The effect of adjuvant therapy for patients with intrahepatic cholangiocarcinoma after surgical resection: A systematic review and meta-analysis

Qiao Ke; Nanping Lin; Manjun Deng; Lei Wang; Yongyi Zeng; Jingfeng Liu

doi:10.1371/journal.pone.0229292

Peer Review History

Original SubmissionSeptember 29, 2019
30 Dec 2019 Decision Letter - Gianfranco D. Alpini, Editor PONE-D-19-27317 The effect of adjuvant therapy for patients with intrahepatic cholangiocarcinoma after surgical resection: a systematic review and meta-analysis PLOS ONE Dear Dr. Lei Wang, 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. We would appreciate receiving your revised manuscript within 60 days. 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. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. We look forward to receiving your revised manuscript. Kind regards, Gianfranco D. Alpini 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.plosone.org/attachments/PLOSOne_formatting_sample_main_body.pdf and http://www.plosone.org/attachments/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. At this time, we ask that you please provide the full search strategy and search terms for at least one database in the Supplementary information. 3. Thank you for stating the following beneath the Acknowledgments Section of your manuscript: "This study was supported by Startup Fund for scientific research, Fujian Medical University (Grant number: 2018QH1195)." We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: "Not application" Please provide an amended Funding Statement that declares all the funding or sources of support received during this specific study (whether external or internal to your organization) as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now Please state what role the funders took in the study. If any authors received a salary from any of your funders, please state which authors and which funder. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." c. Please include your amended statements within your cover letter; we will change the online submission form on your behalf. 4. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ [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: Yes 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: I read the manuscript Ke et al with great interest. The authors tried to answer the question whether adjuvant therapy (in different forms) for intrahepatic CCA would be useful or not using the meta-analysis of the published paper. With the large cohort of the meta-analysis and included study it looks like the statistical power seems adequate. However, the authors included studies which span over 30 years. I have several comments; 1- Due to 30 years of span (1990-2019), as also can be seen by Table 2, some chemotherapy agents were different. Therefore, the response to chemotherapy could be different. This should be acknowledged in the discussion as the most limiting factor for chemotherapy and chemoradipotherapy. This long time span eventually impacts on the surgical techniques as well. The power of meta-analysis is the large cohort but different surgical techniques, (improved techniques most recently with improved diagnostics) change the overall survival of CCA patients. This should be also acknowledged as an important limitation. 2- page 3, line 70 - Varies should be Various 3- page 4 line 77, OMIT, "badly". Again, the authors should add limitations to the study and soften the conclusion based on these limitations. Reviewer #2: This manuscript by Qiao Ke et al. is a meta-analysis evaluating the effect of adjuvant therapy (AT) for patients with intrahepatic cholangiocarcinoma (ICC) after resection. Resection is still the only potentially curative treatment for patients with intrahepatic cholangiocarcinoma (ICC), but the prognosis remains far from satisfactory. The role of conventional therapies (transarterial chemoembolization, chemotherapy and radiotherapy) has yet to be fully defined, particularly in the adjuvant and second-line settings. This is the first systematic review evaluating the clinical value of AT in the treatment of ICC, including 22 studies with 10181 patients. Results showed that some patients could be benefited from AT in a whole. However, not all AT strategies would bring benefit to patients with ICC, and the benefit of adjuvant radiotherapy needs to be further validated. Identifying the selected patients and choosing the appropriate AT strategy is a major challenge for Clinics. The manuscript is well written and easy to follow. The topic of this manuscript is of great interest. The Reviewer has just some issues to address. MAJOR 1. The major weaknesses of this study are well addressed by the Authors in the Discussion chapter: the studies are retrospective, indicating an obvious selection and recalling bias; most of the studies are multi-centers or based on the database mainly due to the rare incidence of ICC, which meant that procedure of surgical resection and AT were different and bias was hard to avoid; most of the cofounding factors such as radical resection and LNM are hard to be resorted in the original studies, which would weaken the conclusion; RFS is evaluated in only six of the 22 included studies, which is insufficient to evaluate the effect of AT on recurrence; publication bias is found in this meta-analysis. 2. Since a number of pathway-targeted therapies, as well as modulation of the immune environment, hold promise for patients with intrahepatic cholangiocarcinoma, the Authors should add this topic in the discussion. ****** 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". If this link does not appear, there are no attachment files to be viewed.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0229292.r001
Revision 1
31 Jan 2020 Author Response Dear editor, Firstly, we would like to thank the reviewers and the editor for the positive and constructive comments and suggestions. We have substantially revised our manuscript after reading the comments, and the revision was marked in red. In addition, the revision was re-edited literally, and the part of the method, especially the statistics, was checked repeatedly. Point by point responses to reviewers: 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.plosone.org/attachments/PLOSOne_formatting_sample_main_body.pdf and http://www.plosone.org/attachments/PLOSOne_formatting_sample_title_authors_affiliations.pdf Response: Thank you for your kindly reminder. We are sure that our manuscript is well meet the requirements of PLOS ONE. 2. At this time, we ask that you please provide the full search strategy and search terms for at least one database in the Supplementary information. Response: Thank you for your professional comment. Full search strategy and search terms for PubMed was uploaded as the Supplementary file. However, manually searching was repeated conducted through the references of the included studies, reviews, letters and comments. 3. Thank you for stating the following beneath the Acknowledgments Section of your manuscript: "This study was supported by Startup Fund for scientific research, Fujian Medical University (Grant number: 2018QH1195)." We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: "Not application" a.Please provide an amended Funding Statement that declares all the funding or sources of support received during this specific study (whether external or internal to your organization) as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now b.Please state what role the funders took in the study. If any authors received a salary from any of your funders, please state which authors and which funder. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." c.Please include your amended statements within your cover letter; we will change the online submission form on your behalf. Response: Thank you for your kindly reminder. Lei Wang is the grantee of the funding, but "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." We removed funding-related text from the manuscript and update our Funding Statement as you suggested. 4. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ Response: Thank you for your kindly reminder. We have added all the authors’s ORCID and updated our information. Reviewer #1: I read the manuscript Ke et al with great interest. The authors tried to answer the question whether adjuvant therapy (in different forms) for intrahepatic CCA would be useful or not using the meta-analysis of the published paper.With the large cohort of the meta-analysis and included study it looks like the statistical power seems adequate. However, the authors included studies which span over 30 years. I have several comments; 1- Due to 30 years of span (1990-2019), as also can be seen by Table 2, some chemotherapy agents were different. Therefore, the response to chemotherapy could be different. This should be acknowledged in the discussion as the most limiting factor for chemotherapy and chemoradipotherapy. This long time span eventually impacts on the surgical techniques as well. The power of meta-analysis is the large cohort but different surgical techniques, (improved techniques most recently with improved diagnostics) change the overall survival of CCA patients. This should be also acknowledged as an important limitation. Response: Thank you for your professional comment. Firstly, we admitted that the span of the included researches was a little longer. Considering that most of the included studies were after 2010, we conducted a subgroup analysis stratified by the publication year before and after 2010 as you suggested, and results showed that the results of two subgroup analysis were coincident with the whole, which indicated that the conclusion was robust to some extent. Secondly, as you indicated that “some chemotherapy agents were different “, and the relevant subgroup analysis was published previously, which was depicted in the “Discussion”. And, the emphasis and innovation were the subgroup analysis stratified by different adjuvant strategies including chemotherapy, TACE, radiotherapy, and chemoradiotherapy. Thirdly, as you pointed out that “different surgical techniques, (improved techniques most recently with improved diagnostics) change the overall survival of CCA patients”, but relevant subgroup analysis such as laparoscopic vs. open hepatectomy, major vs. minor hepatectomy, hepatectomy with or without lymphadenectomy were unable to conduct due to most of the data was unavailable. However, these limitations were emphasized in the “Discussion” as you suggested. 2- page 3, line 70 - Varies should be Various Response: Thank you for kindly reminder, and we corrected it in the revised manuscript. 3- page 4 line 77, OMIT, "badly". Response: Thank you for kindly reminder, and we corrected it in the revised manuscript. Again, the authors should add limitations to the study and soften the conclusion based on these limitations. Response: Thank you for kindly reminder, and we had softened our conclusion in the revised manuscript. Reviewer #2: This manuscript by Qiao Ke et al. is a meta-analysis evaluating the effect of adjuvant therapy (AT) for patients with intrahepatic cholangiocarcinoma (ICC) after resection. Resection is still the only potentially curative treatment for patients with intrahepatic cholangiocarcinoma (ICC), but the prognosis remains far from satisfactory. The role of conventional therapies (transarterial chemoembolization, chemotherapy and radiotherapy) has yet to be fully defined, particularly in the adjuvant and second-line settings. This is the first systematic review evaluating the clinical value of AT in the treatment of ICC, including 22 studies with 10181 patients. Results showed that some patients could be benefited from AT in a whole. However, not all AT strategies would bring benefit to patients with ICC, and the benefit of adjuvant radiotherapy needs to be further validated. Identifying the selected patients and choosing the appropriate AT strategy is a major challenge for Clinics. The manuscript is well written and easy to follow. The topic of this manuscript is of great interest. The Reviewer has just some issues to address. MAJOR 1. The major weaknesses of this study are well addressed by the Authors in the Discussion chapter: the studies are retrospective, indicating an obvious selection and recalling bias; most of the studies are multi-centers or based on the database mainly due to the rare incidence of ICC, which meant that procedure of surgical resection and AT were different and bias was hard to avoid; most of the cofounding factors such as radical resection and LNM are hard to be resorted in the original studies, which would weaken the conclusion; RFS is evaluated in only six of the 22 included studies, which is insufficient to evaluate the effect of AT on recurrence; publication bias is found in this meta-analysis. Response: Thank you for your professional comments, and these limitations above were hardly avoided, and would weaken the conclusion of this study. Hence, we had softened the conclusion in the revised manuscript. 2. Since a number of pathway-targeted therapies, as well as modulation of the immune environment, hold promise for patients with intrahepatic cholangiocarcinoma, the Authors should add this topic in the discussion. Response: Thank you for your professional comment. Considering the great advances in the pathway-targeted therapies and immunotherapies, prognosis of patients with intrahepatic cholangiocarcinoma following resection would be improved. Hence, we checked the latest reports on this topic, and added the progress in the revised “Discussion”. We are looking forward to receive your letter, and please contact me without any hesitation if you have any question. Best Regards, Yours sincerely, Qiao Ke Corresponding to Lei Wang, E-mail: wangleiy001@126.com Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0229292.r002
4 Feb 2020 Decision Letter - Gianfranco D. Alpini, Editor The effect of adjuvant therapy for patients with intrahepatic cholangiocarcinoma after surgical resection: a systematic review and meta-analysis PONE-D-19-27317R1 Dear Dr. Lei Wang, 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, Gianfranco D. Alpini Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ******** 2. 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: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 4. 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 ****** 5. 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 ****** 6. 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: Authors responded to all my comments properly and appropriate changes were made. No further comments. Reviewer #2: The Authors answered satisfactorily to reviewers' comments. ****** 7. 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 https://doi.org/10.1371/journal.pone.0229292.r003
Formally Accepted
7 Feb 2020 Acceptance Letter - Gianfranco D. Alpini, Editor PONE-D-19-27317R1 The effect of adjuvant therapy for patients with intrahepatic cholangiocarcinoma after surgical resection: a systematic review and meta-analysis Dear Dr. Wang: 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. Gianfranco D. Alpini Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0229292.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .