Title: Prognostic Value of Platelet-to-Lymphocyte Ratio in Hepatocellular Carcinoma Patients
Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis
Version: 1 Date: 19 Apr 2025
Reviewer's report:
In this article, Zhou and colleagues performed a systematic review and meta-analysis on the
prognostic significance of the platelet-to-lymphocyte ratio (PLR) on hepatocellular carcinoma
patients receiving immune checkpoint inhibitors. Their results suggest that a high PLR is
associated with worse prognosis; these results seem to be consistent across multiple subgroup
analyses.
I have the following comments and suggestions:
1) I recommend that the authors clearly identify this article as a systematic review and meta-
analysis (not just a meta-analysis) in both the title and the abstract
2) A specific strategy rather than keywords should be presented to ensure reproducibility of their
search methodology.
3) The use of random vs. fixed effects models should depend on the authors' assumptions
regarding the different study populations and the presence of one or multiple true effect
sizes rather than the use of statistical heterogeneity metrics. The authors clearly demonstrate
significant differences between the study populations, such as country and treatment agent used.
Therefore it becomes imperative that a random effects model be used in all analyses.
4) The authors use the terms predictive and prognostic interchangeably, however the two terms
have very different meanings - a biomarker that forecasts a clinical outcome vs. a  biomarker that
forecasts the outcome after the exposure to a therapeutic agent. The latter requires a comparative
design that includes a control group by default (in this case, it would require a comparison of
HCC patients NOT receiving ICIs). Therefore, PLR in this meta-analysis  is being investigated
as a prognostic, not a predictive biomarker; therefore all references to "predictive" need to be
changed to prognostic.
5) Important prognostic variables that act as confounders as well as sources of heterogeneity
need to be reported in  Table  1 - including Child-Pugh stage,  BCLC stage; line of treatment;
performance status if available; hepatitis status. These also need to further studied in subgroup
analyses if they significantly differ between studies.
6) Pooling effect estimates from different multivariable analyses can be problematic if the
adjusted variables were not uniform across all studies, as they have different interpretations.
I suggest that the authors specify which variables were included in each of the multivariable
models in a table as well as mention this limitation in the limitations section.
Title: Prognostic Value of Platelet-to-Lymphocyte Ratio in Hepatocellular Carcinoma Patients
Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis
Version: 1 Date: 19 Apr 2025
Reviewer's report:
In this article, Zhou and colleagues performed a systematic review and meta-analysis on the
prognostic significance of the platelet-to-lymphocyte ratio (PLR) on hepatocellular carcinoma
patients receiving immune checkpoint inhibitors. Their results suggest that a high PLR is
associated with worse prognosis; these results seem to be consistent across multiple subgroup
analyses.
I have the following comments and suggestions:
1) I recommend that the authors clearly identify this article as a systematic review and meta-
analysis (not just a meta-analysis) in both the title and the abstract
2) A specific strategy rather than keywords should be presented to ensure reproducibility of their
search methodology.
3) The use of random vs. fixed effects models should depend on the authors' assumptions
regarding the different study populations and the presence of one or multiple true effect
sizes rather than the use of statistical heterogeneity metrics. The authors clearly demonstrate
significant differences between the study populations, such as country and treatment agent used.
Therefore it becomes imperative that a random effects model be used in all analyses.
4) The authors use the terms predictive and prognostic interchangeably, however the two terms
have very different meanings - a biomarker that forecasts a clinical outcome vs. a  biomarker that
forecasts the outcome after the exposure to a therapeutic agent. The latter requires a comparative
design that includes a control group by default (in this case, it would require a comparison of
HCC patients NOT receiving ICIs). Therefore, PLR in this meta-analysis  is being investigated
as a prognostic, not a predictive biomarker; therefore all references to "predictive" need to be
changed to prognostic.
5) Important prognostic variables that act as confounders as well as sources of heterogeneity
need to be reported in  Table  1 - including Child-Pugh stage,  BCLC stage; line of treatment;
performance status if available; hepatitis status. These also need to further studied in subgroup
analyses if they significantly differ between studies.
6) Pooling effect estimates from different multivariable analyses can be problematic if the
adjusted variables were not uniform across all studies, as they have different interpretations.
I suggest that the authors specify which variables were included in each of the multivariable
models in a table as well as mention this limitation in the limitations section.
Please review this paper.
user
Title: Prognostic Value of Platelet-to-Lymphocyte Ratio in Hepatocellular Carcinoma Patients
Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis
Version: 1 Date: 19 Apr 2025
Reviewer's report:
In this article, Zhou and colleagues performed a systematic review and meta-analysis on the
prognostic significance of the platelet-to-lymphocyte ratio (PLR) on hepatocellular carcinoma
patients receiving immune checkpoint inhibitors. Their results suggest that a high PLR is
associated with worse prognosis; these results seem to be consistent across multiple subgroup
analyses.
I have the following comments and suggestions:
1) I recommend that the authors clearly identify this article as a systematic review and meta-
analysis (not just a meta-analysis) in both the title and the abstract
2) A specific strategy rather than keywords should be presented to ensure reproducibility of their
search methodology.
3) The use of random vs. fixed effects models should depend on the authors' assumptions
regarding the different study populations and the presence of one or multiple true effect
sizes rather than the use of statistical heterogeneity metrics. The authors clearly demonstrate
significant differences between the study populations, such as country and treatment agent used.
Therefore it becomes imperative that a random effects model be used in all analyses.
4) The authors use the terms predictive and prognostic interchangeably, however the two terms
have very different meanings - a biomarker that forecasts a clinical outcome vs. a  biomarker that
forecasts the outcome after the exposure to a therapeutic agent. The latter requires a comparative
design that includes a control group by default (in this case, it would require a comparison of
HCC patients NOT receiving ICIs). Therefore, PLR in this meta-analysis  is being investigated
as a prognostic, not a predictive biomarker; therefore all references to "predictive" need to be
changed to prognostic.
5) Important prognostic variables that act as confounders as well as sources of heterogeneity
need to be reported in  Table  1 - including Child-Pugh stage,  BCLC stage; line of treatment;
performance status if available; hepatitis status. These also need to further studied in subgroup
analyses if they significantly differ between studies.
6) Pooling effect estimates from different multivariable analyses can be problematic if the
adjusted variables were not uniform across all studies, as they have different interpretations.
I suggest that the authors specify which variables were included in each of the multivariable
models in a table as well as mention this limitation in the limitations section.
assistant