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: 16 Sep 2022
Reviewer's report:
The present study is an analysis of 85 HCC patients treated in six Japanese centers
with the combination of Atezolizumab and Bevacizumab (Atez/Bev). The prevalence of
hyperprogressive disease (HPD) under this treatment was evaluated, defined as a faster tumor
growth rate under the treatment compared to the time period before. Depending on the definition,
HPD prevalence in the analysed cohort was 9.4% or 5.9%, respectively. Furthermore, no
difference of baseline characteristics or OS between patients with and without HPD was
detected.
There are several issues that need to be addressed before considering the publication of this
manuscript.
Major issues:
- The authors mention that they excluded patients with pseudoprogression from the analysis.
Pseudoprogression is a well-known phenomenon in HCC patients treated with immunotherapy
and can have a (seemingly) rapid tumor growth rate. It seems reasonable that all patients
that were excluded for this reason did, in fact, have pseudoprogression. However, it remains
unclear if the assessment of the other patients was sufficient (follow-up long enough, sufficient
number of imaging scans) to rule out pseudoprogression. Otherwise, some patients with
pseudoprogression might have been (mis)declared as patients with progressive disease or even
HPD. Please comment on this matter.
- Some patients did not receive Atez/Bev as first line treatment. However, the authors do not
mention what treatment those patients received before and what the reason for discontinuation
of the previous treatment was (progression vs. toxicity). Most importantly, authors should
clarify if the imaging before baseline ("reference scan") was done while the patients were on
another treatment and if not, which time period was between the discontinuation of the previous
treatment and the "reference scan". If the time period between the treatments was short, another
(effective) treatment might have slowed down the tumor progression in the "reference period",
hence distorting the difference of tumor growth between "reference period" and "experimental
period".
- Although it might have been sufficient for assessment of the prevalence of HPD, the authors
should discuss if the observation period (median 6.2 months) was too short or the number of
patients with HPD (8 or 5 patients with HPD, respectively) was too low for a meaningful OS
analysis.
- Further known risk factors for progression under immunotherapy (such as CRP or the
CRAFITY score) should be included in the analyses.
Minor issues:
- (Anti-)PD-1 antibody does not mean (Anti-)"progressive disease" antibody. Please correct the
sentence in the introduction.
- Number at risk arrays should be included in the Kaplan-Meier curves.
- The authors should explain how the variables were selected for multivariable OS analysis.
- It would be interesting to know if the patients with HPD had any change in their characteristics
(such as liver function or performance status) over time.