Identification of CT Values That Could Be Predictive of Necrosis (N-CTav) in Hepatocellular Carcinoma after Lenvatinib Treatment

Round 1

Reviewer 1 Report

Dear Editor, thank you so much for inviting me to revise this manuscript about HCC.

This study addresses a current topic.

The manuscript is quite well written and organized. English could be improved.

Figures and tables are comprehensive and clear.

The introduction explains in a clear and coherent manner the background of this study.

We suggest the following modifications:

• Introduction section: although the authors correctly included important papers in this setting, we believe some studies regarding lenvatinib and novel agents in HCC should be cited within the introduction (PMID: 34167433; PMID: 33549983), only for a matter of consistency. We think it might be useful to introduce the topic of this interesting study.
• Methods and Statistical Analysis: nothing to add.
• Discussion section: Very interesting and timely discussion. Of note, the authors should expand the Discussion section, including a more personal perspective to reflect on. For example, they could answer the following questions – in order to facilitate the understanding of this complex topic to readers: what potential does this study hold? What are the knowledge gaps and how do researchers tackle them? How do you see this area unfolding in the next 5 years? We think it would be extremely interesting for the readers.

However, we think the authors should be acknowledged for their work. In fact, they correctly addressed an important topic, the methods sound good and their discussion is well balanced.

One additional little flaw: the authors could better explain the limitations of their work, in the last part of the Discussion.

We believe this article is suitable for publication in the journal although some revisions are needed. The main strengths of this paper are that it addresses an interesting and very timely question and provides a clear answer, with some limitations.

We suggest a linguistic revision and the addition of some references for a matter of consistency. Moreover, the authors should better clarify some points.

Author Response

We are grateful to the reviewers for the critical comments and useful suggestions that have helped us to improve our paper. As indicated in the responses that follow, we have taken all these comments and suggestions into account in the revised version of our paper.

Additionally, I would like to make the following correction to the previously erroneously mentioned CT value (CTv) (Line 268).

“The CTv corresponding to “necrotic areas” in the resected specimen was 27.0 ± 8.0 HU, ”

 

 

Reviewer 1

 

1. Introduction section: although the authors correctly included important papers in this setting, we believe some studies regarding lenvatinib and novel agents in HCC should be cited within the introduction (PMID: 34167433; PMID: 33549983), only for a matter of consistency. We think it might be useful to introduce the topic of this interesting study.

 

Response

As suggested by the reviewer, we have cited the following two references (PMID: 34167433; PMID: 33549983) in the introduction and added them to the list of references (Lines 486-490).

8. Rizzo, A.; Dadduzio, V.; Ricci AD, Massari, F.; Di Federico, A.; Gadaleta-Caldarola, G.; Brandi, G. Lenvatinib plus pembrolizumab: the next frontier for the treatment of hepatocellular carcinoma? Expert Opin Investig Drugs. 2022, 31:371-378. doi: 10.1080/13543784.2021.1948532.
9. Rizzo, A.; Brandi, G. Biochemical predictors of response to immune checkpoint inhibitors in unresectable hepatocellular carcinoma. Cancer Treat Res Commun. 2021; 27:100328. doi: 10.1016/j.ctarc.2021.100328.

 

2. Discussion section: Very interesting and timely discussion. Of note, the authors should expand the Discussion section, including a more personal perspective to reflect on. For example, they could answer the following questions – to facilitate the understanding of this complex topic to readers:

• What potential does this study hold?

 

Response

It is currently unknown whether lesions rated as achieving a CR by mRECIST criteria for tumor blood flow are necrotic or degenerated tumors. This study's results might help to objectively differentiate whether HCC tumors have undergone necrosis after MTA treatment, and might eventually lead to the development of criteria for follow-up of CR lesions after MTA therapy.

As suggested by the reviewer, we have added the following sentences (Lines 411-415) in the revised manuscript:

“The results of this study might enable objective differentiation of whether the HCC tumors have undergone necrosis in response to MTA treatment, and might eventually lead to the development of criteria for the follow-up of CR lesions after MTA therapy.”

 

• What are the knowledge gaps and how do researchers tackle them?

 

Response

Even in cases evaluated as CR by mRECIST, there is a large discrepancy between necrosis and degeneration in terms of the subsequent course of the disease.

As suggested by the reviewer, we have added the following sentences in the revised manuscript (Lines 376-379, Lines 414-416).

“Even in cases evaluated as CR by mRECIST, there is a large discrepancy between necrosis and degeneration in terms of the subsequent course of the disease.”

“At this time, we believe it is important for clinicians to follow up on patients after MTA treatment, as shown by the results of this study.”

 

• How do you see this area unfolding in the next 5 years? We think it would be extremely interesting for the readers.

 

Response

Various molecular targeted therapies have been introduced for the treatment of HCC, and several more will probably be clinically available in the future.

Going forward, lesions that present CR by mRECIST might be validated on a drug-by-drug basis to see if the results are similar to the present results.

As suggested by the reviewer, we have added the following sentences (Lines 419-426) in the revised manuscript:

“Another limitation is whether the results can be applied to MTA treatment other than lenvatinib. CT values of necrosis in lesions that were assessed as CR due to molecular targeted therapies other than lenvatinib were not investigated in this study. However, since we demonstrated that CT values of 30 HU are suggestive of necrosis in surgical cases, which is the same as that with lenvatinib, it is possible that CT values for other drugs might be similar. In future, it would be desirable to validate N-CTv values in CR lesions by mRECIST following other molecular targeted therapies.”

 

3. One additional little flaw: the authors could better explain the limitations of their work, in the last part of the Discussion.

 

Response

As suggested by the reviewer, we have added the text mentioned in our response to comment 3 in the limitations section.

Author Response File: Author Response.docx

Reviewer 2 Report

The authors present the outcomes from a multicenter retrospective study with the objective of identifying CTav that can be used to identify necrosis in uHCC tumors after lenvatinib treatment (N-CTav), and to clarify the association between the tumor N-CTav occupancy rate and maintenance of CR following lenvatinib treatment. The authors analyzed data for 30 tumors in 12 patients. Based on their outcomes they concluded that the N30-CTav determined in this study might be an appropriate cut-413 off value to identify necrosis in HCC after MTA treatment, and the N30-CTav occupancy rate of 30.6% might be a predictive of maintenance of complete response.

This is a very interesting study with significant clinical weight. It is well written in terms of language and clarity while figures are quite illustrative. The authors adequatelly discuss their outcomes in the context of the published literature. A number of issues which however should be addressed by the authors:

• I believe the methods section needs to be revised; Table 1 with patient characteristics should be moved to the results section. Avoid starting a section with a figure without having cited it yet.
• Start your discussion by summarizing the outcomes of your study.
• The limitations section is rather poor and should be expanded.
• Since the authors included only patients who were administered Lenvatinib specifically do they find it is correct to the generalize outcomes to other regimens? since the refer to MTA in general?
• Equally this needs to be added to the limitations section; other regimens might have different cutoff values
• The title is far too long and possibly confusing with regards to the 2nd part (the Association between the N-4 CTav Occupancy Rate in the Tumor and Maintenance of Com-5 plete Response with Lenvatinib Treatment)

Author Response

We are grateful to the reviewers for the critical comments and useful suggestions that have helped us to improve our paper. As indicated in the responses that follow, we have taken all these comments and suggestions into account in the revised version of our paper.

Additionally, I would like to make the following correction to the previously erroneously mentioned CT value (CTv) (Line 268).

“The CTv corresponding to “necrotic areas” in the resected specimen was 27.0 ± 8.0 HU, ”

 

Reviewer 2

1. I believe the methods section needs to be revised; Table 1 with patient characteristics should be moved to the results section. Avoid starting a section with a figure without having cited it yet.

 

Response

As suggested by the reviewer, we moved the patient background description and Table 1 to the Results section.

 

2. Start your discussion by summarizing the outcomes of your study.

 

Response

As suggested by the reviewer, we have started the discussion by summarizing the outcomes of our study in the following sentences (Lines 360-365).

“In this study, we determined a CTav of less than 30.2 HU as the threshold value that might be indicative (N30-CTav) of pathological necrosis in HCC tumors after lenvatinib treatment. Moreover, tumors in which more than 30.6% of the maximum tumor area was occupied by CTav of N30-CTav after lenvatinib treatment showed a low rate of local recurrence. These results are novel and could provide important scientific information for the practice of MTA for HCC.”

 

3. The limitations section is rather poor and should be expanded.

 

Response

As suggested by the reviewer, we have added the description of the response to comment 4 below in the limitations section (Lines 419-426).

 

4. Since the authors included only patients who were administered Lenvatinib specifically do they find it is correct to the generalize outcomes to other regimens? since the refer to MTA in general? Equally, this needs to be added to the limitations section; other regimens might have different cutoff values

 

Response

As suggested by the reviewer, we have added the following sentences in the revised manuscript (Lines 419-426).

“Another limitation is whether the results can be applied to MTA treatment other than lenvatinib. CT values of necrosis in lesions that were assessed as CR due to molecular targeted therapies other than lenvatinib were not investigated in this study. However, since we demonstrated that CT values of 30 HU are suggestive of necrosis in surgical cases, which is the same as that with lenvatinib, it is possible that CT values for other drugs might be similar. In future, it would be desirable to validate N-CTv values in CR lesions by mRECIST following other molecular targeted therapies.”

 

5. The title is far too long and possibly confusing with regards to the 2nd part (the Association between the N-4 CTav Occupancy Rate in the Tumor and Maintenance of Com-5 plete Response with Lenvatinib Treatment)

 

Response

As suggested by the reviewer, we have shortened the title to:

Identification of CT Values that Could Be Predictive of Necrosis (N-CTav) in Hepatocellular Carcinoma after Lenvatinib Treatment.

 

 

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

The authors modified the manuscript according to our suggestions.

We recommend Acceptance.

Reviewer 2 Report

The authors have adequately addressed my remarks.