Review for 10.1186/s12876-022-02210-3 (2022)

Title: Comparison of the outcomes between sorafenib and lenvatinib as the first-line systemic
treatment for HBV-associated hepatocellular carcinoma: a propensity score matching analysis
Version: 5 Date: 03 Feb 2022
Reviewer's report:
The authors did a lot of effort to revise their article which makes this study more scientific.
Several points I raised for the authors.
Major questions:
1. It is not appropriate to use “Subsequent HCC treatment” as a factor to do the logistic regression
analysis. It may lead to immortal time bias (page 12, line 3). Please remove this factor and the
discussion section (Page 18, line 18) accordingly. But to include the variable “previous HCC
treatment” is fine for analysis.
2. The authors should use “prognostic factor” to describe the variables for OS in logistic
regression analysis, rather than “predictors” (page 12, line 2). But predictors for PFS is fine.
3. For the discussion about comparable OS between two groups, authors have already mentioned
the point that in page 18, line 16 “patients with post-lenvatinib or post-sorafenib treatment
had significantly longer OS than those who did not receive subsequent anti-HCC treatment
after lenvatinib or sorafenib.”. Therefore, the analysis of supplemental figure 1 is redundant
in page 14, line 10 “Although the lenvatinib and sorafenib groups showed similar OS, the
subset of patients who received subsequent treatment after sorafenib had longer OS than all the
patients treated with lenvatinib (12.4 vs 7.0 months, p = 0.001; Supplementary Figure 1).” Please
consider removed this figure. Supplemental figure 2 is enough.
4. I doubt that subsequent treatment will affect the PFS between two groups. It is not reasonable.
I believe that they have explained the reason why sorafenib group has comparable OS with
lenvatinib group, so the discussion in page 17, section 2 is ambiguous. Please consider remove
this section.
Minor questions:
1. The response of ORR by mRECIST is relatively low in lenvatinib. Please make sure they used
mRECIST, but not RECIST 1.1. Refer to page 13, line 11 “Therefore, lenvatinib had a better
ORR (18.2% vs 4.5%, p = 0.02) and DCR (77.3% vs 47.7%, p = 0.001) than sorafenib.”
2. It is not appropriate to compare the role of the frontline and subsequent line treatment. So,
please avoid statements like page 18, line 9” This finding might be due to the subsequent
anti-HCC treatment rather than the first-line medication.”, and page 19, line 20 “Therefore,
subsequent treatment is just as important as the efficacy of the first-line drug.”, and conclusion
section “These results suggest that subsequent treatment could be as important as the first-line
medication itself in prolonging OS for HBV-related HCC patients.”
3. It is redundant for their conclusion section. They have a nice finding about the impact of
subsequent treatment on survival. Please condense the statement in page 22, line 3 “When
divided into subgroups with and without subsequent treatment, subsequent treatment prolonged
OS regardless of the first-line medication. These results suggest that subsequent treatment could
be as important as the first-line medication itself in prolonging OS for HBV-related HCC
patients.”.