Review for 10.1186/s12876-023-02731-5 (2023)

Title: Hyperprogressive disease during atezolizumab plus bevacizumab treatment in patients
with advanced hepatocellular carcinoma from Japanese real-world practice
Version: 3 Date: 13 Nov 2022
Reviewer's report:
The paper by Yumita et al., aims at reporting the incidence of hyper-progression in patient treated
with atezolizumab plus bevacizumab for advanced HCC. The topic is interesting and some useful
information emerge from the paper. However I have some concerns about the high risk of bias
related to the retrospective nature of the radiological assessment and to the heterogeneity of the
cohort, furthermore the short follow up does not allow to derive definitive conclusions. I would
suggest the following major revisions and some additional analyses, prior to consider the paper
for publication:
• Title: Reporting a causative correlation between HPD and Atez/Bev is not supported by the
paper which aims at describing the incidence of HPD in patients treated with Atez/Bev but does
not show any causality: I would suggest to rephrase.
• Introduction: The introduction is clear and comprehensive, I would however suggest to report
what is known about the biological factors that could drive HPD in HCC.
Please see below for some minor revisions:
-Please correct the spelling of PD-1 as “programmed cell death” instead of “progressive
disease” (line 114).
-I would suggest to amend 2010s with 2020 (line 117).
-I would suggest to use the generic term “cancers” instead of “carcinomas” which is usually
referred only to epithelial tumours (line 124).
-Please provide more details about the incidence of HPD in patients receiving Atez/Bev
(“Another report from Japan initially demonstrated the occurrence rate of HPD in patients with
advanced HCC who were treated Atez/Bev in either the front or later lines”).
-I would suggest language editing for the following sentences that are not fully understandable:
“Very recently, HPD in patients with advanced HCC who received ICI is gradually clarified.”
“Kim GG et al. reported the incidence of HPD in patients with advanced HCC treated with
nivolumab monotherapy was 12.7%”. “Another report from Japan initially demonstrated the
occurrence rate of HPD in patients with advanced HCC who were treated Atez/Bev in either
the front or later lines”.
• Methods: The methods are clear, however I have some concerns about the presence of bias
related to the evaluation of response in retrospective studies. I would suggest clarifying the
following points:
-The authors report that all the patients received the scan at 12 weeks after treatment start, and
that scans were evaluated according to RECIST v1.1 criteria. Was there a central review of the
images or was it done locally in each centre? Was a review of the imaging done for the study
or were the reports retrieved retrospectively?
-Authors stated to have retrospectively included only patients having had “appropriate
radiological assessment” excluding therefore also those deteriorating or dying before reaching
the “experimental” scan timepoint. This is a common source of selection bias in retrospective
studies, I would suggest to acknowledge this, and to perform a landmark survival analysis at 12
weeks to compare OS according to progression (Figure 4).
-Please use the term “sex” instead of “gender” when referring to the biological gender.
-Which test was used to compare continuous variables? (Chi squared test applies only for
categorial ones).
-How was the median follow-up length estimated?
-Authors state to have performed Univariate and multivariate logistic regression analyses were
performed to identify predictive factors associated with HPD, however it is not consistent with
the results where results of Cox regression analyses for prognostic factors associated with OS
are reported (Supplementary tables).
• Results:
-The objective response rate reported by the authors is far below that reported in the IMbrave150
and in other real-life studies, where it is around 27-30% compared to 5.9% (1.2% CR+ 4.7%
PR), is there an explanation for this huge difference?
-If median OS cannot be estimated due to short FUP, I would suggest to provide the overall
survival rate, I would also advise to show the KM curves for both OS and PFS in the whole
cohort.
-Please provide median OS for each arm in figure 4.
-How was median OS compared between HPD yes, no and no PD? (was it a log-rank test? Please
specify).
-How was the cut-off for NLR chosen?
-Which treatment did patients receiving Atez/Bev as second line have at first line?
-Is there any information about subsequent lines after Atez/Bev?