Author s response to reviews

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1 Author s response to reviews Title: Association between Charlson comorbidity index score and outcome in patients with stage IIIB-IV non-small cell lung cancer Authors: Lei Zhao (zhaoleilei0507@126.com) Lai-Han Leung (Lai-Han@126.com) Jing Wang (wangjing81@189.cn) Huihui Li (huihui_muzi@tom.com) Juanjuan Che (chejuan_2004@126.com) Lian Liu ( @qq.com) Xiaojun Yao (xjyao@must.edu.mo) Bangwei Cao (oncology@ccmu.edu.cn) Version: 1 Date: 16 Jun 2017 Author s response to reviews: PULM-D Jun Dear Dr. Alberto Di Leo, Thank you very much for your letter dated 24 May 2017, and the referees reports. Our manuscript entitled Association between Charlson comorbidity index score and outcome of patients with stage IIIB-IV non-small cell lung cancer" has been carefully revised on the original manuscript according to Editor and Reviewers suggestions.

2 We have provided a point-by-point response to the reviewers' comments and those portions have been changed by using red color in our revised manuscript. Here below is our point-to-point response to the Reviewers' suggestions. Thank you very much for your nice help. Sincerely yours, Prof. Bangwei Cao Reviewers' comments: Reviewer #1: Thank you for the opportunity to review the manuscript entitled "Association between Charlson comorbidity index score and outcome of patients with stage IIIB-IV non-small cell lung cancer" by Lei Zhao.TNM stage system evaluates cancer extension, but it does not include information of patient health condition. Performance status is usually used to evaluate general patient health condition in clinical practice. PS is, however, a rough index and subjective. A patient with PS0 sometimes has severe comorbidities. The Charlson comorbidity index predicts the one-year mortality for a patient who may have a range of comorbid conditions, such as heart disease, or cancer and is considered more objective and more accurate than PS index. It is well known that not only TNM stage but also patient general health condition is associated with OS significantly and a treatment strategy should be selected considering these factors. This article evaluated CCI score and other parameters including age, gender and smoking status and so on in patients with Stage IIIB/IV. 1. A major concern is that CCI system includes factors of TNM staging system. For example, metastatic tumor means M1 Stage IV and scores 6 point by CCI. The authors divided the CCI score between >=9 and <9. It is considered that presence of the "M" factor played a significant role in this study. I wonder if it might be a right method to evaluate CCI and TNM stage together in multivariate analysis.

3 Response: We agree with the reviewer's criticism and suggestion. We have added a section in Discussion to illustrate the effect of TNM stage and CCI in the prognosis of NSCLC patients. 2. A prediction using CCI would be more accurate than one using TNM stage in this patient population, because CCI includes not only a part of TNM stage but patient other health information. In this study, a difference in OS between IIIB and IV was 3 months and one between CCI >=9 and <9 was 3 months. It seems the same. Although this paper showed that CCI was an independent prognostic factor, I do not think that CCI is more useful and more accurate than TNM. I wonder if CCI system does not fit well in the patients with stage IIIB/IV whose expected lifetime was short as 1-2 years. Response: We agree with the reviewer's criticism and suggestion. We have added a section in Discussion to illustrate the effect of TNM stage and CCI in the prognosis of NSCLC patients. 3. I think that disease stage was decided according to 7th edition in this paper. A comment should be added somewhere in Methods. Response: We agree with the reviewer's suggestion. We have added a comment in Methods in our revised manuscript. Reviewer #2: The Authors presented the results of a study on the association between Charlson comorbidity index score and outcome of patients with stage IIIB-IV non-small cell lung cancer. Only patients without gene mutations of EGFR or ALK were included in the study. 1. The manuscript is interesting and well written; anyway I would suggest a language revision (e.g. in the "patient population" paragraph, please rephrase the statement: "Patients were excluded who did not fulfill the inclusion criteria.") The Methods section is clear and well structured; the statistical analysis was well carried out and results were clearly presented. However the relatively small sample size represents an important limitation of the study. Response: We agree with the reviewers criticism and have made correction in our revised manuscript. According to the Reviewer s suggestion, we also have seeked the assistance of language editing service offered by Nature Research Editing Service.

4 2. The discussion section should include more updated references on how comorbidities may influence the progression of aggressive cancers (e.g. Grosso G, BMC Surg. 2012; 12 Suppl 1:S20; Grosso G Nutr Cancer. 2014; 66(4):558-65; Marventano S, BMC Surg. 2013; 13 Suppl 2:S15). Response: We agree with the reviewer's suggestion. We have updated the references and in the discussion section. 3. Also, I would include a statement in the conclusion paragraph on the future direction and usefulness of Charlson comorbidity index for predicting overall survival in patients with different type of tumors. Response: We agree with the reviewer's suggestion. We have added a statement in the conclusion paragraph on the future direction and usefulness of Charlson comorbidity index for predicting overall survival in patients with different type of tumors. Editor's comments: 1. Please include a cover letter with a point-by-point response to the comments, describing any additional experiments that were carried out and including a detailed rebuttal of any criticisms or requested revisions that you disagreed with. Please also ensure that all changes to the manuscript are indicated in the text by highlighting or using track changes. Response: We have provided a point-by-point response to the reviewers' comments. This is the cover letter containing detailed point-by-point response to the reviewers' comments and those portions have been changed by using red color in our revised manuscript. 2. Please also ensure that your revised manuscript conforms to the journal style, which can be found in the Instructions for Authors on the journal homepage. Response: We agree with the editor's suggestion. The manuscript was carefully refined and improved before the revision was submitted according to the Instructions for Authors.

5 3. If improvements to the English language within your manuscript have been requested, you should have your manuscript reviewed by someone who is fluent in English. If you would like professional help in revising this manuscript, you can use any reputable English language editing service. We can recommend our affiliates Nature Research Editing Service ( and American Journal Experts ( for help with English usage. Response: We agree with the editor's suggestion. We have seeked the assistance of language editing service offered by Nature Research Editing Service.