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.

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.

Mortality in late nineteenth-century Montreal: geographic pathways of contagion.

In the City of Montreal, 1881, the presence of three cultural communities with different profiles of economic status makes it possible to observe the way social settings affected survival over a lifetime. Regression models show culturally determined maternal factors dominant for infants, and persistent throughout childhood. For post-neonates, children aged 1-4, and adults aged 15-59 household poverty has a comparable effect. Among adults, a gender penalty differs among the three communities. Models are improved when differentiated by cause of death. Locating households using a GIS reveals high levels of residential segregation by ethnicity and income, spatial correlation of environmental hazards, and constraints on exit from zones of risk, which together produce neighbourhood effects as large as household effects. Attention to groups excluded (foundlings and inmates of institutions) confirms that models limited to full household-level information significantly underestimate the impacts of poverty and exclusion.

Specificity of the jump-to-conclusions bias in deluded patients.

OBJECTIVE: To investigate the specificity of the 'jump-to-conclusions' (JTC) bias in delusions. METHODS: Thirty-seven psychotic patients were divided into two separate groupings: (1) deluded versus non-deluded individuals and (2) individuals with and without a diagnosis of schizophrenia. Groups were compared on three reasoning tasks ('Beads' task, Wason's 2-4-6 task, and Wason's selection task). RESULTS: Deluded participants had a tendency to show a JTC bias on data-gathering tasks, but no differences were found with the schizophrenia diagnosis grouping. There were no differences between any groups on tasks of general reasoning and probability judgments. CONCLUSION: The results suggest that JTC is specific to delusions rather than diagnosis, and to data gathering rather than a general deficit in reasoning.

Reconciling cross-sectional and longitudinal measures of fertility, Quebec 1890-1900.

In the absence of vital registration, studies of the onset and early phases of the fertility transition in North America have been seriously hampered and yet the seemingly early timing of the decline, the multi-ethnic nature of the population and continuous flow of immigrants from Europe suggest that North America has much to offer to this debate. This paper is primarily methodological drawing on parallel data for the city of Montreal and surrounding region. By reconciling cross-sectional census measures of fertility using the own-child methods (1901) with those derived from a longitudinal ten-year panel (1891-1901) using family reconstitution, it exposes some of the weaknesses and the potentials of the two methods most often currently used and the advantages of combining methods. Own-children measures of marital fertility are seriously affected by significant local differences in infant survival between rural and urban areas and between cultural groups as well as by residual effects of duration and timing of marriage, while small-scale longitudinal studies in complex environments cannot always render reliable results for all sub-populations not can they necessarily be 'scaled up.' They suggest that national and even regional averages of fertility may conceal large diversity, which in turn raises questions about the existence of any single transition with uniform characteristics and timing, or universal cause. Instead we argue different groups in different environments may actually have been fine-tuning their fertility behaviour to compensate for the differential effects of mortality through adjustments to both marriage and fertility within marriage.