Clinico-characteristics of patients which correlated with preferable treatment outcomes in immunotherapy for advanced hepatocellular carcinoma: a systematic review and meta-analysis

Background and aims: Hepatocellular carcinoma (HCC) is the third-most lethal malignant tumor worldwide. The rapid development of immunotherapy utilizing immune checkpoint inhibitors for advanced HCC patients has been witnessed in recent years, along with numerous randomized clinical trials demonstrating the survival benefits for these individuals. This systematic review and meta-analysis aimed to identify specific clinico-pathological characteristics of advanced HCC patients that may lead to preferable responses to immunotherapy in terms of overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Methods: The included clinical trials were retrieved from PubMed, Embase, the Cochrane library, and the Web of Science databases published in English between 1 January 2002 and 20 October 2022. A systematic review and meta-analysis for first-line and second-line phase II/III studies were conducted on immunotherapy for patients with advanced HCC by using OS as the primary outcome measure, and PFS and ORR as the secondary outcome measures to obtain clinico-pathological characteristics of patients which might be preferable responses to programmed death-1 (PD-1) and programmed cell death-Ligand 1 (PD-L1) inhibitors. Toxicity and specific treatment-related adverse events (TRAEs) were also determined. Results: After screening 1392 relevant studies, 12 studies were included in this systematic review and meta-analysis to include 5948 patients. Based on the analysis of interaction, the difference in OS after first-line immunotherapy between the subgroups of viral hepatitis [hazard ratio (HR)=0.73 vs 0.87, P for interaction=0.02] and macrovascular invasion and/or extrahepatic spread (HR=0.73 vs 0.89, P for interaction=0.02) were significant. The difference in PFS between the subgroups of viral hepatitis was highly significant (pooled HR=0.55 vs 0.81, P for interaction=0.007). After second-line immunotherapy, the difference in ORR between the subgroups of Barcelona Clinic Liver Cancer was significant (pooled ES=0.12 vs 0.23, P for interaction=0.04). Compared with PD-L1 inhibitors, PD-1 inhibitors may have a higher probability to cause TRAEs. Diarrhea, increased aspartate aminotransferase, and hypertension were the top three TRAEs. Conclusions: This systematic review and meta-analysis represents the first pilot study aimed at identifying crucial clinico-pathological characteristics of patients with advanced HCC that may predict favorable treatment outcomes in terms of OS, PFS, and ORR to immunotherapy. Findings suggest that patients with viral hepatitis positivity (especially hepatitis B virus) and macrovascular invasion and/or extrahepatic spread may benefit more in OS when treated with PD-1/PD-L1 immune checkpoint inhibitors.


Did the research questions and inclusion criteria for the review include the components of PICO?
For Yes: √ Population √ Intervention √ Comparator group √ Outcome Optional (recommended) ◻ Timeframe for follow-up √ ◻

Yes No
2. Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol?
For Partial Yes: The authors state that they had a written protocol or guide that included ALL the following: √ review question(s) √ a search strategy √ inclusion/exclusion criteria √ a risk of bias assessment For Yes: As for partial yes, plus the protocol should be registered and should also have specified:

Did the review authors perform study selection in duplicate?
For Yes, either ONE of the following: ◻ at least two reviewers independently agreed on selection of eligible studies and achieved consensus on which studies to include √ OR two reviewers selected a sample of eligible studies and achieved good agreement (at least 80 percent), with the remainder selected by one reviewer.

Yes No
AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or nonrandomised studies of healthcare interventions, or both

Did the review authors perform data extraction in duplicate?
For Yes, either ONE of the following: ◻ at least two reviewers achieved consensus on which data to extract from included studies √ OR two reviewers extracted data from a sample of eligible studies and achieved good agreement (at least 80 percent), with the remainder extracted by one reviewer.

Did the review authors explain their selection of the study designs for inclusion in the review
?For Yes, the review should satisfy ONE of the following:◻ Explanation for including only RCTs ◻ OR Explanation for including only NRSI √ OR Explanation for including both RCTs and NRSI √ ◻Yes No4.

Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review?
Yes in the review.Note: Reporting that the reviewers looked for this information ◻ No but it was not reported by study authors also qualifies AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or nonrandomised studies of healthcare interventions, or both

If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis?
For Yes:√ included only low risk of bias RCTs ◻ OR, if the pooled estimate was based on RCTs and/or NRSI at variable RoB, the authors performed analyses to investigate possible impact of RoB on summary estimates of effect.

they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review?
critical appraisal tool for systematic reviews that include randomised or nonrandomised studies of healthcare interventions, or both 16.

Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review?
For Yes:√ The authors reported no competing interests OR ◻ The authors described their funding sources and how they managed potential conflicts of interest Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, Moher D, Tugwell P, Welch V, Kristjansson E, Henry DA.AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both.BMJ.2017 Sep 21;358:j4008.