP. Interventions: Invasive interventions – deep brain stimulation (DBS), motor cortex stimulation (MCS), spinal cord stimulation (SCS) and dorsal root ganglion (DRG) stimulation. Non-invasive interventions – repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). Main outcome measures: Phantom limb pain and quality of life. Data sources: Twelve databases (including MEDLINE and EMBASE) and clinical trial registries were searched in May 2017, with no date limits applied. Review methods: Two reviewers screened titles and abstracts and full texts. Data extraction and quality assessments were undertaken by one reviewer and checked by another. A questionnaire was distributed to clinicians via established e-mail lists of two relevant clinical societies. All results were presented narratively with accompanying tables. Results: Seven randomised controlled trials (RCTs), 30 non-comparative group studies, 18 case reports and 21 epidemiology studies were included. Results from a good-quality RCT suggested short-term benefits of rTMS in reducing PLP, but not in reducing anxiety or depression. Small randomised trials of tDCS suggested the possibility of modest, short-term reductions in PLP. No RCTs of invasive therapies were identified. Results from small, non-comparative group studies suggested that, although many patients benefited from short-term pain reduction, far fewer maintained their benefits. Most studies had important methodological or reporting limitations and few studies reported quality-of-life data. The evidence on prognostic factors for the development of chronic PLP from the longitudinal studies also had important limitations. The results from these studies suggested that pre-amputation pain and early PLP intensity are good predictors of chronic PLP. Results from the cross-sectional studies suggested that the proportion of patients with severe chronic PLP is between around 30% and 40% of the chronic PLP population, and that around one-quarter of chronic PLP patients find their PLP to be either moderately or severely limiting or bothersome. There were 37 responses to the questionnaire distributed to clinicians. SCS and DRG stimulation are frequently used in the NHS but the prevalence of use of DBS and MCS was low. Most responders considered SCS and DRG stimulation to be at least sometimes effective. Neurosurgeons had mixed views on DBS, but most considered MCS to rarely be effective. Most clinicians thought that a randomised trial design could be successfully used to study neurostimulation therapies. Limitation: There was a lack of robust research studies. Conclusions: Currently available studies of the efficacy, effectiveness and safety of neurostimulation treatments do not provide robust, reliable results. Therefore, it is uncertain which treatments are best for chronic PLP. Future work: Randomised crossover trials, randomised N-of-1 trials and prospective registry trials are viable study designs for future research. Study registration: The study is registered as PROSPERO CRD42017065387. Funding: The National Institute for Health Research Health Technology Assessment programme.

The Centre for Reviews and Dissemination and Centre for Health Economics Technology Assessment Group at the University of York was commissioned by the National Institute for Health and Care Excellence (NICE) Highly Specialised Technologies (HST) programme to act as the independent Evidence Review Group (ERG) for an appraisal of Strimvelis^®, a gene therapy treatment for adenosine deaminase deficiency–severe combined immunodeficiency (ADA-SCID). This paper describes the manufacturing company’s submission of clinical and economic evidence, the ERG’s review and the resulting NICE guidance. For Strimvelis^® compared with haematopoietic stem cell transplant (HSCT) from a matched unrelated donor (MUD) and HSCT from a haploidentical donor, the company base-case deterministic incremental cost-effectiveness ratios (ICERs) were £36,360 and £14,645 per quality-adjusted life-year (QALY) gained, respectively (using a discount rate of 1.5%). Although overall survival in patients receiving Strimvelis^® was substantially higher than historical comparator data on HSCT from a MUD or haploidentical donor, the ERG was concerned that the estimated treatment benefit remained highly uncertain. The ERG critiqued some assumptions in the cost-effectiveness model, including that all patients return to general population mortality and morbidity after a successful procedure; that all patients receive a matched sibling donor following an unsuccessful engraftment; and that differences in wait times exist between the treatments. Incorporating a number of changes to the model, the ERG’s base-case ICERs were £86,815 per QALY gained for Strimvelis^® compared with HSCT from a MUD and £16,704 per QALY gained compared with HSCT from a haploidentical donor (using a discount rate of 1.5%). The ICER for Strimvelis^® compared with HSCT from a MUD was highly sensitive to the difference in procedural mortality and could exceed NICE’s £100,000 per QALY gained threshold for HSTs, if HSCT survival rates have improved since the most recent data. The evaluation committee concluded that the most plausible ICERs were lower than £100,000 per QALY gained and that Strimvelis^® should be recommended for treatment of ADA-SCID where a matched related donor is unavailable.