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Article
Peer-Review Record

Outcomes of Geriatric Patients with Hepatocellular Carcinoma

Curr. Oncol. 2022, 29(6), 4332-4341; https://doi.org/10.3390/curroncol29060346
Reviewer 1: Ashish Manne
Reviewer 2: Giovanni Brandi
Curr. Oncol. 2022, 29(6), 4332-4341; https://doi.org/10.3390/curroncol29060346
Received: 7 May 2022 / Revised: 12 June 2022 / Accepted: 14 June 2022 / Published: 16 June 2022

Round 1

Reviewer 1 Report

This study, Outcomes of Geriatric Patients with Hepatocellular Carcinoma is a very important study. It tried to look at the outcomes in elder populations. It is an excellent attempt, but its relevance in its current form is questionable for the global audience.

Firstly, it would be helpful if the authors discussed the current and previous approaches to HCC in Taiwan. It puts some aspects into perspective.  Some issues to address are

·         Is MELD score used to classify the tumors?

·         Is TNM staging relevant? Most liver disease groups are moving away from this.

·         Is BCLC used in management? Child-Pugh score and its role?

·         Is systemic-immune-inflammation index used to classify or manage HCC?

·         When we are talking about outcomes, treatment is important.  How were the patients treated? Did that influence the outcome? This goes back to dividing the study population into stages, TNM or BCLC or MELD/Child-Pugh based.

Table 3 – it would be helpful if we could do a separate analyses for younger and elderly patients. That goes in line with the study. Possible explanations or mention if there is none for better prognosis with interferon (for hepatitis treatment?) or statin use. This is very important for management

 

Overall, it is an excellent attempt but needs tweaking to suit it to be relevant (for the global audience). As a physician-scientist, I understand it is difficult to go back to the drawing board and redo this study but at least acknowledging it in the limitations section would go a long way if changes cannot be done. 

Author Response

Comment: This study, Outcomes of Geriatric Patients with Hepatocellular Carcinoma is a very important study. It tried to look at the outcomes in elder populations. It is an excellent attempt, but its relevance in its current form is questionable for the global audience.

Response: Thank you for reviewing our manuscript.

Firstly, it would be helpful if the authors discussed the current and previous approaches to HCC in Taiwan. It puts some aspects into perspective.  Some issues to address are

Comment: Is MELD score used to classify the tumors?

 

Response: Thank you for the comment. In this study, the MELD score has been used to classify the tumor.We found that major risk factors for HCC survival were systemic immune-inflammation index (SII) ≥610 × 109cells/L, advanced tumor stage, and MELDscore, etc.

 

Comment: Is TNM staging relevant? Most liver disease groups are moving away from this.

 

Response: Thank you for the comment. The TNM staging is relevant. We confirmed that major risk factors for HCC survival were systemic immune-inflammation index (SII) ≥610 × 109cells/L, advanced tumor stage, and MELDscore, etc.

 

Comment: Is BCLC used in management? Child-Pugh score and its role?

Response: Thank you for the comment. Since this is a retrospective review of hospital records, we apologize that the data of BCLC staging of HCC and Child-Pugh score of liver cirrhosis are incomplete and lacking. The limitations have been stressed in the Discussion section.

Comment: Is systemic-immune-inflammation index used to classify or manage HCC?

Response: Thank you for the comment. The systemic-immune-inflammation index has been used to classify HCC. We found that major risk factors for HCC survival were systemic immune-inflammation index (SII) ≥610 × 109cells/L, advanced tumor stage, and MELDscore, etc.

Comment: When we are talking about outcomes, treatment is important.  How were the patients treated? Did that influence the outcome? This goes back to dividing the study population into stages, TNM or BCLC or MELD/Child-Pugh based.

Response: Thank you for the comment. At our hospital, the HCC patients with BCLC stage 0 and stage A disease generally underwent operation, hepatic transplantation, or interventional treatments for local tumor, comprising radiofrequency ablation, ethanol or acetic acid injection, and transcatheter arterial chemo-embolizatio.Patients with BCLC stage B disease undertook transcatheter arterial chemo-embolization and radiofrequency ablation.Patients with BCLC stage C disease received palliative chemotherapy, transcatheter arterial chemo-embolization, or radiotherapy, along with supportive medications, and those with BCLC stage D disease obtained palliative medications.A new therapeutic option for unresectable HCC is immunotherapy. HCC is a classic example of inflammation-linked malignancy, and the tumor microenvironment is infiltrated with diverse kinds of immune active cells, for example, T cells, natural killer cells, myeloid cells, etc. Currently, there are some published or ongoing clinical trials evaluating the benefit of dual immune checkpoint blockade or a combination of immune checkpoint inhibitors and biological therapy in patients with unresectable HCC.Furthermore, De Lorenzo et al reported that metronomic capecitabine therapy could be another option for HCC patients with Child–Pugh B liver cirrhosis. The information has been included in the Introduction section.

Since this is a retrospective review of hospital records, we apologize that the data of BCLC staging of HCC, Child-Pugh score of liver cirrhosis and treatment are incomplete and lacking. The limitations have been stressed in the Discussion section.

Comment: Table 3 – it would be helpful if we could do a separate analyses for younger and elderly patients. That goes in line with the study. Possible explanations or mention if there is none for better prognosis with interferon (for hepatitis treatment?) or statin use. This is very important for management

Response: Thank you for the comment. We apologize for not performing separate analysis for younger and elderly patients. Major risk factors for HCC survival were systemic immune-inflammation index (SII) ≥610 × 109cells/L, advanced tumor stage, and model for end-stage liver disease (MELD) score, etc (Table 3). Nevertheless, age was not an independent factor for mortality in patients with HCC after 3 years. In addition, use of interferon/nucleosideanaloque and statin/fibrate could reduce the HCC mortality rate. Please advise us again if we still miss out on anything.

Comment: Overall, it is an excellent attempt but needs tweaking to suit it to be relevant (for the global audience). As a physician-scientist, I understand it is difficult to go back to the drawing board and redo this study but at least acknowledging it in the limitations section would go a long way if changes cannot be done. 

Response: Thank you again for reviewing our manuscript. We feel that the comments are very helpful in improving the legibility, objectivity and scientific evaluation of the manuscript.

Reviewer 2 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 the background of medical treatment for HCC should be better explained and some recent studies should be cited within the introduction (PMID: 34429006; PMID: 29968763 ; PMID: 34431725), 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 major 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

Author Response

Comment: 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.

Response: Thank you for reviewing our manuscript.

Comment: We suggest the following modifications.

 

Introduction section: although the authors correctly included important papers in this setting, we believe the background of medical treatment for HCC should be better explained and some recent studies should be cited within the introduction (PMID: 34429006; PMID: 29968763; PMID: 34431725), only for a matter of consistency. We think it might be useful to introduce the topic of this interesting study.

1. Introduction

The incidence of cancer is elevated 11-fold in adults older than 65 years compared with those 65 years or younger. In hepatocellular carcinoma (HCC), the incidence increases with age, and the risk of HCC increases more than 15-fold after 65 years in patients infected with hepatitis C. The global median survival and 1-, 3-, and 5-year survival rates of older HCCpatients were 27 months and 71%, 36%, and 16%, respectively, which were worse than those of younger patients (33 months, 77%, 44%, and 21%, respectively) (p= 0.002).

Response: Thank you for the comment. The information has been included in the Introduction section.

The HCC patients with BCLC stage 0 and stage A disease generally underwent operation, hepatic transplantation, or interventional treatments for local tumor, comprising radiofrequency ablation, ethanol or acetic acid injection, and transcatheter arterial chemo-embolization.Patients with BCLC stage B disease undertook transcatheter arterial chemo-embolization and radiofrequency ablation.Patients with BCLC stage C disease received palliative chemotherapy, transcatheter arterial chemo-embolization, or radiotherapy, along with supportive medications, and those with BCLC stage D disease obtained palliative medications.A new therapeutic option for unresectable HCC is immunotherapy. HCC is a classic example of inflammation-linked malignancy, and the tumor microenvironment is infiltrated with diverse kinds of immune active cells, for example, T cells, natural killer cells, myeloid cells, etc. Currently, there are some published or ongoing clinical trials evaluating the benefit of dual immune checkpoint blockade or a combination of immune checkpoint inhibitors and biological therapy in patients with unresectable HCC.Furthermore, De Lorenzo et al reported that metronomic capecitabine therapy could be another option for HCC patients with Child–Pugh B liver cirrhosis.

 

Comment: Methods and Statistical Analysis: nothing to add.

 

Response: Thank you for the comment.

 

Comment: 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.

 

Response: Thank you for the comment. A paragraph of authors’ perspective has been included in the Discussion section.

 

Literature data on the survival difference between geriatric and younger patients remains controversial. Nevertheless, this retrospective observational cohort study has confirmed that age was not an independent factor for mortality in patients with HCC in the first 3 years. Major risk factors for HCC survival were SII ≥ 610 × 109cells/L, advanced tumor stage, and MELDscore, etc. Therefore, it is suggested that geriatric patients with HCC should be aggressively managed as in the younger patients. Apart from standard conventional anti-cancer therapy, immunotherapy is a new therapeutic option for unresectable HCC. As mentioned,comorbidities and frailty changes due to aging can limit a patient’s ability to endure conventional therapy such as surgery or systemic chemothrapy.Therefore, the immunotherapy could be a promising treatment for geriatric patients in future.

 

Comment: 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.

 

Response: Thank you for the comment. The limitations of the study have been included in the Discussion section.

 

The limitations of this study include retrospective study design, small sample size and lacking data of BCLC stage, Child-Pugh score and treatment modalities. Large-scale prospective studies are necessary to confirm this observation.

 

Comment: We believe this article is suitable for publication in the journal although major 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.

 

Response: Thank you for the comment.

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

Response: Thank you for the comment. The manuscript has been submitted to MDPI Company for language editing before re-submission to Current Oncology. We have revised the manuscript and spotted for the typo errors. Moreover, the suggested literatures are referenced. Please advise us again if we still miss out on anything.

Round 2

Reviewer 1 Report

The explanations and the effort to keep the study relevant should be appreciated. 

Reviewer 2 Report

The authors addressed all the queries and issues we raised.

We recommend Acceptance.

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