Authors' objectives: 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. To review and compare the effectiveness of all current ablative and non-surgical therapies for patients with small hepatocellular carcinoma (≤ 3 cm). Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Around one-third of people with cirrhosis go on to develop HCC. The prognosis of symptomatic HCC is poor, so the National Institute for Health and Care Excellence recommends that patients with cirrhosis are monitored for early HCC with six-monthly ultrasound scans. Patients with early HCC and good liver function can be offered surgical or non-surgical interventions with curative intent. However, liver resection is not always possible due to the location of the tumour, poor liver function or portal hypertension, and liver transplantation is limited by availability. Therefore, ablative or non-surgical therapies are frequently used for treating early HCC, including microwave ablation (MWA) and radiofrequency ablation (RFA). There has been no definitive assessment of these therapies. The aim of this project was to evaluate and compare the effectiveness of ablative and non-surgical therapies for patients with small HCC. The key objectives were to: systematically identify all randomised controlled trials (RCTs) of ablative and non-surgical therapies for HCC evaluate their quality and applicability to UK populations determine the comparative effectiveness of therapies using network meta-analysis (NMA) where the evidence base is insufficient, supplement the RCT evidence with high-quality, non-randomised, prospective comparative studies identify priority areas where additional high-quality evidence is required (in collaboration with patients and clinicians) assess whether future economic analysis would be feasible and worthwhile.

Authors' results and conclusions: 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. 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. Systematic review of randomised controlled trial results Thirty-seven RCTs were included. Most were small, with sample sizes ranging from 30 to 308 patients. The majority of RCTs were conducted in China or Japan. The most frequently assessed therapy was RFA. The majority of RCTs assessed OS, PFS/disease-free survival and/or recurrence, along with response and AEs. One RCT assessed patient satisfaction. The RoB judgement was low for 9 RCTs, high for 12 RCTs and some concerns for 14 RCTs (two RCTs that reported no relevant outcomes were not assessed). For many comparisons, data were limited. Based on a narrative synthesis, RFA appears to be better than both PEI and PAI in terms of OS, PFS and recurrence, although AEs were more frequent after RFA. PAI appears to have similar effectiveness to PEI. For RFA versus resection, results were inconsistent, with some RCTs favouring RFA and some resection; AEs were more frequent after resection. Data from RCTs comparing RFA with MWA, laser ablation or proton beam therapy were limited. RCTs assessing RFA in combination with other treatments were also limited by small sample sizes. AEs were reported inconsistently. There was no RCT evidence for HIFU, cryoablation, IRE, ECT, histotripsy, SABR or wider radiotherapy techniques. Implications for health care There are considerable limitations to the evidence on ablative and non-surgical therapies for early and very early HCC. There is insufficient evidence to draw any conclusions on quality-of-life outcomes. The only firm conclusions that can be drawn from the available data are that PEI and PAI are inferior to RFA, and also appear to be inferior to MWA and resection for certain survival outcomes. MWA and resection are the first-line standard of care for single HCC ≤ 3 cm in the UK. The uptake of specific ablative therapies in the UK appears to be based more on technological advancements and ease or speed of use than on high-quality evidence demonstrating superior clinical effectiveness.

Authors' recommendations: It is difficult to make firm recommendations for research based on our findings. There are currently no comparative data on several ablative and non-surgical therapies, particularly those treatments reserved for the subgroup of patients with more challenging tumours. However, owing to the small number of such patients who would be eligible for both treatment arms within a trial, along with the marginal benefit of novel treatments compared with the existing standard of care, it is likely to be difficult to recruit sufficient numbers of patients. Future studies should assess local recurrence, overall recurrence, OS, PFS, HRQoL and patient acceptability, using clear and consistent definitions, in order to allow results to be compared across studies. Further research on SABR, and possibly other technologies, such as IRE, is required to identify where they should sit in the treatment pathway. Feasibility studies could address potential issues and complexities in undertaking research in this area prior to undertaking a trial. This would enable: investigation of the acceptability of the intervention (and comparator) to both clinicians and patients, and their willingness to participate in a trial; the practicality of delivering the intervention; and the ability to measure relevant outcomes.

Authors' methods: Systematic review and network meta-analysis. Nine databases (March 2021), two trial registries (April 2021) and reference lists of relevant systematic reviews. 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. Many studies were small and of poor quality. No comparative studies were found for some therapies. Systematic review of randomised controlled trials Nine databases (including MEDLINE, Embase, CENTRAL, Science Citation Index) were searched for RCTs and systematic reviews published from 2000 to March 2021. Two trial registries were searched in April 2021 to identify ongoing and unpublished RCTs. The reference lists of relevant systematic reviews were checked and clinical advisors were consulted. Randomised controlled trials of patients with HCC up to 3 cm in size (or data on a subgroup(s) of patients with tumours ≤ 3 cm) were eligible for inclusion. Any ablative or non-surgical therapy was eligible, including: RFA MWA laser ablation high-intensity focused ultrasound (HIFU) cryoablation percutaneous ethanol injection (PEI) percutaneous acetic acid injection (PAI) irreversible electroporation (IRE) transarterial chemoembolisation (TACE) transarterial embolisation selective internal radiation therapy electrochemotherapy (ECT) histotripsy stereotactic ablative radiotherapy [SABR; the term stereotactic body radiotherapy (SBRT) is also used for this technology] wider radiotherapy techniques. Any comparator was eligible, except a different method of undertaking the same intervention. Outcomes of interest were overall survival (OS), progression-free survival (PFS), time to progression (TTP), serious adverse events (AEs), intervention-specific AEs and quality of life. Titles and abstracts were screened by one reviewer, with 10% checked by another reviewer. Full texts were screened by two reviewers independently. Data extraction was checked by a second reviewer. Risk of bias (RoB) was assessed using the Cochrane RoB 2 tool. When studies did not report hazard ratios (HRs) and their variances, Kaplan–Meier data were extracted.

Project Status: Completed

URL for project: https://www.journalslibrary.nihr.ac.uk/programmes/hta/NIHR131224

Year Published: 2023

URL for published report: https://www.journalslibrary.nihr.ac.uk/hta/GK5221

URL for additional information: English

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: England, United Kingdom

DOI: 10.3310/GK5221

Organisation Name: NIHR Health Technology Assessment programme

Contact Address: NIHR Journals Library, National Institute for Health and Care Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK

Contact Name: journals.library@nihr.ac.uk

Contact Email: journals.library@nihr.ac.uk