Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Mazarelli et al. provide a comprehensive overview of systemic therapies for post-transplant HCC recurrence; however, the manuscript could be strengthened by adopting a more structured framework and by incorporating clinical recommendations from the authors, particularly given their recognized expertise in this field. As major comments: 

Treatment selection should be contextualized according to key clinical variables (i.e. tumor burden, graft function, and PS). In addition, combined approaches, including systemic therapy with surgery and/or locoregional treatments, should be deeply discussed.

Authors should discuss clinical scenarios in which lenvatinib might be considered as a first-line alternative to sorafenib.

The lack of a clearly defined review methodology somewhat limits methodological transparency. I recommend adding a brief description of the literature search strategy.

Table 1 is informative but includes data from high-risk patients without documented HCC recurrence. Separate summary tables for tyrosine kinase inhibitors and immune checkpoint inhibitors studies on HCC recurrence should be added to enhance readability.

The ICIs section should be expanded, particularly regarding potential treatment personalization based on PD-1/PD-L1 expression and the role of ICI–TKI combinations.

Finally, the “future perspectives” section remains rather generic, and the inclusion of a clinical algorithm for post-transplant HCC recurrence management would further enhance the manuscript’s clinical relevance.

Author Response

Response to Reviewers
Summary
Thank you very much for taking the time to review this manuscript and for your valuable feedback on my manuscript. We are grateful to the reviewers for their insightful comments on the paper. We have been able to incorporate changes to reflect most of the suggestions provided by the reviewers. Please find the detailed responses below and the corresponding revisions/corrections highlighted in red in the re-submitted files. Moreover, the text was revised by an English teacher to improve readability.   Comments from Reviewer 1 Comment 1: Treatment selection should be contextualized according to key clinical variables (i.e. tumor burden, graft function, and PS). In addition, combined approaches, including systemic therapy with surgery and/or locoregional treatments, should be deeply discussed. Response 1: Thank you for pointing this out. We really appreciate this comments in the paper. Therefore, we have modified the introduction paragraph, adding a part about the relevance of different factors in the treatment choice (page 3, line 61-64, line 76-92). In addition, we have added a new paragraph about the current evidence of combined treatment (systemic + surgery or LR therapy) (page 11, line 541-564)   Comment 2:  Authors should discuss clinical scenarios in which Lenvatinib might be considered as a first-line alternative to sorafenib. Response 2: Thank you for pointing this out. We have, accordingly, modified the text to emphasize this point (page 9, line 313-318).   Comment 3: The lack of a clearly defined review methodology somewhat limits methodological transparency. I recommend adding a brief description of the literature search strategy. Response 3: Thank you for pointing this out. We agree with this comment. Therefore, we have modified the text, adding a new section about the methodological research used (page 4, line 126-135)   Comment 4: Table 1 is informative but includes data from high-risk patients without documented HCC recurrence. Separate summary tables for tyrosine kinase inhibitors and immune checkpoint inhibitors studies on HCC recurrence should be added to enhance readability. Response 4: Agree. We have, accordingly, changed the table, splitting the data in 2 separate tables (page 5, line 162, table 2 about TKIs ongoing trials and page 11, line 538 table 3 about ICIs treatment ongoing trials)   Comment 5: The ICIs section should be expanded, particularly regarding potential treatment personalization based on PD-1/PD-L1 expression and the role of ICI–TKI combinations. Response 5: We agree with this and have incorporated your suggestion in the immunotherapy section. (page 10, line 365-410)   Comment 6: Finally, the “future perspectives” section remains rather generic, and the inclusion of a clinical algorithm for post-transplant HCC recurrence management would further enhance the manuscript’s clinical relevance. Response 6: Thank you for pointing this out. We agree with this comment. Therefore, we have modified the text to empathize the appropriate management (page 14, line 662-672). We have also created an image/table on a possible sequential treatment management in HCC recurrence (page 15, figure 3).

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript is a review article focusing on systemic pharmacological therapies for recurrent hepatocellular carcinoma (HCC) after liver transplantation. Given the remarkable recent advances in systemic therapies for HCC in non–liver transplant settings, and the persistent lack of well-established guidelines for post–liver transplant patients, this review is both timely and clinically meaningful.

Below are several points that I believe could further improve the manuscript.

To ensure the comprehensiveness of the literature review, it would be desirable to include a Materials and Methods section describing the literature search strategy, including the specific keywords used and the number of key studies identified.

Although it is well recognized that most studies on systemic therapy for recurrent HCC after liver transplantation are single-arm, retrospective observational studies, the value of this review would be enhanced by summarizing the efficacy of each agent—such as complete and partial response rates (CR/PR), disease control rate, progression-free survival (PFS), and overall survival (OS)—in a tabulated format. Such a table would greatly facilitate understanding and be far more informative than narrative description alone.

In addition, incorporating a perspective that compares these outcomes with those observed in non-transplant HCC patients would further strengthen the review.

Author Response

Thank you very much for taking the time to review this manuscript and for your valuable feedback on my manuscript. We are grateful to the reviewers for their insightful comments on the paper. We have been able to incorporate changes to reflect most of the suggestions provided by the reviewers. Please find the detailed responses below and the corresponding revisions/corrections highlighted in red in the re-submitted files. Moreover, the text was revised by an English teacher to improve readability.

 

Comments from Reviewer 2

Comment 1: To ensure the comprehensiveness of the literature review, it would be desirable to include a Materials and Methods section describing the literature search strategy, including the specific keywords used and the number of key studies identified

Response 1: Thank you for this comment. We have added a new paragraph about the used methodology (page 4, line 126-135).

 

Comment 2:  Although it is well recognized that most studies on systemic therapy for recurrent HCC after liver transplantation are single-arm, retrospective observational studies, the value of this review would be enhanced by summarizing the efficacy of each agent—such as complete and partial response rates (CR/PR), disease control rate, progression-free survival (PFS), and overall survival (OS)—in a tabulated format. Such a table would greatly facilitate understanding and be far more informative than narrative description alone.

In addition, incorporating a perspective that compares these outcomes with those observed in non-transplant HCC patients would further strengthen the review.

Response 2: Agree. We have, accordingly, created a generic section about the mechanism of action of TKIs and we have also made a new table about the current evidence of OS/PFS of TKIs treatment in transplant and not transplant patients (Page 5, 136-151, Table 1)

Reviewer 3 Report

Comments and Suggestions for Authors

This review is well organized, very easy to read, and provides valuable information for readers. However, the depth of discussion is somewhat insufficient. Please consider the following points.

Major points

1) In the section on regorafenib, the authors conclude with an “In conclusion” paragraph that effectively summarizes the key points. This structure works very well and should also be applied to the sections on sorafenib, cabozantinib, lenvatinib, and other agents.

2) General readers are often interested in differences in treatment efficacy according to histological features and tumor invasion patterns. Although the available literature on this topic is still limited, please address this issue as much as possible based on existing evidence.

3) The overall perspective of the review is somewhat difficult to grasp. Please provide a more integrated overview in the Discussion.

Minor point

4) Abbreviations: The list of abbreviations is incomplete. Many additional abbreviations are used in the text, such as CI, NCT, RET, KIT, REFLECT, and TOR, and these should be included in the list.

Author Response

Thank you very much for taking the time to review this manuscript and for your valuable feedback on my manuscript. We are grateful to the reviewers for their insightful comments on the paper. We have been able to incorporate changes to reflect most of the suggestions provided by the reviewers. Please find the detailed responses below and the corresponding revisions/corrections highlighted in red in the re-submitted files. Moreover, the text was revised by an English teacher to improve readability.

Comments from Reviewer 3

Comment 1: In the section on regorafenib, the authors conclude with an “In conclusion” paragraph that effectively summarizes the key points. This structure works very well and should also be applied to the sections on sorafenib, cabozantinib, lenvatinib, and other agents.

Response 1: We thank the reviewer for this comment. As suggested, a summary sentence has been added at the end of each paragraph to highlight the key points of each agent (page 7, line 226-230; page 8, line 283-286; page 9, line 312-317; page 10, line 406-411)

 

Comment 2:  General readers are often interested in differences in treatment efficacy according to histological features and tumor invasion patterns. Although the available literature on this topic is still limited, please address this issue as much as possible based on existing evidence.

Response 2: Thank you for this suggestion. The current evidence on this topic is very limited. We have 

therefore expanded the text with the published evidence on this topic (page 6, line 201-211; page 9, line 310-311)

 

Comment 3: The overall perspective of the review is somewhat difficult to grasp. Please provide a more integrated overview in the Discussion.

Response 3: We agree with this and have incorporated your suggestion throughout the manuscript.

 

Comment 4: The list of abbreviations is incomplete. Many additional abbreviations are used in the text, such as CI, NCT, RET, KIT, REFLECT, and TOR, and these should be included in the list.

Response 4: Agree. We have modified the section.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have appropriately responded to my comments and significantly improved the manuscript. I am satisfied with the revisions and have no further major concerns.

Reviewer 3 Report

Comments and Suggestions for Authors

I sincerely appreciate the opportunity to review the revised version. This article has been sufficiently revised, and it is acceptable for publication in the present form.