Navigating the Therapeutic Pathway and Optimal First-Line Systemic Therapy for Hepatocellular Carcinoma in the Era of Immune Checkpoint Inhibitors
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsDear Authors
Review article describes well that first-line systemic therapies, particularly ICIs, and sought to facilitate the selection of first-line agents to maximize therapeutic efficacy while avoiding anticipated adverse events.
Strength of the study
1) References are updated in the main text.
2) Figure 1 explains a good way to understand readers.
The combination of atezolizumab and bevacizumab is associated with an improved mOS and mPFS when compared to sorafenib. However, it is crucial to assess the risk of anti-VEGF-related complications, such as gastrointestinal bleeding before treatment. The combination of durvalumab and tremelimumab (the STRIDE regimen) is a viable alternative for patients at high risk of gastrointestinal bleeding, such as those with esophageal varices identified via esophagogastroduodenoscopy (EGD), or those with significant proteinuria.
Limitations of the study
The following steps should provide more clear information for readers to enjoy it
1) Minimize the plagiarism 32% to 20% in the manuscript.
2) Please keep a graphical abstract.
Author Response
Comments 1 : Minimize the plagiarism 32% to 20% in the manuscript.
Response 1 : We sincerely appreciate your careful review. We have thoroughly re-checked the manuscript and extensively revised overlapping or repetitive phrases to ensure that the similarity index has been significantly reduced to meet the recommended threshold.
Comments 2 : Please keep a graphical abstract.
Response 2 : Thank you for this suggestion. A graphical abstract has now been created and included in the revised submission as requested.
Reviewer 2 Report
Comments and Suggestions for AuthorsDear Authors,
Thank you for the opportunity to be able to review your work.
Here are some issues I recommend to be addressed.
- Line 19 and 20: The abbreviations are coming first, and the explanation is in the bracket.
- Please avoid the overuse of capital letters, such as Programmed Death-Ligand 1.
- Why aren't ESMO and NCCN guidelines included in this study?
- I also recommend to delete unnecessary capitals in the references, as well.
- I recommend to include a List of abbreviations in the text.
- Please rephrase this sentence to sound more professional: Therefore, it is important to consider not only the stage of cancer but also the underlying liver function, patient performance status, and history of previous treatments.
- I think the general description of how PD-L1 inhibitors work should be shortened.
- If you use an abbreviation for OS, it would be benefitiary to use one for PFs, as well.
- HCC abbreviation was defined already, then used again in Line 130. Very typical for ChatGpt...
- Line 137: There is an unnecessary '.', even though the sentence does not end, and there is a references before the next sentence ends.
- ICI-Based Regimens as an Alternative to Atezo/Bev - This section is too short. Either expand it, or position it somewhere else.
- Adverse effects are not listed for all medications.
- The Consideration section for Table 1 should include sentences, instead of words.
- Line 235: EASL abbreviation is mentioned yet again.
- Advanced HCC is not defined in the article.
- Line 270: median OS was already abbreviated.
- Figure 1: Please reorganise the abbreviations in the legend into alphabetical order.
- Line 269-271: Why doesn't this sentence have a reference at the end?
Author Response
Comment 1 : Line 19 and 20: The abbreviations are coming first, and the explanation is in the bracket.
Response 1 : Thank you for your comment. We have corrected the formatting so that the full term appears first, followed by the abbreviation.
Comment 2 : Please avoid the overuse of capital letters, such as Programmed Death-Ligand 1.
Response 2 : We appreciate the suggestion. Unnecessary capitalization has been removed for consistency.
Comment 3 : Why aren't ESMO and NCCN guidelines included in this study?
Response 3 : Thank you for your valuable feedback. We have included the ESMO, NCCN, and JSH guidelines in the references and incorporated the relevant content.
Comment 4 : I also recommend to delete unnecessary capitals in the references, as well.
Response 4 : Thank you. Unnecessary capitalization in the reference list has been corrected.
Comment 5 : I recommend to include a List of abbreviations in the text.
Response 5 : We agree with your suggestion. A List of Abbreviations section has been added.
Comment 6 : Please rephrase this sentence to sound more professional: Therefore, it is important to consider not only the stage of cancer but also the underlying liver function, patient performance status, and history of previous treatments.
Response 6 : Thank you for pointing this out. The sentence has been rewritten in a more professional academic tone.
Comment 7 : I think the general description of how PD-L1 inhibitors work should be shortened.
Response 7 : We appreciate the comment. The section has been condensed to improve clarity and focus.
Comment 8 : If you use an abbreviation for OS, it would be benefitiary to use one for PFs, as well.
Response 8 : Thank you. The abbreviation for PFS has been added consistently throughout the text.
Comment 9 : HCC abbreviation was defined already, then used again in Line 130. Very typical for ChatGpt...
Response 9 : Thank you for noting this duplication. The repeated definition has been removed.
Comment 10 : Line 137: There is an unnecessary '.', even though the sentence does not end, and there is a references before the next sentence ends.
Response 10 : Thank you. The typographical error has been corrected.
Comment 11 : ICI-Based Regimens as an Alternative to Atezo/Bev - This section is too short. Either expand it, or position it somewhere else.
Response 11 : We appreciate the suggestion. This section has been moved and expanded with additional content.
Comment 12 : Adverse effects are not listed for all medications.
Response 12 : Thank you for noting this. Adverse effects for all medications have been summarized and added to the table.
Comment 13 : The Consideration section for Table 1 should include sentences, instead of words.
Response 13 : Thank you for your advice. The Consideration section has been rewritten using full sentences.
Comment 14 : Line 235: EASL abbreviation is mentioned yet again.
Response 14 : Thank you. The repeated abbreviation has been removed.
Comment 15 : Advanced HCC is not defined in the article.
Response 15 : We appreciate this important point. The definition of advanced HCC has been added to the Introduction section.
Comment 16 : Line 270: median OS was already abbreviated.
Response 16 : Thank you for catching this. The duplication has been corrected.
Comment 17 : Figure 1: Please reorganise the abbreviations in the legend into alphabetical order.
Response 17 : Thank you for your helpful suggestion. The abbreviations in the figure legend have been reordered alphabetically.
Comment 18 : Line 269-271: Why doesn't this sentence have a reference at the end?
Response 18 : Thank you. A suitable reference has been added to support the statement.
Reviewer 3 Report
Comments and Suggestions for AuthorsThis review article aims to summarize the considerations for selecting systemic therapy for HCC. The topic is relevant, but the article in its current form has several limitations and is not up to date in terms of literature coverage. It does not encompass other relevant major international clinical practice guidelines as well as the effect of systemic therapy in the context of emerging strategies for HCC. Please address all the comments below.
Given the title, there is a severe lack of discussion on immune checkpoint inhibitors (ICI). There should be a separate section on the biology of HCC and how immune checkpoint processes relate to ICI and systemic therapy.
Instead of squeezing all forms of systemic therapy within the introduction. There should also be a separate section detailing all forms of systemic therapy. There should be a table or figure outlining the definitions, descriptions, mechanisms, advantages, and disadvantages of each.
It is unclear what the considerations are and how they are weighed. There should be a separate subsection focusing on and elaborating on each consideration instead of discussing the treatment options right away.
Important safety considerations that must be elaborated further include gastrointestinal bleeding risk and controversy regarding CHild-Pugh B patients.
The article is limited to AASLD and EASL and fails to reference other relevant major international clinical practice guidelines, such as NCCN, ESMO, and JSH. Add references: NCCN Guideline Version 1.2025 for Hepatocellular Carcinoma, DOI: 10.1016/j.annonc.2025.02.006
There is a broad consensus among major guidelines regarding the preferred first-line therapies, but subtle differences exist regarding alternative options and specific patient selection. A key divergence has emerged in 2025 where nivolumab + ipilimumab has been added. Tislelizumab is also recommended by ESMO 2025 and NCCN 2025 as a first-line option if immune checkpoint ICI are desired but combinations are contraindicated.
The manuscript strictly categorizes patients into "resectable" (early stage) vs. "systemic therapy" (advanced stage). This is an outdated binary view. Guidelines acknowledge that patients with unresectable disease who respond to systemic therapy may become candidates for resection or transplantation.
Portal vein embolization (PVE) and portal vein embolization with stem cell augmentation (PVESA) can overcome an insufficient future liver remnant in the context of hepatectomy. PVE and PVESA can act as a bridge that allows patients who are initially considered unresectable due to a small FLR to become candidates for a curative surgical intervention. PVE can be part of a multimodal strategy. For instance, a patient could undergo systemic therapy to control tumor growth, followed by PVE to prepare for resection, and then finally the hepatectomy itself. Add references: https://doi.org/10.1007/s12015-024-10719-1
In the context of resection, AASLD's Critical Update and EASL 2025 now explicitly recommend against the use of adjuvant Atezolizumab + Bevacizumab.
Author Response
Comment 1 : Given the title, there is a severe lack of discussion on immune checkpoint inhibitors (ICI). There should be a separate section on the biology of HCC and how immune checkpoint processes relate to ICI and systemic therapy.
Response 1 : Thank you for this insightful comment. As suggested, we created a separate section dedicated to the immunobiology of HCC and the mechanistic relevance of immune checkpoint pathways. This new section has been placed immediately after the Introduction and before the “Selecting Optimal First-Line Agents” section to improve the logical flow of the manuscript. We sincerely appreciate your guidance on strengthening the structure.
Comment 2 : Instead of squeezing all forms of systemic therapy within the introduction. There should also be a separate section detailing all forms of systemic therapy. There should be a table or figure outlining the definitions, descriptions, mechanisms, advantages, and disadvantages of each.
Response 2 : Thank you for your valuable suggestion. The section previously titled “Selecting Optimal First-Line Agents” has been renamed and reorganized into a stand-alone section on systemic therapy, “Overview” section. We have also developed a comprehensive table that includes definitions, descriptions, mechanisms of action, advantages, and disadvantages for all major first-line systemic therapies. This restructuring greatly enhances clarity, and we appreciate your thoughtful recommendation.
Comment 3 : It is unclear what the considerations are and how they are weighed. There should be a separate subsection focusing on and elaborating on each consideration instead of discussing the treatment options right away.
Response 3 : We will create a separate section. Following your suggestion will make it more comprehensible. Thank you for your valuable input.
Comment 4 : Important safety considerations that must be elaborated further include gastrointestinal bleeding risk and controversy regarding CHild-Pugh B patients.
Response 4 : We previously mentioned the risk of variceal bleeding in the Atezolizumab/Bevacizumab section. Although there is a lack of studies including many Child-Pugh B patients, various studies, including meta-analyses, confirm your point that the risk is particularly high in patients with liver function like Child-Pugh B. We have elaborated on this in Atezolizumab/Bevacizumab (Atezo/Bev) section and added references. Thank you for your valuable insight!
Comment 5 : The article is limited to AASLD and EASL and fails to reference other relevant major international clinical practice guidelines, such as NCCN, ESMO, and JSH. Add references: NCCN Guideline Version 1.2025 for Hepatocellular Carcinoma, DOI: 10.1016/j.annonc.2025.02.006
There is a broad consensus among major guidelines regarding the preferred first-line therapies, but subtle differences exist regarding alternative options and specific patient selection. A key divergence has emerged in 2025 where nivolumab + ipilimumab has been added. Tislelizumab is also recommended by ESMO 2025 and NCCN 2025 as a first-line option if immune checkpoint ICI are desired but combinations are contraindicated.
Response 5 : You're absolutely right that nivolumab + ipilimumab and Tislelizumab are excellent options. Although nivolumab + ipilimumab and Tislelizumab are included as 1st line systemic therapy in the ESMO guideline, our focus was on a review based on all guidelines and well-experienced drugs, which led to their initial exclusion. However, following your valuable feedback, we have added nivolumab + ipilimumab and Tislelizumab to the figure and graphic abstract and briefly described in the Overview of First-Line Systemic Therapies for HCC section. Thank you for your insight.
Comment 6 : The manuscript strictly categorizes patients into "resectable" (early stage) vs. "systemic therapy" (advanced stage). This is an outdated binary view. Guidelines acknowledge that patients with unresectable disease who respond to systemic therapy may become candidates for resection or transplantation.
Portal vein embolization (PVE) and portal vein embolization with stem cell augmentation (PVESA) can overcome an insufficient future liver remnant in the context of hepatectomy. PVE and PVESA can act as a bridge that allows patients who are initially considered unresectable due to a small FLR to become candidates for a curative surgical intervention. PVE can be part of a multimodal strategy. For instance, a patient could undergo systemic therapy to control tumor growth, followed by PVE to prepare for resection, and then finally the hepatectomy itself. Add references: https://doi.org/10.1007/s12015-024-10719-1 .
In the context of resection, AASLD's Critical Update and EASL 2025 now explicitly recommend against the use of adjuvant Atezolizumab + Bevacizumab.
Response 6 : Thank you for your insightful comments; you're absolutely right. Our focus was primarily on systemic therapy rather than indications. It's possible to consider resection or transplantation following other treatments, and we've created a graphic abstract to include your suggestions. We've also added your point about the AASLD and EASL guidelines explicitly recommending against the adjuvant use of Atezolizumab + Bevacizumab in the context of resection. Thank you for your valuable input.
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsDear Authors,
Thank you for carrying out the required modifications.
Reviewer 3 Report
Comments and Suggestions for AuthorsAll issues have been addressed. For formatting purposes, double-check whether the "conclusions" section can be moved to the end.
