Landscape of Biomarkers and Pathologic Response in Rectal Cancer: Where We Stand?

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors review the literature regarding prognostic factors for rectal cancer.

The title is misleading as a lot of the discussion is around survival outcomes.

A tough topic as there are currently no factors with clinical utility, beyond MRI. Given the importance of MRI there should be some discussion of its limitations wrt accuracy of staging, both at diagnosis and after neoadjuvant treatment.

Discussion of areas where the data is contradictory or negative could be abbreviated.

Discussion of the quality of the studies should be included. Much of the literature is small, retrospective cohorts.

More discussion of dMMR and IO outcomes is needed.

More discussion of future directions would be helpful, including radiomics. 

Most useful for the reader would be factors that impact decision making. How do we decide which patient to give what therapy to? This is not covered at all.

Inflammation is considered separately to NLR, PLR etc., which are thought to be markers of inflammation, so should be jointly discussed.

Comments on the Quality of English Language

The quality of the writing is limited. Definite room for improvement with phrasing. Some sentences are overly long, E.g., the first line in the summary and abstract. A careful review of the text is required. Eg., line 21, line 52 doesn`t make sense and some typos E.g, line 291.

Author Response

In first place, thank you for take your time to review our manuscript. We are going to number the modifications applied:

• The title was changed to: Landscape of biomarkers and pathologic response in rectal cancer: where we stand?, we think that is more appropriate to the content in the manuscript.
• We added the limitations of MRI and its importance in the staging and reevaluation.
• We adjusted the areas where data is contradictory and highlighted the quality of studies (retrospectives, small samples, etc).
• We added a new topic dMMR and IO highlighted the importance of this biomarker and the immunotherapy as election treatment.
• We included the future directions and perspectives and included radiomics as promising new tool in evaluation of neoadjuvant therapy.
• We reformulated paragraphs to improve the decision making and comprehension.
• We joined haemotological biomarkers with inflammation biomarkers.

I hope all this changes could be appropriate to consider with this manuscript.

Kind regards

Reviewer 2 Report

Comments and Suggestions for Authors

Colorectal cancer patients are treated with different types of combinatorial therapy, and this includes chemotherapy, radiotherapy and surgery with acceptable pathological complete response (pCR) rates.  IN this review paper, the authors have evaluated the biomarkers to be used in clinical practice, and highlighted their advantageous and disadvantageous and their predictive value.  The authors have discussed in detail the various biomarkers such as Neutrophil-Lymphocyte ratio, Preoperative Plasma Fibrinogen and Neutrophil-Lymphocyte ratio, Platelet to -Lymphocyte ratio, Monocyte-Lymphocyte ratio, Circulating tumor DNA, inflammation biomarkers  etc., They suggest that adaptation of these biomarkers offers a valuable tool to personalize treatments and improve therapy.  

Author Response

Thank you for the effort in making a review of this manuscript. We really appreciate. We made new modifications as have suggested another reviewers, we hope this could have appropriate.

Kind regards

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Authors,

 

Thank you for the opportunity to review your manuscript titled, “Neoadjuvant Therapy in Rectal Cancer: Prognosis Factors of Pathological Response.” Your study on the prognostic factors associated with neoadjuvant therapy in rectal cancer provides valuable insights into this area. I commend your efforts, and I have a few suggestions that may help strengthen the clarity and focus of the paper.

 

Terminology Consistency: In the abstract, you refer to Total Neoadjuvant Therapy (TNT), while in Section 2.1, the term used is Neoadjuvant Treatment (NAT). I recommend clarifying this discrepancy to ensure consistency and avoid potential confusion for the readers.

 

Biomarker Summary Structure: The current summary of biomarkers lacks a clear, organized structure, making it difficult to follow. I suggest the authors compile this information into a table format. This will facilitate easier understanding and reference for readers interested in the specific biomarkers associated with neoadjuvant therapy.

 

Title Accuracy: Given that your study examines the impact of neoadjuvant therapy on colorectal cancer prognosis, I recommend changing “Rectal Cancer” to “Colorectal Cancer” in the title to more accurately reflect the scope of your work.

 

Relevance of MRI Discussion: The connection between Magnetic Resonance Imaging and Total Neoadjuvant Therapy is not fully integrated into the main discussion, making Section 3 feel somewhat disconnected. A more in-depth discussion on the relevance and utility of MRI in the context of neoadjuvant therapy would better align this section with the paper’s core objectives.

 

Abbreviation Table: Given the extensive use of specialized terminology and abbreviations throughout the manuscript, I recommend providing a table of abbreviations. This addition would greatly improve readability, especially for those less familiar with all abbreviations.

 

Thank you once again for your work on this important topic. I hope these suggestions are helpful in further refining your manuscript.

 

Best regards,

 

Reviewer

Author Response

In first place, thank you for take your time to review our manuscript. We are going to number the modifications applied:

• We adjust the terminology and the use during the manuscript, in our case Total Neoadjuvant Therapy (TNT) is no the same as Neoadjuvant Treatment (NAT), TNT is a way of NAT with intensive chemotherapy and radiotherapy before surgery. NAT include TNT as well as long course radiotherapy (LCRT) and short course radiotherapy (SCRT).
• We added a new paragraph describing the different biomarker and it is use to made a better comprehensive reading of the manuscript and we added a new table with the biomarkers.
• We made a change of title: Landscape of biomarkers and pathologic response in rectal cancer: where we stand?, we think as suggested another reviewer that is more adjusted to the content of the paper.
• We added a new connection paragraph between MRI and neoadjuvant therapy to integrate this section in best way with the rest of paper.
• We include an abbreviation table for better comprehension.

We hope that all the changes included are to your liking and appropriate in the evaluation of this manuscript.

Kind regards

Reviewer 4 Report

Comments and Suggestions for Authors

Suggestions for Improvement:

 

1. Methodology Enhancement:

- Include a systematic review methodology section

- Add clear inclusion/exclusion criteria for studies

- Separate analysis of prospective vs retrospective data

- Include quality assessment of included studies

 

2. Data Presentation:

- Add visual summaries of biomarker effectiveness

- Include forest plots for key outcomes

- Create comparison tables for different biomarkers

- Add flowcharts for treatment decision-making

 

3. Clinical Implementation:

- Develop clear recommendations for biomarker use

- Include cost-effectiveness analysis

- Provide specific cut-off values for biomarkers where possible

- Add decision algorithms for treatment selection

 

4. Additional Content:

- Include quality of life outcomes

- Add economic impact analysis

- Expand on potential combinations of biomarkers

- Include more detail on emerging technologies

 

5. Editorial Improvements:

- Enhance abstract structure

- Add more subheadings for better navigation

- Include an executive summary

- Provide clearer future research directions

 

Overall, this is a valuable contribution to the field that could be enhanced with more structured data presentation and clearer clinical implementation guidelines. The comprehensive coverage of biomarkers provides a good foundation for future research and clinical practice.

 

Would you like me to elaborate on any of these aspects or provide more specific recommendations for any particular section?​​​​​​​​​​​​​​​​

Author Response

In first place, thank you for take your time to review our manuscript. We are going to number the modifications applied:

• In methodology area: we discussed the prospective and retrospective data and highlighted the quality studies. We do not add and systematic review methodology section because this manuscript is a narrative review with it is limitations.
• In data presentation: we included a table with different biomarkers. We do not include forest plots for not to be a systematic review and neither the flowcharts for decision-making because none of this biomarkers are available in guidelines to adjust or change treatments, for now they are only possible prognosis biomarkers.
• Clinical implementation: we added possible recommendations for biomarker use, cut-off value where this could possible and a paragraph of cost-effectiveness.
• Additional content: in this area, we added the importance of combinations of biomarkers and a new paragraph of future perspectives.
• Editorial improvements: we enlarged the abstract and more subheadings.

We hope that the changes are appropriate and adequate to evaluate the manuscript.

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

The author has responded to most of the modification suggestions I put forward, replied to the selection of Total Neoadjuvant Therapy and Neoadjuvant Treatment I put forward, and explained several small problems in the title of the paper. The authors also responded to my questions about biomarkers, and overall I think the review meets the criteria for publication.