Predictive factors for long-term survival after surgery for pancreatic ductal adenocarcinoma: Making a case for standardized reporting of the resection margin using certified cancer center data

Dirk Weyhe; Dennis Obonyo; Verena Nicole Uslar; Ingo Stricker; Andrea Tannapfel

doi:10.1371/journal.pone.0248633

Peer Review History

Original SubmissionDecember 4, 2020
13 Jan 2021 Decision Letter - Ulrich Wellner, 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-20-38146 Predictive factors for long-term survival after Surgery for Pancreatic ductal adenocarcinoma: making a case for standardized reporting of the resection margin using certified cancer center data PLOS ONE Dear Dr. Uslar, 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. Please submit your revised manuscript by Feb 14 2021 11:59PM. 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The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information. 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Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. We will update your Data Availability statement on your behalf to reflect the information you provide. [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: Yes 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: Yes 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: Yes Reviewer #2: Yes ****** 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: Surgical procedures are the most effective treatment for pancreatic ductal adenocarcinoma. Currently, there is no uniform standard for surgical margin management. The authors analyzed and compared CRM status and R status on survival after surgery for PDAC of the pancreatic head. Here are some comments and opinions. 1. the positive surgical margin is related to the aggressiveness of tumor. Is it possible to include relevant data such as tumor size, tumor pathological differentiation, and CA199 level into the study 2. is there a difference in the recurrence-free survival of patients 3. 36 months as the cut-off point for long-term survival, how is this time chosen? 4. is it possible to provide data on the causes of patients' death? Reviewer #2: The work by Dirk Weyhe et al., entitled “Predictive factors for long-term survival after Surgery for Pancreatic ductal adenocarcinoma: making a case for standardized reporting of the resection margin using certified cancer center data” systematically explored the issue that standardized reporting of the resection margin after PDAC. The authors performed a retrospective study of 95 patients with pancreatic cancer to analyze two different resection margin definitions using univariate OS and multivariate long-term survival. Results showed that chemotherapy, nodal status and resection margin according to UICC R status were univariate factors for OS after PDAC, while long-term survival seems to depend on wider resection margins than those used in UICC R classification. Therefore, authors suggested that standardized histopathological reporting (including resection margin size) should be agreed upon. Manuscript was well prepared. The topic of this manuscript is meaningful, which focus on the resection margin easily neglected in clinical treatment. Limitations of this study also be discussed. However, several concerns about this manuscript should be pointed out and revised. 1. Although the reasons for using logistic regression instead of Cox regression was explained, the survival time of patients with pancreatic cancer is still an important observation point. It is recommended to use multivariate Cox regression to analyze the long-term survival and present the results in supplementary table. 2. It is needed to explain why nodal status and chemotherapy administration, instead of other factors, are included in the main observation indicators and the subsequent multi-factor logistic regression. 3. The difference in the definition of the resection margin range is the main difference between the two reporting methods (CRM versus UICC R, 1 mm versus 0 mm). In this case, it is recommended to add the analyses of survival of patients with pancreatic ductal adenocarcinoma with a margin of 0 ~ 1 mm, and compare ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". 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Revision 1
22 Feb 2021 Author Response Dear reviewers, dear editor, Thank you very much for your time and effort in reviewing this manuscript. We were happy to note that requests for changes were few, and that the reviews were overall very positive. We addressed all comments and changed the manuscript accordingly. We hope that with the changes made due to your feedback, the revised manuscript is now clearer at those critical points. At least we think that the paper has gained in quality through your comments and the changes based on them. Below you will find your comments and our respective responses. With kind regards and thank you very much for your time, Verena Uslar for all authors Editors’ comments 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 https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf --> Sorry for this inconvenience. We changed the layout accordingly. 2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information. If you are reporting a retrospective study of medical records or archived samples, please ensure that you have discussed whether all data 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 from their medical records used in research, please include this information. --> The respective paragraph now reads: The study was approved by the medical Committee for Research Ethics at the University of Oldenburg (reference number: 2019-071) without the need for Informed Consent due to the retrospective nature of this study, and was registered with the German Clinical Trials Registry (reference number DRKS0017425). It followed the Helsinki Declaration. 3. We noted in your submission details that a portion of your manuscript may have been presented or published elsewhere. "preliminary results were published as an abstract in a conference: Weyhe, D., Uslar, V., Sahlmann, B., & Tannapfel, A. (2018, January). Circumferential Resection Margin influences long term survival after pancreatic adenocarcinoma. In ONCOLOGY RESEARCH AND TREATMENT (Vol. 41, pp. 171-171). ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND: KARGER." Please clarify whether this conference proceeding or publication was peer-reviewed and formally published. If this work was previously peer-reviewed and published, in the cover letter please provide the reason that this work does not constitute dual publication and should be included in the current manuscript. --> The abstract submitted to the conference was peer-reviewed, and was then published in the conference proceedings. Since the publication constitutes only of a 300 word abstract, this does not constitute dual publication from our point of view. We hope you agree. 4. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. We will update your Data Availability statement on your behalf to reflect the information you provide. --> We were not sure about the legal ramifications of publishing our data at the time of submission. We have cleared our questions with our ethics committee and will upload our data set as supporting information with the revised manuscript Reviewers' comments: 1. Is the manuscript technically sound, and do the data support the conclusions? Reviewer #1: Partly Reviewer #2: Yes ________________________________________ 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ________________________________________ 3. Have the authors made all data underlying the findings in their manuscript fully available? Reviewer #1: Yes Reviewer #2: Yes ________________________________________ 4. Is the manuscript presented in an intelligible fashion and written in standard English? Reviewer #1: Yes Reviewer #2: Yes ________________________________________ 5. Review Comments to the Author Reviewer #1: Surgical procedures are the most effective treatment for pancreatic ductal adenocarcinoma. Currently, there is no uniform standard for surgical margin management. The authors analyzed and compared CRM status and R status on survival after surgery for PDAC of the pancreatic head. Here are some comments and opinions. 1. the positive surgical margin is related to the aggressiveness of tumor. Is it possible to include relevant data such as tumor size, tumor pathological differentiation, and CA199 level into the study --> we included tumor size and pathological differentiation in the table with the patient characteristics. We refrained from including CA-19-9 since the time point for which this information was available was very heterogenous across patients, and therefore would not added viable information. 2. is there a difference in the recurrence-free survival of patients --> Yes, RFS differed between CRM pos and CRM neg, and between R0 and R1 respectively. We included this in the patient characteristics table, in the results, and one in sentence in the discussion. 3. 36 months as the cut-off point for long-term survival, how is this time chosen? --> 3 yrs were chosen because it corresponds roughly to the time when about 1/3 of all patients were still alive. We deemed it interesting to analyze why this collective had a better long-term survival as compared to the average PDAC patient. We agree this should be mentioned, and therefore added a sentence explaining this in the methods section. 4. is it possible to provide data on the causes of patients' death? --> sadly, due to the retrospective character of this study, we only know cause of death for about a third of our patients. The tumor documenters who maintain these data unfortunately often receive information on the time of death only from obituaries. However, in those cases we do know, about 90% died because of recurring disease. We included a sentence with regards to this in the manuscript. Reviewer #2: The work by Dirk Weyhe et al., entitled “Predictive factors for long-term survival after Surgery for Pancreatic ductal adenocarcinoma: making a case for standardized reporting of the resection margin using certified cancer center data” systematically explored the issue that standardized reporting of the resection margin after PDAC. The authors performed a retrospective study of 95 patients with pancreatic cancer to analyze two different resection margin definitions using univariate OS and multivariate long-term survival. Results showed that chemotherapy, nodal status and resection margin according to UICC R status were univariate factors for OS after PDAC, while long-term survival seems to depend on wider resection margins than those used in UICC R classification. Therefore, authors suggested that standardized histopathological reporting (including resection margin size) should be agreed upon. Manuscript was well prepared. The topic of this manuscript is meaningful, which focus on the resection margin easily neglected in clinical treatment. Limitations of this study also be discussed. However, several concerns about this manuscript should be pointed out and revised. 1. Although the reasons for using logistic regression instead of Cox regression was explained, the survival time of patients with pancreatic cancer is still an important observation point. It is recommended to use multivariate Cox regression to analyze the long-term survival and present the results in supplementary table. --> This is a very good suggestion that we would normally be very happy to consider. And indeed the results of the Cox regression largely support the results of our logistic regression. However, the Cox regression is not appropriate for our data, as the requirements for the application of this statistical test are violated. We were sorry to note that the manuscript was not very clear in that regard, and changed formulations at a few paragraphs accordingly, to better reflect that decision. In addition to one of the authors being very proficient in statistical analysis, we cleared this with a biometric expert at our university to make sure. 2. It is needed to explain why nodal status and chemotherapy administration, instead of other factors, are included in the main observation indicators and the subsequent multi-factor logistic regression. --> It is known from previous studies using univariate analyses that nodal status and chemotherapy are two of the most important factors influencing survival after PDAC. Therefore, we included those in the univariate analysis, to establish if our data supports this, which indeed is does. In the multivariate analysis we included the following variables as described in the manuscript: age at the time of surgery, sex, ASA score, pT, pN, pM, lymph node ratio, pR, CRM, and systemic therapy received or not. On the one hand, variable selection was made for pragmatic reasons, since those variables were readily and more importantly reliably available. On the other hand, the included variables all made sense from a clinical point of view, and we think the chosen variables represent the most important patient characteristics which might have confounded our findings. We included the following paragraph in the manuscript to that regard. 3. The difference in the definition of the resection margin range is the main difference between the two reporting methods (CRM versus UICC R, 1 mm versus 0 mm). In this case, it is recommended to add the analyses of survival of patients with pancreatic ductal adenocarcinoma with a margin of 0 ~ 1 mm, and compare --> Thank you very much for this comment. We are aware of the ongoing discussion on this topic. For example, we have quoted Strobel et al. However, from our point of view, three arguments speak against this approach. Firstly, our resected specimens have been analyzed by our colleagues in pathology since 2010 according to the Verbeke protocol, and our tumor documenters use the 8th Edition of the UICC TNM classification of malignant tumors, 2017, for R classification, so that our analysis also focuses on these classifications. We now added a sentence in the methods section (histopathological assessment) to explain this. Secondly, since these classifications also are still most common today, at least in Germany, the analysis we have chosen is also very relevant for many colleagues with regard to their own data. And thirdly, with some reworking, we could probably make the desired classification and then analyze it. However, according to our current knowledge, there are only 11 patients in the one group, which does not allow for a meaningful analysis. In addition, we would like to point out, that doing this analysis would in our view completely change the intention and the structure of this paper. Attachments Attachment Submitted filename: Rebuttal letter Weyhe.docx https://doi.org/10.1371/journal.pone.0248633.r002
3 Mar 2021 Decision Letter - Ulrich Wellner, Editor Predictive factors for long-term survival after surgery for pancreatic ductal adenocarcinoma: making a case for standardized reporting of the resection margin using certified cancer center data PONE-D-20-38146R1 Dear Dr. Uslar, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. 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 help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- 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. Kind regards, Ulrich Wellner, PD Dr. med. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0248633.r003
Formally Accepted
9 Mar 2021 Acceptance Letter - Ulrich Wellner, Editor PONE-D-20-38146R1 Predictive factors for long-term survival after surgery for pancreatic ductal adenocarcinoma: making a case for standardized reporting of the resection margin using certified cancer center data Dear Dr. Uslar: I'm 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 let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Ulrich Wellner Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0248633.r004

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