The Impact of Radiotherapy Dose in Patients with Locally Advanced Esophageal Squamous Cell Carcinoma Receiving Preoperative Chemoradiotherapy

Round 1

Reviewer 1 Report

Lo et al provide an analysis of their 141 esophageal squamous cell carcinoma patients treated over time with differing preoperative RT doses. They found dose-dependent improvement in survival and increased complications. Their manuscript is well written and conclusion is supported by data.

Comments:

1. Why did the group adopt higher RT dose in later years? And if higher, why not 41.4 only?
2. Multivariate analysis is referenced in line 166, but a full table is not provided. This remains important, as well as methodology of constructing MVR. Since cancer therapy outcomes are generally improving over time, year of initial diagnosis is typically included.
3. Perhaps the most important addendum to discussion is related to other treatment characteristics which may have changed over time. Some of those may be characteristic to the specific department – including change of surgeons and other physicians, change of technique and patient selection – or deselection for surgical therapy. Please describe whether any of these may have influenced this study. These may or may not be measurable, yet they provide an important context.
4. Perioperative complications have a negative impact on both DFS and OS. Yet, the contrary was observed in this study. This should be discussed as contrarian reports exist in the literature.
5. Did the length of postradiation interval until esophagectomy change over time?
6. In RESULTS section there appear unnecessary data (line 130), as they are described in Tables. Please consider shortening.
7. Please redraw KM graphs in Figure 1. There is no need to provide decimals in time axis.

Author Response

Dear reviewer:

     Thanks for your valuable suggestion. We made some changed in our manuscript and answered your comment in attached file. Thanks for your comment.

Author Response File: Author Response.pdf

Reviewer 2 Report

The authors present a single-center retrospective study on outcomes after preoperative radiochemotherapy for esophageal squamous cell cancer. Indeed, the adequate radiotherapy dose for preoperative treatment remains an interesting issue.

The manuscript is concisely written. The main weakness of the study is the long treatment period of 15 years. Thus, the results are prone to biases. For a better understanding of the differences in patients treated with 36 vs. 50/50.4 Gy, please give a detailed description of recurrence patterns (local/regional/distant failures). Does radiotherapy dose have an effect on local control or distant control? If not, please discuss potential explanations.

Comments by sections

Introduction

Line 41: please correct: …delayed…

Line 52: please correct: …shown…

Material and Methods

Lines 76-77: please add the protocol number of ethical approval, please add a statement on patient informed consent for the study.

Lines 98-99: please modify the statement: ‘After 2009, to achieve higher pathological complete response rate, the radiotherapy total dose to the PTV was modified to 50-50.4 Gy/ 25-28 fractions by our multidisciplinary team.’ Please give references and give a detailed rationale for the dose modification.

Please add information on the duration of patient follow-up in the 36 Gy and 50 Gy groups.

Please add information on the surgical margins (R0/R1/R2 resections).

Discussion

Line 197: ‘p=0.033’. For the comparison of 3-year OS between 36 and 50-50.4 Gy, table 4 gives another p-value of 0.023.

Engel et al. conducted a meta-analysis and found no differences in OS and treatment-related mortality (10.21037/jgo.2019.01.02). Please discuss their results in the context of the present study.

Author Response

Dear reviewer:

     Thanks for your valuable suggestion. We made some changed in our manuscript and answered your comment in attached file. Thanks for your comment.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

The issues from the last decision letter have generally been sufficiently addressed. I only have a few further comments to the current version of the manuscript.

Page 2, line 74: chemoradiation, please correct.

Page 2, line 76: .., please correct.

Page 3, line 155: ..as previously described. Please add information. What is meant by ‘previously’?

Table 5: Please explain how the multivariate analysis was conducted (Table 5). Did you include all parameters with statistical significance in univariate analysis (Table 4)? Did pathological complete response not retain significance in multivariate analysis?

Page 10, line 380: It is well-known that perioperative complications.. please give a reference.

We also used Kaplan–Meier method to generate locoregional recurrence-free survival and distant recurrence-free survival as below for your reference, and the difference between survival curves was tested by a log-rank test. Patients receiving 36Gy preoperative chemoradiotherapy had significant (P=0.035) worse locoregional recurrence-free survival than those receiving 50-50.4Gy preoperative chemoradiotherapy. There is no  significant difference (P=0.52) in distant recurrence-free survival between patients receiving 36Gy preoperative chemoradiotherapy and patients 50-50.4Gy preoperative chemoradiotherapy. We do not put them into the revised manuscript. But if reviewers think it is necessary we are pleased to add the above result into the revised manuscript.

• I suggest to put the LRFS and distant recurrence-free survival plots at least in the supplement. The improvement in LRFS with higher radiotherapy dose should be illustrated for the readers.

Author Response

Please see the attachment. Thanks a lot.

Author Response File: Author Response.docx