Review for 10.1186/s12876-024-03144-8 (2024)

Title: Efficacy and safety of the combination of camrelizumab and apatinib in the treatment of
liver cancer: a systematic review and single-arm meta-analysis
Version: 0 Date: 13 Dec 2023
Reviewer's report:
Chen and colleagues performed an aggregate data single-arm meta-analysis of studies assessing
the efficacy and safety of the combination of camrelizumab plus apatinib for hepatocellular
carcinoma (HCC). A total of 8 studies involving 491 patients were included in the meta-analysis.
Authors reported pooled data for ORR, DCR, PFS, OS and adverse events, concluding that the
combination of camrelizumab and apatinib exhibits commendable effectiveness in patients with
HCC.
Although this study was conducted with rigorous methodology and it could be potentially the
first meta-analysis on this topic, some critical issues need to be revised. The authors should
update the literature search given that relevant studies on this topic have been published in the
last year. Moreover, reporting of characteristics of the included studies should be deeply revised,
as well as methods to try to explore heterogeneity.
Several important methodological issues must be reconsidered.
1) In this meta-analysis, literature search was performed until November 2022. Since then,
other relevant studies have been published that can be included according to inclusion criteria.
For example, the results of the combination arm of CARES-310 trial (https://doi.org/10.1016/
S0140-6736(23)00961-3) needs to be included in the analysis. Please verify if other relevant
studies have been published.
2) After having updated the literature search, consider to add “systematic review” to the title
3) Authors should discuss the results of the recently published CARES-310 trial in terms of
strength and limitations (they could refer to doi: 10.1016/S0140-6736(23)01297-7.)
4) The granularity of the information on patient- and study-level covariates reported in Table 1
should be increased. For example, it is needed to report different study design.
5) Referee acknowledged that given the small number of studies it was difficult to perform
subgroup analyses (except from first- vs second-line). Please try to report subgroup analyses
according to study design (prospective vs retrospective).
6) Heterogeneity is high in most of the presented analyses. Authors should perform a meta-
regression analysis to try to identify covariates significantly associated with the outcomes of
interest.
7) Safety analysis: the rate of hepatotoxicity (please correct typo in Table 3) seems lower
than that reported in CARES-310 trial (about 50% of patients had increase in AST or ALT).
Immune-related liver injury is common in patients with hepatocellular carcinoma and deserves
clinical consideration. Authors could discuss the safety profile of camrelizumab plus apatinib in
patients with HCC in the light of results of a recently published study (https://doi.org/10.1016/
j.jhep.2023.10.040)
8) Only few studies were pooled for survival outcomes (PFS or OS). Rather than exclude studies
with short follow-up and possibly not reached median OS, consider to pool 6-month actuarial
rates, for example.
9) Since direct comparison between camrelizumab plus apatinib and other combination therapies
including immune checkpoint inhibitors are lacking, network meta-analyses could be useful to
obtain indirect comparisons. Authors could discuss the results of a recently published network
meta-analysis (https://doi.org/10.1159/000531744)
10) Inclusion criteria: authors stated that only study whose patients received a histopathological
diagnosis of HCC were included. Please check and revise it, since diagnosis of hepatocellular
carcinoma is radiological in patients with cirrhosis and it is unlikely that included studies only
focused on patients with histological diagnosis.
11) Conclusions: authors referred to combination treatments but this conclusion is not supported
by the results of the present meta-analysis. Consider to discuss the opportunity of combining
systemic and locoregional treatments in another section of the discussion, underlining the need
for a multidisciplinary care, given the high clinical complexity of this field (authors could refer
to doi: 10.1016/S1470-2045(23)00186-9)