Ten years of experience with endometrial cancer treatment in a single Brazilian institution: Patient characteristics and outcomes

Cristina Anton; Rodolpho Truffa Kleine; Eric Mayerhoff; Maria del Pilar Esteves Diz; Daniela de Freitas; Heloisa de Andrade Carvalho; João Paulo Mancusi de Carvalho; Alexandre Silva e Silva; Maria Luiza Nogueira Dias Genta; André Lopes de Faria e Silva; Rafael Calil Salim; Andrea Aranha; Rossana Veronica Mendoza Lopez; Filomena Marino Carvalho; Edmund Chada Baracat; Jesus Paula Carvalho

doi:10.1371/journal.pone.0229543

Peer Review History

Original SubmissionNovember 25, 2019
6 Jan 2020 Decision Letter - Jason Chia-Hsun Hsieh, Editor Transfer Alert This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present. PONE-D-19-32782 Ten years of experience with endometrial cancer treatment in a single Brazilian institution: Patient characteristics and outcomes PLOS ONE Dear Dr. Cristina Anton, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. ============================== ACADEMIC EDITOR: The manuscript might be significant for public health strategy in Brazil. However, the analysis of prognostic factors in Table 2 only by a univariate analysis seems inadequate. Please consider a multivariate analysis for all the factors before you draw a scientific conclusion. Also, there is no limitation in this study mentioned. Please provide a paragraph of the potential limitations in the present analysis. ============================== We would appreciate receiving your revised manuscript by Feb 20 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. 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We look forward to receiving your revised manuscript. Kind regards, Jason Chia-Hsun Hsieh, M.D. Ph.D Academic Editor PLOS ONE Journal requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Thank you for including your ethics statement in the manuscript: 'This retrospective study (institutional review board approval no. 457913–2018) involved the analysis of data from 703 patients diagnosed with endometrial cancer attended at the ICESP between December 2008 and January 2018.' a) Please amend your current ethics statement to include the full name of the ethics committee/institutional review board(s) that approved your specific study and confirm that your named institutional review board or ethics committee specifically approved this study. b) Once you have amended this/these statement(s) in the Methods section of the manuscript, please add the same text to the “Ethics Statement” field of the submission form (via “Edit Submission”). For additional information about PLOS ONE ethical requirements for human subjects research, please refer to http://journals.plos.org/plosone/s/submission-guidelines#loc-human-subjects-research 3. In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records/samples used in your retrospective study. Specifically, please ensure that you have discussed whether all data/samples were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data/samples from their medical records used in research, please include this information. 4. We noticed you have some minor occurrence(s) of overlapping text with the following previous publication(s), which needs to be addressed: https://doi.org/10.3802/jgo.2018.29.e100 In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the Methods section. Further consideration is dependent on these concerns being addressed. Additional Editor Comments (if provided): The manuscript might be significant for public health strategy in Brazil. However, the analysis of prognostic factors in Table 2 only by a univariate analysis seems inadequate. Please consider a multivariate analysis for all the factors before you draw a scientific conclusion. Also, there is no limitation in this study mentioned. Also, please provide a paragraph of the potential limitations in the present analysis. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: No Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: No Reviewer #2: No ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Im very appreciated to have reviewing this manuscript. The purpose of retrospective study is analyzed and evaluated the characteristics and prognostic factors of 703 patients with endometrial cancer treated at a single center over ten years, The data showed in this study was interesting and meaningful, but I have some comments and suggestions: 1. Firstly, please submit as a regular and standardized format of Plos One, it will help for the whole system and structure of this article; 2. Weaknesses are retrospective study and no something new point. It is better to describe more reasons to accept the authors' hypothesis. 3. In Table 1, the what is the foundation of your claim to stratified “Age” as 53 years, and “KPS stratified as 70 and 90”, and so on in the Table1. The methods are not mention in the statistical analysis. 4. This study is a valuable study but I think it is somewhat insufficient to publish in this journal. Reviewer #2: In this study, the authors analyze the characteristics, prognostic factors and outcomes of patients with endometrial cancer treated at a single tertiary Brazilian institution over a 10-year period. It was finally concluded that histological type and LVSI were strong prognostic predictors in this population. This study reports the characteristics and outcomes of endometrial cancer in a large population from a single institution. Its findings may be used to guide public policies of endometrial cancer in Brazil. In my opinion, the methodology of this manuscript is correct and the statistical is appropriate. However, what is the innovation of the study? The prognostic factors related to endometrial cancer mainly include clinical stage, histological type, LN metastatic status, LVSI, etc. Why is the conclusion of this study only related to histological type and LVSI? It is recommended that the author give interpretation and discussion and highlight the novelty of the study. Moreover, the manuscript needs substantial revision and improvement in English writing which are critical to the understanding of the research. Here are some comments； 1) “The disease-free and overall survival did not differ significantly between patients with stages II and III disease.” Please give the P values in each of the situation. 2) “Tumor size ranged from 0 to 16.5 cm (median 4cm Most tumors were endometrioid low grade.” There missed a “)” after “4cm”. 3) “Before surgery, 583 patients underwent CA125 testing. The median values were 21.9 (range 3–2293) U/mL overall, 15.4 (3–2220) U/mL among patients with stage I tumors, and 37.2 (5.3–2293) U/mL among those with stages III and IV tumors.” Please analysis whether there is a survival difference between high CA125 group and low CA125 group (the author can use 21.9U/ml as a cutoff value). 4) Please describe the method of calculating the adjusted hazard ratios (HR). ****** 6. 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Revision 1
7 Feb 2020 Author Response PONE-D-19-32782 Ten years of experience with endometrial cancer treatment in a single Brazilian institution: Patient characteristics and outcomes R.: We thank the editor and the reviewers for the careful analysis of our work. Please find below our answers and we are available for further clarification. Journal requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf R.: All the format alterations according PLoS style were done and we chose to highlight (in yellow) only text modifications and not formatting changes. 2. Thank you for including your ethics statement in the manuscript: 'This retrospective study (institutional review board approval no. 457913–2018) involved the analysis of data from 703 patients diagnosed with endometrial cancer attended at the ICESP between December 2008 and January 2018.' a) Please amend your current ethics statement to include the full name of the ethics committee/institutional review board(s) that approved your specific study and confirm that your named institutional review board or ethics committee specifically approved this study. b) Once you have amended this/these statement(s) in the Methods section of the manuscript, please add the same text to the “Ethics Statement” field of the submission form (via “Edit Submission”).3. In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records/samples used in your retrospective study. Specifically, please ensure that you have discussed whether all data/samples were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data/samples from their medical records used in research, please include this information. R.: We included the statement in the Methods statement, highlighted in yellow. 4. We noticed you have some minor occurrence(s) of overlapping text with the following previous publication(s), which needs to be addressed: https://doi.org/10.3802/jgo.2018.29.e100 In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the Methods section. Further consideration is dependent on these concerns being addressed. R.: Sorry, but we couldn’t identify the overlapping text. If you can help us by pointing out the sections with a problem more accurately, we appreciate it. Additional Editor Comments (if provided): The manuscript might be significant for public health strategy in Brazil. However, the analysis of prognostic factors in Table 2 only by a univariate analysis seems inadequate. Please consider a multivariate analysis for all the factors before you draw a scientific conclusion. Also, there is no limitation in this study mentioned.Also, please provide a paragraph of the potential limitations in the present analysis. R.: Thanks for the comments. The multivariate analysis was done and it is in 4th and 5th columns of Table 2. The description of the statistical method is highlighted in blue in the Method section. Potential limitations as strengths were highlighted in green, in the Discussion section. Reviewers' comments: Reviewer #1: Im very appreciated to have reviewing this manuscript. The purpose of retrospective study is analyzed and evaluated the characteristics and prognostic factors of 703 patients with endometrial cancer treated at a single center over ten years, The data showed in this study was interesting and meaningful, but I have some comments and suggestions: R.: Thanks for the comments and useful suggestions. 1. Firstly, please submit as a regular and standardized format of Plos One, it will help for the whole system and structure of this article; R.: All the format alterations according PLoS style were done. We chose to highlight (in yellow) only text modifications and not formatting changes. 2. Weaknesses are retrospective study and no something new point. It is better to describe more reasons to accept the authors' hypothesis. R.: Thanks for the comment. We agree and we have provided a more detailed description of the strengths and weaknesses in the discussion section (highlighted in green). 3. In Table 1, the what is the foundation of your claim to stratified “Age” as 53 years, and “KPS stratified as 70 and 90”, and so on in the Table1. The methods are not mention in the statistical analysis. R.: The 50y cut-off was selected because is the average age of natural menopause in Brazil, so we could have an idea of premenopausal incidence. We explained better in the Method section. The KPS 90 or 100 was compared to 70 or less because we want to identify the proportion of patients without disabilities vs. those with significant symptoms, excluding the cases doubtful. We justified in the Method section (highlighted in green). 4. This study is a valuable study but I think it is somewhat insufficient to publish in this journal. R.: We hope that after the changes, mostly motivated by your comments, the paper become more attractive. Reviewer #2: In this study, the authors analyze the characteristics, prognostic factors and outcomes of patients with endometrial cancer treated at a single tertiary Brazilian institution over a 10-year period. It was finally concluded that histological type and LVSI were strong prognostic predictors in this population. This study reports the characteristics and outcomes of endometrial cancer in a large population from a single institution. Its findings may be used to guide public policies of endometrial cancer in Brazil. In my opinion, the methodology of this manuscript is correct and the statistical is appropriate. However, what is the innovation of the study? The prognostic factors related to endometrial cancer mainly include clinical stage, histological type, LN metastatic status, LVSI, etc. Why is the conclusion of this study only related to histological type and LVSI? It is recommended that the author give interpretation and discussion and highlight the novelty of the study. R.: Thanks for the comments. We provided some changes, particularly in discussion, including weaknesses and strengths. Furthermore, we emphasized our finding related to similar prognosis of stages II and III (highlighted in green in the Discussion section and in the abstract). Besides, this study exposes an important problem, common to less developed countries, which is late diagnosis and encourages a changing in the approach of diagnosis (office biopsy instead of hysteroscopy). Moreover, the manuscript needs substantial revision and improvement in English writing which are critical to the understanding of the research. R.: We sent this version of the manuscript to revision by a professional edition service (Write Science Right; see certificate of edit) and they made a lot of changes. These changes are highlighted in pink. Please, let me know if it’s OK. Here are some comments； R.: Thanks for observations. 1) “The disease-free and overall survival did not differ significantly between patients with stages II and III disease.” Please give the P values in each of the situation. R.: Done. Highlighted in blue. 2) “Tumor size ranged from 0 to 16.5 cm (median 4cm Most tumors were endometrioid low grade.” There missed a “)” after “4cm”. R.: Thanks! Highlighted in blue 3) “Before surgery, 583 patients underwent CA125 testing. The median values were 21.9 (range 3–2293) U/mL overall, 15.4 (3–2220) U/mL among patients with stage I tumors, and 37.2 (5.3–2293) U/mL among those with stages III and IV tumors.” Please analysis whether there is a survival difference between high CA125 group and low CA125 group (the author can use 21.9U/ml as a cutoff value). R.: Thanks for the suggestion. We included HR for DFS and OS using the cut-off of median (21.9U/ml) (highlighted in blue). 4) Please describe the method of calculating the adjusted hazard ratios (HR). R.: The method was described in the inserted text highlighted in blue in the last paragraph of the Study cohort and statistical analysis Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0229543.r002
10 Feb 2020 Decision Letter - Jason Chia-Hsun Hsieh, Editor Ten years of experience with endometrial cancer treatment in a single Brazilian institution: Patient characteristics and outcomes PONE-D-19-32782R1 Dear Dr. Anton, We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements. Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication. Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. With kind regards, Jason Chia-Hsun Hsieh, M.D. Ph.D Academic Editor PLOS ONE Additional Editor Comments (optional): All the questions were answered and revised adequately. Reviewers' comments: https://doi.org/10.1371/journal.pone.0229543.r003
Formally Accepted
18 Feb 2020 Acceptance Letter - Jason Chia-Hsun Hsieh, Editor PONE-D-19-32782R1 Ten years of experience with endometrial cancer treatment in a single Brazilian institution: Patient characteristics and outcomes Dear Dr. Anton: I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. For any other questions or concerns, please email plosone@plos.org. Thank you for submitting your work to PLOS ONE. With kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Jason Chia-Hsun Hsieh Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0229543.r004

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