Total neoadjuvant therapy versus standard therapy in locally advanced rectal cancer: A systematic review and meta-analysis of 15 trials

Xiping Zhang; Shujie Ma; Yinyin Guo; Yang Luo; Laiyuan Li

doi:10.1371/journal.pone.0276599

Peer Review History

Original SubmissionApril 5, 2022
16 Jun 2022 Decision Letter - Norikatsu Miyoshi, Editor PONE-D-22-09905Total Neoadjuvant Therapy versus Standard Therapy in Locally Advanced Rectal Cancer:A Systematic Review and Meta-Analysis of 16 TrialsPLOS ONE Dear Dr. Li, 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 Jul 31 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're 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. 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Thank you for stating the following financial disclosure: “The Natural Science Foundation of Gansu Province (No.20JR10RA371, L.LY), Fundamental Research Funds for the Central Universities (No.lzujbky-2019-kb21 L.L.Y & No.lzujbky-2020-kb22 L.Y), and Institute Scientific Research Fund Project/Youth Project(No. 20GSSY4-8 L.L.Y).” Please state what role the funders took in the study. 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." If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. [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: These findings come from a meta-analysis of 16 research, eight of which were non-randomized and eight of which were randomized controlled trials comparing TNT to regular CRT. However, there are a few aspects that need to be clarified: 1. Before therapy, the characteristics of tumors in both groups should be evaluated and the results given (T stage N stage, whether they threaten CRM). 2. Both groups' post-radiotherapy waiting periods must be compared. 3. Distant metastases were investigated, but not local recurrence rates. Local recurrence rates, which are a crucial predictor of preoperative neoadjuvant therapy success, should not be overlooked. 4. Minor correction: Disease-free survival should be shortened to DFS. Reviewer #2: The authors meta-analysis answered a significant research question in the field of surgical oncological treatment for locally advanced rectal cancer . However, the following issues needed to be addressed before this piece of work could be published 1. There are spelling mistakes "PFS wrongly used for DFS" 2. The authors didn't give a based argument on the subject of TNT and standard care (CRT). In line 5, under discussion, the authors were silent /did not discuss the controversies surrounding the result from Habr -Gama et al, there are other excellent centres in the world who have not been able to reproduce the same result following TNT 3. The sentence in 15 is unclear to me "In this meta-analysis, the DFS and distant metastasis of TNT were significantly superior to nCRT alone, despite studies have shown that the watch-and-wait approach is associated with higher preserved rectum, which may be at the cost of reducing the rate of OS and increasing the risk of distant metastasis" 4. There is a similar publication on this subject by Liu S, Jiang T, Xiao L, Yang S et .at in cancer 2021. Why would you repeat a similar meta-analysis within a year part. I would have expected the authors to make reference to this study and show us a clear benefit of there's over the 2021 publication- this have not been done. 5. I would have expected the authors to buttress the positive findings from TNT by citing other authors report and perhaps proffer suggestion why there is no significant difference as regards surgical complication , R0 resection rate and distant metastasis . 6. I am not sure if the authors were meant to use the term superiority when referencing to the overall benefit of TNT over standard CRT. The superiority and inferiority test mostly applies to original research where is a null or alternative hypothesis to prove or disprove , hence to my understanding it does not apply to this meta-analysis. 7. There are other limitations to this study that was not discussed. 8. Would have expected the authors to make reference to QOL in TNT vs CRT even though , this might have not been discussed in the other main articles. ****** 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: Yes: Cihangir Akyol,MD. 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.] 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0276599.r001
Revision 1
21 Jul 2022 Author Response Dear Editors and Reviewers: Thank you for your letter and for the reviewers’ comments concerning our manuscript entitled “Total Neoadjuvant Therapy versus Standard Therapy in Locally Advanced Rectal Cancer:A Systematic Review and Meta-Analysis of 15 Trials” (ID: PONE-D-22-09905).Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our researches. We have studied comments carefully and have made correction which we hope meet with approval. Revised portion are marked in red in the paper. The main corrections in the paper and the responds to the reviewer’s comments are as flowing: We appreciate for Editors/Reviewers’ warm work earnestly, and hope that the correction will meet with approval. Once again, thank you very much for your comments and suggestions. Laiyuan Li Review Comments to the Author Reviewer #1: These findings come from a meta-analysis of 16 research, eight of which were non-randomized and eight of which were randomized controlled trials comparing TNT to regular CRT. However, there are a few aspects that need to be clarified: 1.Before therapy, the characteristics of tumors in both groups should be evaluated and the results given (T stage N stage, whether they threaten CRM). Response –We are very sorry for our negligence of characteristics of tumors, We have added CRM+ in Table 1, due to space constraints, only the stage of T4 N2 was added. 2.Both groups' post-radiotherapy waiting periods must be compared. Response –We have added in table 1. 3.Distant metastases were investigated, but not local recurrence rates. Local recurrence rates, which are a crucial predictor of preoperative neoadjuvant therapy success, should not be overlooked. Response –We have added it in methods and results section. 4. Minor correction: Disease-free survival should be shortened to DFS. Response –Yes, we have revised it.Special thanks to you for your careful revision. Reviewer #2: The authors meta-analysis answered a significant research question in the field of surgical oncological treatment for locally advanced rectal cancer . However, the following issues needed to be addressed before this piece of work could be published 1.There are spelling mistakes "PFS wrongly used for DFS" Response –We are very sorry for our incorrect writing, we have revised it. 2.The authors didn't give a based argument on the subject of TNT and standard care (CRT). In line 5, under discussion, the authors were silent /did not discuss the controversies surrounding the result from Habr -Gama et al, there are other excellent centres in the world who have not been able to reproduce the same result following TNT Response –We have made correction according to the comments.We made the following comments about the study: pCR for rectal cancer is associated with excellent long-term prognosis, independent of treatment strategy. Surgical resection may not improve outcomes while increasing the incidence of temporary or permanent stoma and unnecessary morbidity and mortality.Please find it on page 6, line 15. 3.The sentence in 15 is unclear to me "In this meta-analysis, the DFS and distant metastasis of TNT were significantly superior to nCRT alone, despite studies have shown that the watch-and-wait approach is associated with higher preserved rectum, which may be at the cost of reducing the rate of OS and increasing the risk of distant metastasis" Response –Considering the your suggestion,we have revised it as follow: In our meta-analysis, the rates of DFS and OS was significantly higher in the TNT group than in the nCRT group, although studies have shown that watch-and-wait approach is associated with higher rectal preservation, which may be at the expense of lower OS rates and increased risk of distant metastasis.Please find it on page 6, line 27. 4.There is a similar publication on this subject by Liu S, Jiang T, Xiao L, Yang S et .at in cancer 2021. Why would you repeat a similar meta-analysis within a year part. I would have expected the authors to make reference to this study and show us a clear benefit of there's over the 2021 publication- this have not been done. Response –Our comments are follow: Our results were consistent with previous reports.(PMID 33987952), however, our meta-analysis included more and newer studies, which further confirmed the advantage of TNT in rectal cancer. This study was conducted at an appropriate time, because enough data was available to use meta-analytical methods which enabled us to provide the most up-to-date information on this topic.Please find it on page 6, line 3. Liu S, Jiang T, Xiao L, et al. Total Neoadjuvant Therapy (TNT) versus Standard Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: A Systematic Review and Meta-Analysis. The oncologist 2021. 5.I would have expected the authors to buttress the positive findings from TNT by citing other authors report and perhaps proffer suggestion why there is no significant difference as regards surgical complication , R0 resection rate and distant metastasis. Response –Special thanks to you for your good comments.We have added relevant discussion as follow: However, these results should be interpreted with caution, as the lack of standardization of postoperative morbidity reports limits the interpretation of the results.Another disadvantage is the short follow-up period, so the assessment of long-term distant metastases needs to be cautious. Please find it on page 7, line 4. 6.I am not sure if the authors were meant to use the term superiority when referencing to the overall benefit of TNT over standard CRT. The superiority and inferiority test mostly applies to original research where is a null or alternative hypothesis to prove or disprove , hence to my understanding it does not apply to this meta-analysis. Response –We have re-written this sentence according to your suggestion:The rates of pCR was significantly higher in the TNT group than in the nCRT group.Please find it on page 1, line 25. 7.There are other limitations to this study that was not discussed. Response –Considering the Reviewer’s suggestion, we have added discussion as follow: However, these results should be interpreted with caution, as the lack of standardization of postoperative morbidity reports limits the interpretation of the results.Another disadvantage is the short follow-up period, so the assessment of long-term distant metastases needs to be cautious.Please find it on page 6, line 4. 8.Would have expected the authors to make reference to QOL in TNT vs CRT even though , this might have not been discussed in the other main articles. Response –We are very sorry for our incorrect writing, we have added it: Assessment of QoL was not included in this study, in a recent analysis of the EXPERT-C trial, intensified neoadjuvant strategy for QoL and bowel function did not appear to be significantly affected (PMID:26031368). Nevertheless, the absence of a control group of standard CRT limits the general applicability of our results and a definitive conclusion on the role of TNT in high-risk LARC can only be provided by randomised phase III trials.Please find it on page 7, line 9. Sclafani F, Peckitt C, Cunningham D, et al. Short- and Long-Term Quality of Life and Bowel Function in Patients With MRI-Defined, High-Risk, Locally Advanced Rectal Cancer Treated With an Intensified Neoadjuvant Strategy in the Randomized Phase 2 EXPERT-C Trial. Int J Radiat Oncol Biol Phys 2015; 93(2): 303-12. 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. Response –I agree with including full peer review and any attached files.Special thanks to you for your good comments. Attachments Attachment Submitted filename: Reviewer response.docx https://doi.org/10.1371/journal.pone.0276599.r002
11 Oct 2022 Decision Letter - Alessandro Rizzo, Editor Total Neoadjuvant Therapy versus Standard Therapy in Locally Advanced Rectal Cancer:A Systematic Review and Meta-Analysis of 15 Trials PONE-D-22-09905R1 Dear Dr. Li, 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, Alessandro Rizzo 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 ******** 2. Is the manuscript technically sound, and do the data support the conclusions? Reviewer #1: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? Reviewer #1: Yes ****** 6. Review Comments to the Author Reviewer #1: I would want to express my gratitude to the authors for all of the revisions. I believe that this study will be published in the form of a meta-analysis in the scientific literature. This meta-analysis will be an important cornerstone in the multidisciplinary treatment of rectal cancer, which is updated every day. I would also like to thank them for detecting the duplicate article that both reviewers overlooked and removed it from the study after they realized there was a problem. My opinion is that the version of the paper that is now being worked on is ready for publication. ****** 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: Yes: Cihangir Akyol ******** https://doi.org/10.1371/journal.pone.0276599.r003
Formally Accepted
13 Oct 2022 Acceptance Letter - Alessandro Rizzo, Editor PONE-D-22-09905R1 Total Neoadjuvant Therapy versus Standard Therapy in Locally Advanced Rectal Cancer:A Systematic Review and Meta-Analysis of 15 Trials Dear Dr. Li: 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. Alessandro Rizzo Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0276599.r004

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