Outcome of Patients with Locally Advanced Rectal Cancer Pursuing Non-Surgical Strategy in National Cancer Database

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Hanna Kakish and co-authors present a high quality and well-written experimental manuscript focused on the outcome of patients with locally advanced rectal cancer pursuing non-surgical strategy in the national cancer database.

Authors examined the outcomes of patients with locally advanced rectal cancer (LARC) who underwent non-operative management (NOM) instead of surgery in routine clinical practice. Using data from the National Cancer Database.

Authors analyzed LARC patients from the National Cancer Database with the following features: treated between 2010 and 2020, age 18-65 years, Charlson comorbidity index (CCI) ≤1, received neoadjuvant multiagent chemotherapy plus radiation ≥45 Gray, and underwent surgery or NOM. Patients were stratified into two groups: A) clinical T1-3 tumors with positive nodes (cT1-3N+), and B) clinical T4 tumors, N+/- (cT4N+/-). They performed a comparative analysis of overall survival (OS) with NOM versus surgery by Kaplan-Meier method and propensity score matching. Additionally, a multivariable analysis explored the association between NOM and OS. 

Authors found that those who did not undergo surgery had lower survival rates than those who had surgical interventions. Specifically, patients with high-risk features, for example, patients with T4 tumors, had much inferior survival with NOM than with surgery. NOM exhibited significantly lower OS than surgery in both groups. In cT1-3N+ patients, NOM resulted in a 5-year OS of 73.9% versus 84.5% with surgery. In the cT4N+/- group, NOM yielded a 5-year OS of 44.5% versus 72.5% with surgery. Propensity score matching and multivariable analyses revealed similar conclusions.

Finally, authors conclude that the current analysis underscores the importance of carefully selecting patients when considering organ preservation for patients with LARC. It specifically advises against the indiscriminate adoption of the non-operative strategy in patients who exhibit a higher risk of systemic failure. The results presented in this study are hypothesis-generating and strongly advocate for a randomized controlled trial targeting high-risk LARC patients who have achieved cCR following multimodality neoadjuvant therapy, comparing survival outcomes between non-operative strategy and surgery.

Overall, the manuscript is highly valuable for the scientific community and should be accepted for publication.

======================

Other comments to authors:

1) Please check for typos throughout the manuscript.

2) Please improve figures/tables where appropriate.

 

Author Response

We are highly appreciative of the comments. We are honored that the reviewer scrutinized the manuscript rigorously and supported our view that the NOM strategy for high-risk LARC patients should be investigated in clinical trials before widespread adoption. As the reviewer indicated, this paper is hypothesis-generating and calls for well-designed randomized trials to examine the validity of the data presented.

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you for submitting this outstanding manuscript comparing OS of  locally advanced rectal 

cancer (LARC) patients who went through non-operative management (NOM) vs those who received surgery after neoadjuvant therapy.  To increase the impact of the article it would be benefit to discuss in details

1. Methods that can be used to improve the selection criteria for NOM approach for instance a) using radiological complete response (MRI) rather than the inaccurate clinical response. B) the role of biomarkers or genomic tests that can be used to improve the selection of NOM.
2. A proposed plan for the next steps to validate the clinical utility of the results to be widely adopted
3. The future directions and recommendations

Comments on the Quality of English Language

No major issues

Author Response

1. Methods that can be used to improve the selection criteria for the NOM approach for instance A) using radiological complete response (MRI) rather than the inaccurate clinical response. B) the role of biomarkers or genomic tests that can be used to improve the selection of NOM.

Response: We appreciate these comments. However, the NCDB does not provide detailed radiologic/MRI-guided response data or genomic data, and hence we could not include those in the patient selection criteria. We agree with the reviewer that those information would have enhanced the value of this manuscript.

2. A proposed plan for the next steps to validate the clinical utility of the results to be widely adopted.

Response: We thank the reviewer for highlighting this aspect. We have elaborated this aspect in the discussion section by adding a new paragraph as follows-

‘A critical question at this juncture is how to address the concerns raised by the current dataset. As previously indicated, an appropriate clinical trial design to evaluate the long-term efficacy and safety of the NOM strategy would be a randomized, phase III trial. In this trial, patients with LARC achieving cCR would be randomized to either standard surgery or NOM, with a well-balanced distribution of risk characteristics in each arm. The trial design should incorporate a preplanned subset analysis for high-risk patients and include robust endpoints such as 3-year or 5-year disease-free survival (DFS), overall survival (OS), local and systemic recurrence rates, and quality of life measures, including bowel, urinary, and sexual function. Additionally, uniform criteria for determining cCR should be applied to all patients. A post-hoc analysis of the genomic profiles of patients achieving long-term survival compared to those experiencing cancer relapse would further enhance our understanding and aid in the precise selection of patients for NOM.’

3. The future directions and recommendations.

Response:

 We agree with the reviewer that we need to elaborate on future directions and recommendations. The new paragraph added to the discussion section addresses this critique-

‘A critical question at this juncture is how to address the concerns raised by the current dataset. As previously indicated, an appropriate clinical trial design to evaluate the long-term efficacy and safety of the NOM strategy would be a randomized, phase III trial. In this trial, patients with LARC achieving cCR would be randomized to either standard surgery or NOM, with a well-balanced distribution of risk characteristics in each arm. The trial design should incorporate a preplanned subset analysis for high-risk patients and include robust endpoints such as 3-year or 5-year disease-free survival (DFS), overall survival (OS), local and systemic recurrence rates, and quality of life measures, including bowel, urinary, and sexual function. Additionally, uniform criteria for determining cCR should be applied to all patients. A post-hoc analysis of the genomic profiles of patients achieving long-term survival compared to those experiencing cancer relapse would further enhance our understanding and aid in the precise selection of patients for NOM.’

 

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you for submitting this revised manuscript in which my previous comments have been addressed.