Integration of Radical Intent Treatment in Colorectal Liver Metastases

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

I have no additional questions or comments for the authors. I recommend the article for publication.

Author Response

The authors would like to thank the reviewer for the time dedicated to the manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

The introduction asserts that optimum patient selection continues to provide a considerable issue. Nonetheless, it does not include particular citations of contemporary research that delineate these problems.
Could the authors furnish further specific instances or citations to elucidate the literature gaps that their review addresses?

The study indicates limits in the application of prognostic models but fails to adequately elaborate on these constraints.
Question: What particular constraints do the authors recognize in existing prognostic models, and what solutions do they suggest to mitigate these challenges?
Although advancements in locoregional and systemic therapies are highlighted, the justification for these selections need further elucidation.
Inquiry: What parameters do the authors employ to delineate success in various therapeutic modalities, and in what manner are patient results assessed?

The chapter outlines various surgical methods (e.g., liver-first versus primary-first) but fails to provide a critical appraisal of the evidence underpinning these decisions.
Question: Could the authors clarify their methodology for determining the timing of surgical operations in accordance with existing clinical evidence?

The discourse on the ramifications and possible detrimental effects of incorporating novel medicines such as immunotherapy is minimal.
What potential hazards are linked to the new therapies discussed, and how are these concerns weighed against the anticipated benefits?

The conclusions are vague and fail to offer definitive future insights or research options.
Question: What particular future research avenues do the authors deem essential to explore in light of their findings, and how do they correspond with existing clinical guidelines?

Author Response

The authors would like to thank the reviewer for the time dedicated to the manuscript.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The numerous references are differently cited: please select a single style and use it.

You might mention the use of intra-operative Echo to control already known liver metastases and detect some other.

Author Response

The authors would like to thank the reviewer for the time dedicated to the manuscript.

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

The authors have written a review on ‘Integration of radical intent treatment in colorectal liver metastases’. The paper has touched upon important issues and provides a lot of supporting data. 

Major points

1. In patients with synchronous bilobar CRLM, could the authors present an algorithm to make appropriate decisions? In keeping with the title of the paper, the intent is to offer radical (curative intent) treatment to the maximum number of patients. Factors to consider include

candidacy for resection vs. transplant vs. non-surgical modalities

primary first or liver first approach

how to decide between parenchyma sparing hepatectomy vs. two stage hepatectomy

how to decide among PVE, ALPSS and hepatic vein deprivation

2. How is a systemic treatment regimen chosen in a particular patient? What is the role of molecular profiling? Role for adding Bevaxizumab, Cetuximab in right vs left vs rectal primaries

3. In patients with initially unresectable CRLM, how many can be converted to curative intent surgery with systemic± locoregional treatment? Are there predictors for these?

Minor points

Figure 1 Prognostic factors: Should the title of better and worse prognosis swapped?

For ‘disappearing liver metastases’, is there data to suggest MRI is better than CT

Line 146 page 3      Typo       las 5 years

Can it be vascular control instead of hemorrhagic control  page  6 line 246

TARE is traditionally not considered as a liver enhancing procedure. Could the authors clarify or modify appropriately page 7, line 270

If the latter alternative is chosen, it seems logical to limit the number of preoperative chemotherapy cycles and consider surgery as soon as its aggressiveness has been documented. Page 10, lines 472, 473. It seems counter intuitive. If the patient has aggressive disease progressing on chemotherapy, does it not imply that doing surgery might also result in early recurrence, poor outcomes; are these patients for second line systemic treatment?

In patients with potentially resectable disease, systemic therapy guided by molecular and anatomical characteristics can enable……….. Line 675 page 14; should it be unresectable instead of resectable

Author Response

The authors would like to thank the reviewer for the time dedicated to the manuscript.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The author responds to my comments.

Author Response

No more questions are proposed.

Reviewer 4 Report

Comments and Suggestions for Authors

Thank you very much for addressing all comments.

1. May I suggest a couple of changes to the algorithm. Since the title is synchronous CRLM, 

a. In the Unresectable CRLM stem, transplant can be omitted. 

Unresectable.. Doublet/Triplet....then 2 stems Conversion to 1. resectable/ potentially resectable   2. Still unresectable... second line therapy   

Transplantation is an option in metachronous CRLM when criteria have been satisfied as so well described in the manuscript

b. If the primary is asymptomatic, irrespective of the level of complexity of hepatectomy or colectomy, a liver first approach would be justified as treatment of liver metastases would determine survival

2. For molecular marker guided therapy for unresectable CRLM, the following points could be highlighted with relevant references. For MSI high or dMMR type, Pembrolizumab is the first line therapy recommended. It could be emphasized the for right sided primary tumors that are MSI stable, RAS wild type, Bevaxuzimab is added to chemotherapy while for left sided tumors, Cetuximab is the choice.  For BRAF 600 E mutant, progressed after at least one line of treatment, Encorafenib + Cetuximab is recommended

3. The authors could add a small paragraph about evidence for ALPSS in CRLM. Contemporary evidence indicates it induces rapid hypertrophy as compared to PVE without compromising oncological outcomes and reducing drop out rates. A brief comparison on combined HVD+ PVE versus ALPSS can be discussed with the authors' take on when to use which modality. I understand these may be specific scenarios to discuss in a MDT but the framework for this decision making will help readers understand this complex topic well. This is in keeping with the title of the manuscript: 'the intent of integrating radical  treatment in CRLM'

Author Response

The authors thank the Reviewer for the recommendations suggested.

Author Response File: Author Response.docx