Trimodal Therapy in Esophageal Squamous Cell Carcinoma: Role of Adjuvant Therapy Following Neoadjuvant Chemoradiation and Surgery

Round 1

Reviewer 1 Report

1) Please focus on ESCC not including adenocarcinoma. And, GEJ cancers might affect the results as those have rather specific characteristics than typical ESCC in the esophagus involvement alone, and recommend exclusion too. 

2) Please provide practical numbers for each chemotherapeutic regimen.  And authors should specify practical numbers of usage of immune check point inhibitors that were used in detail; i.e., dosage, duration, interval and irAEs presence or absence. In the case, authors should describe diverse events in a supplemental table. 

3) Please modify survival curves as for slenderness rate oppositely for readability even including supplemental ones.  

4) Please provide additive publications the reason why authors selected chemotherapeutic drugs. 

5) Authors should describe perspective how we can translate the study outcomes in real practice. Conclusive messages seem ambiguous. 

6) Please make a new table comparing the present outcomes and prior publications. And, in cases of discordance , authors discuss more with explanations. The retrospective single center analysis should not be included in those, as the enrolled cohorts were relatively large enough.

7) Do not abbreviate in Tables. Authors should describe each full terminology in index. LVI and PNI could not be included in the same column in Table 1. 

8) Alcohol consumption are lacking? 

9) Please let inform why authors set the line of tumor length to 3cm. 

10) There are series of publications in the related topic, while the references' number was too small. Introduction seems short. Authors should summarize related publications more complehensively, resultantly increasing references. 

Author Response

Comment 1: Please focus on ESCC not including adenocarcinoma. And, GEJ cancers might affect the results as those have rather specific characteristics than typical ESCC in the esophagus involvement alone, and recommend exclusion too.

Answer 1: Thank you for your suggestions. The revised manuscript only included ESCC patients in the study. And the patients with GEJ esophageal cancer were also excluded.

• Please provide practical numbers for each chemotherapeutic regimen.  And authors should specify practical numbers of usage of immune check point inhibitors that were used in detail; i.e., dosage, duration, interval and irAEs presence or absence. In the case, authors should describe diverse events in a supplemental table.

Answer 2: Thank you for your suggestions. We have described the details of adjuvant therapy in revised manuscript. Meanwhile, the strategy of adjuvant therapy was described in Supplementary Table 2.

Comment 3: Please modify survival curves as for slenderness rate oppositely for readability even including supplemental ones.  

Answer 3: Thank you for your useful suggestions. We have re-make the survival curves and made it more readable.

Comment 4: Please provide additive publications the reason why authors selected chemotherapeutic drugs.

Answer 4: The chemotherapeutic drugs were selected according to NCCN Guidelines for esophageal and esophagogastric junction cancers and previous publications.

• Authors should describe perspective how we can translate the study outcomes in real practice. Conclusive messages seem ambiguous.

Answer 5: Thank you for your suggestion. We have revised our conclusion to better translate the study outcomes in real practice.

Change 5: Conclusion: The results of our study indicate that adjuvant therapy after neoadjuvant chemoradiotherapy and surgery could reduce the OS and DFS in patients with ESCC. Meanwhile, adjuvant therapy is an independently unfavourably prognostic factor for DFS. Therefore, adjuvant therapy is not recommended for ESCC patients after neoadjuvant chemoradiotherapy and esophagectomy, especially for patients with node-negative after neoadjuvant therapy. A large-scale well-designed prospective study will be needed to confirm these results.

• Please make a new table comparing the present outcomes and prior publications. And, in cases of discordance , authors discuss more with explanations. The retrospective single center analysis should not be included in those, as the enrolled cohorts were relatively large enough.

Answer 6: Thank you for your useful suggestions. We have made a table comparing the prior publications and present outcomes.

Change: Thank you for your careful review and suggestion. We have made a new table containing brief information and outcomes from several high-quality publications to compare them with the present study. Furthermore, we discussed more with explanations regarding the discordance among the studies in the “Discussion” section.

Comment 7: Do not abbreviate in Tables. Authors should describe each full terminology in index. LVI and PNI could not be included in the same column in Table 1.

Answer 7: Thank you for your notification. We have removed the abbreviate in Tables. LVI and PNI were separated in two individual column and described in full terminology in Tables.

Comment 8: Alcohol consumption are lacking?

Answer 8: Sorry for the negligence. We have added the alcohol consumption status in the Table 1.

Comment 9: Please let inform why authors set the line of tumor length to 3cm.

Answer 9: Thank you for your suggestions. The median of the tumor length is 3cm which was used as the cut-off value.

Change 9: The median of the tumor length is 3cm which was used as the cut-off value.

Comment 10: There are series of publications in the related topic, while the references' number was too small. Introduction seems short. Authors should summarize related publications more complehensively, resultantly increasing references.

Answer 10: Thank you for pointing out this limitation. We have added several references focusing on the related topic in the manuscript and the “Introduction” was expanded as well.

Author Response File: Author Response.doc

Reviewer 2 Report

1-      Title: Although the title reflects the content, I would suggest rephrasing it in a better way to attract readers. A suggestion is: Trimodal Therapy in Esophageal Squamous Cell Carcinoma and Adenocarcinoma: Role of Adjuvant Therapy Following Neoadjuvant Chemoradiation and Surgery.

2-      English: The manuscript could benefit from editing for grammar, missing words, and subject-verb agreement, etc. It is recommended that authors delete irrelevant "general" phrases and sentences, repeated and unneeded words. They should use short sentences. Also, some Introductory sentences are irrelevant or are not needed. There are also typos in the manuscript.

3-      Abbreviations: All abbreviations should be revised and defined at their first use. For example, ypTNM stages in the Simple Summary section.

4-      Abstract: Change “The aim of this study was to determine role” to “The aim of this study is to determine the role.”

5-      Abstract: Add a space between (EC) and Methods in: “cancer (EC).Methods.”

6-      Abstract: “506 patients with clinical positive lymph nodes and non-metastasis.” Correct: “506 patients with clinically positive lymph nodes and no metastasis.”

7-      Abstract: “506 patients with clinical positive lymph nodes and non-metastasis.” What do authors mean by clinically positive lymph nodes? To assess whether there is lymph node metastasis, there should be pathologic evaluation. Also, authors should be more specific and say “no distant metastasis” as metastasis incorporates both lymph node and distant metastases.

8-      Abstract: “Patients receiving adjuvant therapy had a shorter post-resection overall survival (OS) and disease-free survival (DFS), with a significant difference between two groups.” What are the two groups? And What are the patients comparing “Patients receiving adjuvant therapy” to? Readers might also be confused here between adjuvant and neoadjuvant. It is not clear whether the patients included already underwent neoadjuvant chemoradiation followed by surgery prior to taking additional adjuvant therapy or they took adjuvant prior to surgery.

9-      Abstract: “significantly unfavourable independently prognostic factor.” Change independently to independent.

10-  Abstract: “P<0.001).Conclusion:” Add a space before “Conclusion.”

11-  Abstract: “Adjuvant therapy is associated with poor OS and DFS in patients” The conclusions are actually quiet shocking. I wonder if authors adjusted their results and the analysis for other potential confounding factors such as comorbidities, age sex, etc. Unless patients were adjusted for all potential confounding factors, results will not be reliable. Theoretically, any adjuvant therapy is expected to instigate a favorable effect and prolong survival for patients and not the opposite.

12-  References: Many old references used need to be updated. An example is reference [1] from 2018. Updated versions in 2021 exist. Other resources to get the data from include Siegel et al. 2022.

13-  Introduction: “varies extremely from areas and countries” should be “varies extremely among areas and countries.”

14-  Introduction: “Literatures” is wrong. In English, there is no pleural for literature. Authors should do extensive English editing for their manuscript.

15-  Introduction: Line 47: “with/without adjuvant with/without neoadjuvant.” What is the difference between adjuvant and neoadjuvant therapies? Not all readers might be familiar with this, so authors are recommended to elaborate more and explain the clinical stages of EC and therapeutic strategies used. Another important point here is that authors are using the term EC which included different malignant neoplasms including adenocarcinoma, squamous cell carcinoma, and leiomyosarcoma among others. It would be beneficial to also add some data to the introduction to give a background on EC malignancies, their epidemiology and management.

16-  Introduction: “no guideline recommendation to treat EC patients with adjuvant therapy.” Give more details about the adjuvant therapy that could be given following neoadjuvant and surgery.

17-  Introduction: “As there is presently no clear evidence in previous study to guide the use of adjuvant therapy after neoadjuvant therapy and esophagectomy especially in east Asian region, there is uncertainty regarding which patients to consider treating and how pathology could influence these clinical decisions.” What previous study are the authors referring to? When there is mention of a study, there should be a reference citing that study.

18-  Introduction: “To add evidences to this important.” Change to evidence as there is no pleural for the word evidence.

19-  Methods: “patients pathologically were diagnosed as EC before treatment.” Change to “diagnosed with.”

20-  Methods: Among the inclusion criteria, authors mentioned that “patients were staged according to the American Joint Committee on Cancer (AJCC) 8th edition.” However, those guidelines were published in 2016. Does that mean that the patients (2014-2020) were staged according to older guidelines and then restaged for the purpose of this study? This needs to be clarified and mentioned clearly.

21-  Methods: “patients were diagnosed as clinical lymph node metastasis positive (cN+) and non-metastasis (cM0) before any treatments.” Clarify what is clinical LN metastasis (based on imaging?) and non-metastasis (do authors mean distant metastasis?).

22-  Methods: “after radical esophagectomy with R0 resection.” What is meant by R0 resection?

23-  Methods: “and were classified squamous cell, adenocarcinoma, adenosquamous carcinoma or other.” Correct to: “and were classified into squamous cell, adenocarcinoma, adenosquamous carcinoma or others.”

24-  Figure 1: Change “Patients for Analysis” to “Patients meeting criteria to be included in the study.”

25-  Figure 1: Legend needs to be more informative of the results presented.

26-  Figure 1: Based on what did authors decide to stratify patients into Adjuvant versus non-Adjuvant treatments?

27-  Methods: “gastroscopy, and blood test were performed.” Change blood test to tests and add the full word for the acronym CT before using it for the first time.

28-  Methods: The section on Neoadjuvant Therapy is confusing. Probably, transforming this into a Table would make it easier for readers to track the different treatment options given and which patients were eligible for each.

29-  Methods: “with thoracic anastomoses combining with radical lymph node.” Change combining to combined.

30-  Methods: “Two experienced pathologists fixed the dissected specimens, then embedded and stained them with diaminobenzidine chromogen counterstain solution and hematoxylin to routinely assess resected specimens histologically and pathologically.” This is not necessary. Authors could just say that specimens were sent to Pathology Department for further analysis where representative sections of the tumor and periesophageal tissues were taken for sufficient pathologic evaluation and staging.

31-  Methods: “Chemoradiotherapy was the radiotherapy conducted from the first day of the first chemotherapy cycle.” Consider rephrasing for better clarification: “Combined chemoradiotherapy included giving radiotherapy from the first day of the first chemotherapy cycle.”

32-  Methods: “Usually, adjuvant therapy started 4 to 6 weeks after surgery.” Were there any guidelines followed to decide this?

33-  Results: “Adjuvant therapy was documented for in.” this sentence is incomplete and needs revision.

34-  Results: “Patients receiving adjuvant therapy were more likely to have: gender of male, poorer differentiation, poorer tumor stage, more positive lymph nodes, advanced stage, lymphovascular and peripheral nerve invasion, and poorer response to neoadjuvant therapy.” This assumption should be also statistically analyzed. Authors need to compare between each of the patients’ demographics and characteristics in the two patient groups “non-adjuvant” versus “adjuvant” and add a column including p-values.

35-  Table 1: when there is no missing data for a parameter, there is no need to add a row “missing.” Also, I suggest just removing the rows “missing” and adding the total number of patients for each parameter next to the variable name. For example, Cardiovascular disease (n=502).

36-  Results: In Table 1 top row, No. (%) (n-506) is not correct as not all variables had complete data and there were missing data from some.

37-  Table 1: Formatting of this Table needs to be revised. Titles of variables can be in bold, and their categories below them not bolded. Authors can refer to this paper to have an idea how to better represent their results: Tables 1, 2, and 3 in https://linkinghub.elsevier.com/retrieve/pii/S1092-9134(21)00024-1. Same applies to Table 2.

38-  Figure 2: Presentation of results here is very weak. Numbers in the images are super tiny and hard to read. I suggest diving the figure into two or more figures and enlarging the graphs to make them clear.

39-  Figure 2: Authors did not mention whether those results are adjusted for confounding factors. If not, this is a major limitation in the study and makes all results not reliable.

40-  Results: “Ten variables were selected for multivariate Cox regression model entry due to P<0.05 on univariate analysis.” Kindly provide results of the univariate analysis as a supplementary material.

41-  Figure 4 legend: “Hazard ratios with 95% CI for the disease-free survivalin prespecified.” What is survivalin?

42-  Figures: All the figure legends can be revised as to be more informative of the images presented. Also, statistical tests used and meaning of asterix need to be added. Abbreviations used withing Tables and Figures should be defined as well in the legends at the end.

43-  Discussion: Authors should focus more on the main findings and avoid repeating results presentation in the discussion. Authors could also correlate their findings with what has been published in literature. Clinical relevance should be added.

Author Response

Comment 1: Title: Although the title reflects the content, I would suggest rephrasing it in a better way to attract readers. A suggestion is: Trimodal Therapy in Esophageal Squamous Cell Carcinoma and Adenocarcinoma: Role of Adjuvant Therapy Following Neoadjuvant Chemoradiation and Surgery.

Answer 1: Thank you for your useful suggestion. We have revised the title into: Trimodal Therapy in Esophageal Squamous Cell Carcinoma: Role of Adjuvant Therapy Following Neoadjuvant Chemoradiation and Surgery.

Comment 2: English: The manuscript could benefit from editing for grammar, missing words, and subject-verb agreement, etc. It is recommended that authors delete irrelevant "general" phrases and sentences, repeated and unneeded words. They should use short sentences. Also, some Introductory sentences are irrelevant or are not needed. There are also typos in the manuscript.

Answer 2: Thank you for your useful suggestions. We have invited a native English speaker to edit our manuscript. And we have rewritten the Introduction and Discussion.

3 Abbreviations: All abbreviations should be revised and defined at their first use. For example, ypTNM stages in the Simple Summary section.

Answer 3: Thank you for your suggestion. We have defined the all abbreviations at their first use.

4 Abstract: Change “The aim of this study was to determine role” to “The aim of this study is to determine the role.”

Answer 4: Thank you for your correction. We have revised the sentence.

5  Abstract: Add a space between (EC) and Methods in: “cancer (EC).Methods.”

Answer 5: Thank you for your correction. We have added a space between (EC) and Methods in: “cancer (EC).Methods.”

6 Abstract: “506 patients with clinical positive lymph nodes and non-metastasis.” Correct: “506 patients with clinically positive lymph nodes and no metastasis.”

Answer 6: Thank you for your correction. We have revised the sentence according to your suggestion.

7  Abstract: “506 patients with clinical positive lymph nodes and non-metastasis.” What do authors mean by clinically positive lymph nodes? To assess whether there is lymph node metastasis, there should be pathologic evaluation. Also, authors should be more specific and say “no distant metastasis” as metastasis incorporates both lymph node and distant metastases.

Answer 7: Thank you for your notifications. We have change “no metastasis” to “no distant metastasis”. All of the included patients received neoadjuvant chemoradiotherapy since they were clinically diagnosed as positive lymph nodes through imaging evidence from computerized tomography. Therefore, our inclusion criteria included: patients were diagnosed as clinical lymph node metastasis positive (cN+) and no distant metastasis (cM0) before any treatments. Since all the patients received neoadjuvant chemoradiotherapy which could influence the pathologic status, we can not evaluate the lymph node metastasis pathologically before neoadjuvant therapy.

8  Abstract: “Patients receiving adjuvant therapy had a shorter post-resection overall survival (OS) and disease-free survival (DFS), with a significant difference between two groups.” What are the two groups? And What are the patients comparing “Patients receiving adjuvant therapy” to? Readers might also be confused here between adjuvant and neoadjuvant. It is not clear whether the patients included already underwent neoadjuvant chemoradiation followed by surgery prior to taking additional adjuvant therapy or they took adjuvant prior to surgery.

Answer 8: Thank you for your suggestions. We have revised into: Patients receiving adjuvant therapy had a significantly shorter post-resection overall survival (OS) and disease-free survival (DFS) compared with patients not receiving adjuvant therapy (Log-Rank, OS: P = 0.002; DFS: P < 0.001). And in the result section of Abstract we described the inclusion criteria: Results: 447 patients with clinical positive lymph nodes and no distant metastasis following neoadjuvant chemoradiotherapy and esophagectomy were eligible for analysis.

Comment 9: Abstract: “significantly unfavourable independently prognostic factor.” Change independently to independent.

Answer 9: Thank you for your correction. We have revised the word according to your suggestion.

Comment 10: Abstract: “P<0.001).Conclusion:” Add a space before “Conclusion.”

Answer 10: Thank you for your correction. We have added a space before “Conclusion” in abstract..

Comment 11: Abstract: “Adjuvant therapy is associated with poor OS and DFS in patients” The conclusions are actually quiet shocking. I wonder if authors adjusted their results and the analysis for other potential confounding factors such as comorbidities, age sex, etc. Unless patients were adjusted for all potential confounding factors, results will not be reliable. Theoretically, any adjuvant therapy is expected to instigate a favorable effect and prolong survival for patients and not the opposite.

Answer 11: Propensity score matching was used to balance the baseline characteristics between two groups.

Change 11: Due to the heterogeneity between two groups, propensity score matching was used to balance the baseline characteristics between “adjuvant” group and “non-adjuvant” group. After propensity score matching, there were 120 patients left in each group and patients were adjusted for all potential confounding factors (Table 1).

12  References: Many old references used need to be updated. An example is reference [1] from 2018. Updated versions in 2021 exist. Other resources to get the data from include Siegel et al. 2022.

Answer 12: Thank you for your notification. We have updated the references according to your suggestions.

13 Introduction: “varies extremely from areas and countries” should be “varies extremely among areas and countries.”

Answer 13: Thank you for your notification. We have revised the sentence according to your suggestions.

14 Introduction: “Literatures” is wrong. In English, there is no pleural for literature. Authors should do extensive English editing for their manuscript.

Answer 14: Thank you for your notification. We have revised the word according to your suggestions.

15 Introduction: Line 47: “with/without adjuvant with/without neoadjuvant.” What is the difference between adjuvant and neoadjuvant therapies? Not all readers might be familiar with this, so authors are recommended to elaborate more and explain the clinical stages of EC and therapeutic strategies used. Another important point here is that authors are using the term EC which included different malignant neoplasms including adenocarcinoma, squamous cell carcinoma, and leiomyosarcoma among others. It would be beneficial to also add some data to the introduction to give a background on EC malignancies, their epidemiology and management.

Answer 15: Thank you for your suggestions. In our revised manuscript, we only included squamous cell carcinoma. Meanwhile, we have revised the Introduction according to your useful suggestions.

Change 15: Esophageal cancer (EC) is the sixth leading cause of cancer deaths worldwide and the second deadliest gastrointestinal cancer after gastric carcinoma [1]. Literature reported that about 200,000 people die of EC annually worldwide and most cases of EC were diagnosed at advanced stages [1]. Esophageal squamous cell carcinoma (ESCC) represents the predominant subtype of EC, most of which are found in eastern Asia, and the morbidity varies extremely among areas and countries [2,3].

Although tremendous improvement of therapeutic modalities has been seen recently, the patient’s quality of life remains poor and the 5-year survival rate rarely exceeds 40% [3]. Currently, surgery remains the major treatment for patients with early stage resectable ESCC, whereas neoadjuvant therapy (chemotherapy, radiotherapy, or their combination prior to surgery) followed by esophagectomy is the standard of care for those with locally advanced disease (cT1-2N+ or cT3-4aN1-3). It has been proved that patients with locally advanced esophageal cancer could benefit from trimodal therapy (neoadjuvant concurrent chemoradiation followed by surgery) compared to surgery alone [2]. However, additional adjuvant therapy (chemotherapy and/or radiotherapy after surgery) may be necessary for patients not fully respond to neoadjuvant therapy, characterized as pathologically confirmed residual disease and lymph node metastasis (ypN1-3). Nevertheless, the use of adjuvant therapy remains controversial for these patients because the therapeutic efficacy may be insufficient to control the residual disease. In addition, patients are at additional risk of adverse events. Currently, there is no guideline recommendation to treat ESCC patients with adjuvant therapy after they receiving neoadjuvant chemoradiotherapy and esophagectomy [2]. Due to restricted number of clinical studies concerning this topic, the indication for adjuvant therapy after trimodal therapy is highly patients and institution dependent [4]. Although there are several large-scale studies investigating the utility of adjuvant therapy after neoadjuvant therapy and surgery in western populations, the majority of the cases included in these cohorts are esophageal adenocarcinoma, and the information about treatment regimens are missing [5-7]. Therefore, no clear evidence could guide the utilization of adjuvant therapy after trimodal therapy in patients with ESCC especially in east Asian region.

16 Introduction: “no guideline recommendation to treat EC patients with adjuvant therapy.” Give more details about the adjuvant therapy that could be given following neoadjuvant and surgery.

Answer 16: The details were added in the Introduction and the references were also be added.

17 Introduction: “As there is presently no clear evidence in previous study to guide the use of adjuvant therapy after neoadjuvant therapy and esophagectomy especially in east Asian region, there is uncertainty regarding which patients to consider treating and how pathology could influence these clinical decisions.” What previous study are the authors referring to? When there is mention of a study, there should be a reference citing that study.

Answer 17: The references were also be added in the manuscript.

18 Introduction: “To add evidences to this important.” Change to evidence as there is no pleural for the word evidence.

Answer 18: Thank you for your notification. We have revised the word according to your suggestions.

19  Methods: “patients pathologically were diagnosed as EC before treatment.” Change to “diagnosed with.”

Answer 19: Thank you for your notification. We have revised the word according to your suggestions.

20 Methods: Among the inclusion criteria, authors mentioned that “patients were staged according to the American Joint Committee on Cancer (AJCC) 8th edition.” However, those guidelines were published in 2016. Does that mean that the patients (2014-2020) were staged according to older guidelines and then restaged for the purpose of this study? This needs to be clarified and mentioned clearly.

Answer 20: Thank you for your suggestions. The patients included in our study from 2014 to 2016 were all re-staged according to the AJCC 8th edition.

Change 20: patients were staged according to the American Joint Committee on Cancer (AJCC) 8th edition (the patients included from 2014 to 2016 were staged according to AJCC 7th edition and then re-staged for the purpose of the study)

Comment 21:  Methods: “patients were diagnosed as clinical lymph node metastasis positive (cN+) and non-metastasis (cM0) before any treatments.” Clarify what is clinical LN metastasis (based on imaging?) and non-metastasis (do authors mean distant metastasis?).

Change 21: patients were diagnosed as clinical lymph node metastasis positive (cN+) (based on imaging evidence) and no distant metastasis (cM0) before any treatments.

22 Methods: “after radical esophagectomy with R0 resection.” What is meant by R0 resection?

Answer 22: The R0 resection means complete tumor resection.

Change 22: patients were assessed as negative surgical margin pathologically after radical esophagectomy with complete tumor resection (R0 resection).

23  Methods: “and were classified squamous cell, adenocarcinoma, adenosquamous carcinoma or other.” Correct to: “and were classified into squamous cell, adenocarcinoma, adenosquamous carcinoma or others.”

Answer 23:  The sentence has been revised into “Only patients with ESCC were included.” since the revised manuscript only included ESCC patients.

24  Figure 1: Change “Patients for Analysis” to “Patients meeting criteria to be included in the study.”

Answer 24: Thank you for your suggestions. We have changed “Patients for Analysis” to “Patients meeting criteria to be included in the study.”.

25  Figure 1: Legend needs to be more informative of the results presented.

Answer 25: Thank you for your suggestions. More informative of the results were presented in the figure legends.

26 Figure 1: Based on what did authors decide to stratify patients into Adjuvant versus non-Adjuvant treatments?

Answer 26: After the doctor's careful explanation the merits and demerits of adjuvant therapy, patients will choose the adjuvant treatments by themselves.

27  Methods: “gastroscopy, and blood test were performed.” Change blood test to tests and add the full word for the acronym CT before using it for the first time.

Answer 27: Thank you for your notification. We have revised the sentence according to your suggestions.

28  Methods: The section on Neoadjuvant Therapy is confusing. Probably, transforming this into a Table would make it easier for readers to track the different treatment options given and which patients were eligible for each.

Answer 28: Thank you for your suggestions. We have made a Table to describe our strategy of neoadjuvant therapy.

Change: Supplementary Table 1.

29  Methods: “with thoracic anastomoses combining with radical lymph node.” Change combining to combined.

Answer 29: Thank you for your notification. We have revised the word according to your suggestions.

30 Methods: “Two experienced pathologists fixed the dissected specimens, then embedded and stained them with diaminobenzidine chromogen counterstain solution and hematoxylin to routinely assess resected specimens histologically and pathologically.” This is not necessary. Authors could just say that specimens were sent to Pathology Department for further analysis where representative sections of the tumor and periesophageal tissues were taken for sufficient pathologic evaluation and staging.

Answer 30: Thank you for your suggestions. The sentence has been revised.

Change 30: Specimens were sent to Pathology Department for further analysis where representative sections of the tumor and periesophageal tissues were taken for sufficient pathologic evaluation and staging.

31  Methods: “Chemoradiotherapy was the radiotherapy conducted from the first day of the first chemotherapy cycle.” Consider rephrasing for better clarification: “Combined chemoradiotherapy included giving radiotherapy from the first day of the first chemotherapy cycle.”

Answer 31: Thank you for your notification. We have revised the sentence according to your suggestions.

32 Methods: “Usually, adjuvant therapy started 4 to 6 weeks after surgery.” Were there any guidelines followed to decide this?

Answer 32: Typically, adjuvant therapy is administered 4 to 6 weeks after esophagectomy based on NCCN Guideline [2,12].

33  Results: “Adjuvant therapy was documented for in.” this sentence is incomplete and needs revision.

Answer 33: Thank you for your notification. The sentence was revised into “Adjuvant therapy was performed in 163 (32.2%) patients.”

Change 33: Adjuvant therapy was performed in 163 (32.2%) patients.

Comment 34:  Results: “Patients receiving adjuvant therapy were more likely to have: gender of male, poorer differentiation, poorer tumor stage, more positive lymph nodes, advanced stage, lymphovascular and peripheral nerve invasion, and poorer response to neoadjuvant therapy.” This assumption should be also statistically analyzed. Authors need to compare between each of the patients’ demographics and characteristics in the two patient groups “non-adjuvant” versus “adjuvant” and add a column including p-values.

Answer 34: Thank you for your notification. We have compared between each of the patients’ demographics and characteristics in the two patient groups “non-adjuvant” versus “adjuvant” and add a column including p-values.

35 Table 1: when there is no missing data for a parameter, there is no need to add a row “missing.” Also, I suggest just removing the rows “missing” and adding the total number of patients for each parameter next to the variable name. For example, Cardiovascular disease (n=502).

Answer 35: Thank you for your useful suggestion. We have removed the rows “missing” and adding the total number of patients for each parameter next to the variable name.

36  Results: In Table 1 top row, No. (%) (n-506) is not correct as not all variables had complete data and there were missing data from some.

Answer 36: Thank you for your notification. We have removed the rows “missing” and adding the total number of patients for each parameter next to the variable name. The No. (%) (n=447) means the total number of the included patients.

37 Table 1: Formatting of this Table needs to be revised. Titles of variables can be in bold, and their categories below them not bolded. Authors can refer to this paper to have an idea how to better represent their results: Tables 1, 2, and 3 in https://linkinghub.elsevier.com/retrieve/pii/S1092-9134(21)00024-1. Same applies to Table 2.

Answer 37: Thank you for your suggestions. Tables were revised according to your suggestions.

Comment 38  Figure 2: Presentation of results here is very weak. Numbers in the images are super tiny and hard to read. I suggest diving the figure into two or more figures and enlarging the graphs to make them clear.

Answer 38: Thank you for your suggestions. We have enlarging the graphs to make them clear.

39  Figure 2: Authors did not mention whether those results are adjusted for confounding factors. If not, this is a major limitation in the study and makes all results not reliable.

Answer 39: Thank you for your suggestions. We used propensity score matching to adjust the confounding factors and eliminate the heterogeneity between two groups.

40 Results: “Ten variables were selected for multivariate Cox regression model entry due to P<0.05 on univariate analysis.” Kindly provide results of the univariate analysis as a supplementary material.

Answer 40: Thank you for your suggestions. The results of the univariate analysis was provided in the supplementary material.

41  Figure 4 legend: “Hazard ratios with 95% CI for the disease-free survivalin prespecified.” What is survivalin?

Answer 41: Sorry for the mistake. Hazard ratios with 95% CI for the disease-free survival in prespecified subgroups.

Change 41: Hazard ratios with 95% CI for the disease-free survival in prespecified subgroups.

 42 Figures: All the figure legends can be revised as to be more informative of the images presented. Also, statistical tests used and meaning of asterix need to be added. Abbreviations used withing Tables and Figures should be defined as well in the legends at the end.

Answer 42: Thank you for your suggestions. We have revised the figure legends according to your suggestions.

43  Discussion: Authors should focus more on the main findings and avoid repeating results presentation in the discussion. Authors could also correlate their findings with what has been published in literature. Clinical relevance should be added.

Answer 43: We have compared the present and previous publications in Discussion. And the clinical relevance was also added.

Author Response File: Author Response.doc

Round 2

Reviewer 1 Report

n/a

Reviewer 2 Report

Thank you.