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Review
Peer-Review Record

Drug Treatment for Advanced Hepatocellular Carcinoma: First-Line and Beyond

Curr. Oncol. 2022, 29(8), 5489-5507; https://doi.org/10.3390/curroncol29080434
Reviewer 1: Akshay Pandey
Reviewer 2: Héloïse Bourien
Curr. Oncol. 2022, 29(8), 5489-5507; https://doi.org/10.3390/curroncol29080434
Received: 13 June 2022 / Revised: 29 July 2022 / Accepted: 2 August 2022 / Published: 4 August 2022
(This article belongs to the Special Issue New Insights of Liver Cancer and Its Treatment)

Round 1

Reviewer 1 Report

The authors present a review summarizing the evolution of therapeutic modalities for hepatocellular carcinoma. They describe how multikinase inhibitors were first choice followed by a combinatorial therapeutic modalitie with ICIs.

The authors , however, do not review/ discuss in detail the cases where relapse of HCC occurs. They do briefly talk about the counterintuitive effects of combinatorial therapy but do not expand much on this. More information should be provided on how and why the cancer stem cells, EMT and signaling pathways contribute to drug resistance and whether they are connected with increasing toxicity in the combinatorial therapies.

 

good luck!

 

Author Response

Reviewer 1

 

Reviewer comment

The authors, however, do not review/ discuss in detail the cases where relapse of HCC occurs. They do briefly talk about the counterintuitive effects of combinatorial therapy but do not expand much on this. More information should be provided on how and why the cancer stem cells, EMT and signaling pathways contribute to drug resistance and whether they are connected with increasing toxicity in the combinatorial therapies.

Author Response

Thank you for this suggestion.

 

We have not included the management of relapsed HCC because this is outside the scope of this article which focuses on advanced HCC. In general, HCC that relapses from previous treatment follows similar pathway as de novo HCC in which locoregional treatments are considered first if feasible. If that is not feasible, systemic therapy will be used as we described in this article.

 

Regarding the patient selection on starting combination therapy versus single agent therapy, in clinical practice, if patients are very fit, such as with performance status 0 to 1, with no significant medical comorbidities, we will start them with combination therapy. For the initiation of atezolizumab-bevacizumab, a pre-treatment OGD is required to treat any unbanded varices as the dose used for bevacizumab is quite high with increased bleeding risk. These are clarified in the discussion session (Line 413-420).

 

Further to that we have added a paragraph to provide supporting evidence of drug resistance secondary to the presence of cancer stem cells and EMT (Line 452-460).

 

Reviewer 2 Report

 

 This review of systemic treatment in HCC offers to the reader a synthesis to the main trials which led to practice changing.

Authors had to clarify some points.

The title focus on advanced HCC whereas authors discuss adjuvant treatment.

 

First-line systemic therapy:

 

Table 1: Authors could highlight which trial was statistically significant or not, and add the year of drugs’ approval.

As the authors separate paragraph for 1st and second lines, it could be clearer to separate in two tables, one for treatment in 1st line and the other for treatment in 2nd line.

The authors had to separate the last paragraph beginning line 181 from the paragraph “Atezolizumab and Cabozantinib”, this is the conclusion of the first part.

 

Line 86: The authors had to explain “less fit patients”. Sorafenib and Lenvatinib could not be recommended for patients Child B.

 

Line 193-194: The authors could explain which trial supported their adaptation of dose schedule? It could not be recommended in 1st intention. Authors has to specify that it is practice suggestions and not international recommendations.

 

Authors could add a conclusion to this part, to summarize for which patients which systemic therapy was recommended, and which option could be proposed in case of contraindication. A figure could resume this part.

 

Second-line systemic therapy:

Same remarks than for paragraph for 1st line of systemic therapies, authors had to conclude, in order to help clinician in clinical practice.

 

Ongoing trials:

This paragraph was difficult to understand and follow, Table 2 could not be the 1st element of this paragraph; authors had to organize their ideas:

-       Adjuvant setting
If the authors decided to discuss trial in adjuvant setting, they had to describe failures of adjuvant trial with TKI. A paragraph had to be added in 1st part of the review.

-       Unresectable HCC :

o   Association ICI / TKI

o   Association ICI / locoregional treatment. The authors were not exhaustive in locoregional treatment, there is no description of trials including hepatic arterial infusion chemotherapy, radiotherapy or radio-embolization.

Discussion

Authors had to underline that observations on non-viral HCC patients were done retrospectively, with no stratification factors decided at the moment of the analysis. This cannot lead to modify clinical practice for patients with HCC depending of etiology of their HCC.

Line 459: could the authors quickly develop the rationale of studying the modification of microbiote for HCC patients treated with ICI.

 

Table 2: trials in adjuvant and neoadjuvant setting were not included, if authors chose to discuss about adjuvant setting, they had to add it on table 2.

There are much more studies ongoing in HCC, could the authors explain their criteria of selection?

Author Response

Reviewer 2

 

Ref. 2.1. Regarding the theme of the review

Reviewer comment

The title focuses on advanced HCC whereas authors discuss adjuvant treatment.

Author Response

Thank you for raising this concern. The review focuses on advanced HCC, thus the adjuvant and locoregional treatment parts were deleted in “ongoing trials” to make the whole context consistent with the topic.

 

Ref. 2.2 Regarding the Table 1 revision

Reviewer comment

First-line systemic therapy:

Table 1: Authors could highlight which trial was statistically significant or not, and add the year of drugs’ approval.

Author Response

Thank you for the suggestion. Year of drugs’ approval was added, and for those trials without statistical significance, “no statistical significance” was indicated in OS/PFS/year of approval column.

 

Ref. 2.3 Separating two Tables for different lines of treatment

Reviewer comment

As the authors separate paragraph for 1st and second lines, it could be clearer to separate in two tables, one for treatment in 1st line and the other for treatment in 2nd line.

Author Response

Thank you for the suggestion. Table 1 was separated into two tables: Table 1 for first-line and Table 2 for second-line systemic treatment.

 

Ref. 2.4 Reconstructing the paragraphs

Reviewer comment

The authors had to separate the last paragraph beginning line 181 from the paragraph “Atezolizumab and Cabozantinib”, this is the conclusion of the first part.

Author Response

Thank you for the suggestion. The paragraph beginning line 181 was separated from “Atezolizumab-cabozantinib” part. The summary in first-line systemic therapy was updated (Line 200-216).

 

Ref. 2.5 Elaborating with details regarding “less fit patients”

Reviewer comment

Line 186: The authors had to explain “less fit patients”. Sorafenib and Lenvatinib could not be recommended for patients Child B.

Author Response

Thank you for the suggestion. Line 186 “less fit patients” was modified and more information was added (Line 206-210).

 

Ref. 2.6 Elaborating with details regarding adaptation of dose schedule of sorafenib

Reviewer comment

Line 193-194: The authors could explain which trial supported their adaptation of dose schedule? It could not be recommended in 1st intention. Authors has to specify that it is practice suggestions and not international recommendations.

Author Response

Thank you for pointing out this issue. We agree that it is a practice suggestion and not an international recommendation. We have deleted the recommendation of dose schedule for sorafenib.

 

Ref. 2.7 Addition of a summary with a figure in “First-line systemic therapies” part

Reviewer comment

Authors could add a conclusion to this part, to summarize for which patients which systemic therapy was recommended, and which option could be proposed in case of contraindication. A figure could resume this part.

Author Response

Thank you for the recommendation. An updated summary with a figure were added in “first-line systemic therapies” part to summarize our recommended sequence of treatment (Line 200-216).

 

Ref. 2.8 Addition of a summary with a figure in “Second-line systemic therapies” part

Reviewer comment

Second-line systemic therapy:

Same remarks than for paragraph for 1st line of systemic therapies, authors had to conclude, in order to help clinician in clinical practice.

Author Response

Thank you for the recommendation. Conclusion and a figure were added in “second-line systemic therapies” part to summarize our recommended sequence of treatment (Line 345-357).

 

Ref. 2.9 Clarifying the contents covered in “Ongoing trials”

Reviewer comment

Ongoing trials:

This paragraph was difficult to understand and follow, Table 2 could not be the 1st element of this paragraph; authors had to organize their ideas:

-       Adjuvant setting

If the authors decided to discuss trial in adjuvant setting, they had to describe failures of adjuvant trial with TKI. A paragraph had to be added in 1st part of the review.

-       Unresectable HCC:

o   Association ICI / TKI

o   Association ICI / locoregional treatment. The authors were not exhaustive in locoregional treatment, there is no description of trials including hepatic arterial infusion chemotherapy, radiotherapy or radio-embolization.

Author Response

Thank you for your insightful comment. “Ongoing trials” was narrowed down to “ongoing trials in combination systemic treatment”, thus adjuvant and locoregional treatment parts were deleted in “ongoing trials” to make the whole context consistent with the topic. Adjuvant and locoregional treatment will not be discussed.

 

Ref. 2.10 Underlining limitations on observational studies of non-viral HCC

Reviewer comment

Discussion

Authors had to underline those observations on non-viral HCC patients were done retrospectively, with no stratification factors decided at the moment of the analysis. This cannot lead to modify clinical practice for patients with HCC depending of etiology of their HCC.

Author Response

Thank you for making this point. We agree the inferior outcomes observed for non-viral HCC patients receiving immunotherapy were performed retrospectively. Therefore, this cannot lead to change of clinical practice for patients with HCC based on the etiology of HCC. We have added this concern in the “Discussion” part (Line 443-447).

 

Ref. 2.11 Elaborating with details regarding the relationship between microbiota and HCC patients treated with ICI

Reviewer comment

Line 459: could the authors quickly develop the rationale of studying the modification of microbiote for HCC patients treated with ICI.

Author Response

Thank you for your suggestion. The rationale of studying the microbiota for HCC patients treated with ICI was elaborated in the “Discussion” part (Line 476-482).

 

Ref. 2.12 Elaborating the selection criteria of ongoing trials included in Table 2

Reviewer comment

Table 2: trials in adjuvant and neoadjuvant setting were not included, if authors chose to discuss about adjuvant setting, they had to add it on table 2.

There are much more studies ongoing in HCC, could the authors explain their criteria of selection?

Author Response

Thank you for your insightful comment. “Ongoing trials” was narrowed down to “ongoing trials in combination systemic treatment”, this part mainly discussed some key clinical trials in combination systemic treatment. Adjuvant and locoregional treatment will not be discussed. Table 3 was modified accordingly.

 

Round 2

Reviewer 2 Report

None

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