Effect of Yttrium-90 transarterial radioembolization in patients with non-surgical hepatocellular carcinoma: A systematic review and meta-analysis

Simon Lemieux; Alex Buies; Alexis F. Turgeon; Julie Hallet; Gaétan Daigle; François Côté; Steeve Provencher

doi:10.1371/journal.pone.0247958

Peer Review History

Original SubmissionOctober 31, 2020
10 Dec 2020 Decision Letter - Yi-Hsiang Huang, Editor PONE-D-20-34186 Effect of Yttrium-90 transarterial radioembolization in patients with non-surgical hepatocellular carcinoma: a systematic review and meta-analysis PLOS ONE Dear Dr. Lemieux, 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 Jan 23 2021 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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Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. Kind regards, Yi-Hsiang Huang, 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 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 amend your list of authors on the manuscript to ensure that each author is linked to an affiliation. Authors’ affiliations should reflect the institution where the work was done (if authors moved subsequently, you can also list the new affiliation stating “current affiliation:….” as necessary). [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: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: N/A 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: The authors conducted a systematic review and meta-analysis study to evaluate the outcome of Yttrium-90 transarterial radioembolization in patients with non-surgical hepatocellular carcinoma. There are several comments: I. Strengths: A. This study was conducted under an exhaustive search and unpublished data from the reference authors were requested. B. All the enrolled studies were published RCTs and is different from prior meta-analysis studies which included cohort studies. II. Weakness: The enrolled studies were categorized into Y90-TARE vs. cTACE and Y90-TARE vs. Sorafenib initially, but in data analysis, all the studies were mixed and were divided as Y90-TARE vs. standard of care. Most subgroup analyses were also not very robust considering the limited number of trials Reviewer #2: In this systemic review with meta-analysis, the authors observed that Y90-TARE does not have significant clinical benefits for tumor control or survival in patients with non-surgical HCC. Major comments 1. Although the methods and statistics are correct in this study, major limitation still could not be ignored in the enrolled studies because 2 of 8 trials with a high risk of bias and 2 trials with concerns of bias in analysis of overall survival. In addition, most trials were at high risk of bias or of concerns in analysis of secondary outcomes, including progression-free survival, time to progression, disease control rate, etc. Such limitations would have great impact on the results in this study. The authors would at least eliminate two trials of high risk of bias in analysis of primary outcome. 2. Subgroup analysis according to the presence of co-treatment with systemic therapy was conducted for the rates of gastrointestinal ulcers. The authors still have better to perform similar subgroup analysis in other outcomes. Minor comments 1. There are many clinical evidences real-world data to support the new treatments of advanced or unresectable HCC. Therefore, the authors have better to revise the introduction “although new treatments are available, the survival benefit is still not optimal and new alternatives are sought”. 2. Citation should be added on the each trial in the table 1. 3. Y90-TARE seems to yield a significantly longer time to progression in the glass microsphere subgroup. The authors have to discuss this finding well. ****** 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.] 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.0247958.r001
Revision 1
22 Jan 2021 Author Response Comments from the editors: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. We have revised our manuscript according to PLOS ONE’s style requirements. We have also reviewed all file naming. 2. Please amend your list of authors on the manuscript to ensure that each author is linked to an affiliation. Authors’ affiliations should reflect the institution where the work was done (if authors moved subsequently, you can also list the new affiliation stating “current affiliation:….” as necessary). The list of authors has been revised and modifications have been made to ensure that each author is linked to an affiliation. Response to reviewer #1 comments: Strengths: A. This study was conducted under an exhaustive search and unpublished data from the reference authors were requested. B. All the enrolled studies were published RCTs and is different from prior meta-analysis studies which included cohort studies. Thank you for noting this. Weakness: The enrolled studies were categorized into Y90-TARE vs. cTACE and Y90-TARE vs. Sorafenib initially, but in data analysis, all the studies were mixed and were divided as Y90-TARE vs. standard of care. Most subgroup analyses were also not very robust considering the limited number of trials We thank the reviewer for his comment. The main purpose of a meta-analysis is to synthesize treatment effects considering all available data. By pooling data from different trials, the power to detect a differential effect is increased. Trials included in a systematic review frequently present some degree of clinical heterogeneity. This recommended approach improves the ability to answer important research questions and understand the modifiers of important treatment effects, such as type of comparator treatment. We however planned subgroup analyses a priori to evaluate whether the type of comparator could explain the findings. Response to reviewer #2 comments: Major comments 1. Although the methods and statistics are correct in this study, major limitation still could not be ignored in the enrolled studies because 2 of 8 trials with a high risk of bias and 2 trials with concerns of bias in analysis of overall survival. In addition, most trials were at high risk of bias or of concerns in analysis of secondary outcomes, including progression-free survival, time to progression, disease control rate, etc. Such limitations would have great impact on the results in this study. The authors would at least eliminate two trials of high risk of bias in analysis of primary outcome. We thank the reviewer for the thorough assessment of our work. As highlighted in our risk of bias assessment section, some of the included trials were at high risk of bias. However, rather than excluding trials, we explored the potential effect of the risk of bias in our subgroup analyses, as suggested by the Cochrane Methodology of systematic reviews and meta-analysis.[1] Subgroup analyses are in such situation more informative than sensitivity analyses where removing analyses would only inform of the remaining subgroup. 2. Subgroup analysis according to the presence of co-treatment with systemic therapy was conducted for the rates of gastrointestinal ulcers. The authors still have better to perform similar subgroup analysis in other outcomes. We performed subgroup analyses for each of our outcomes when possible to do so. Some could however not be conducted due to the absence of trials in each subgroup category. Progression-free survival, time to progression, and disease control rate were outcomes which only included Y90-TARE without co-treatment. We added specifications regarding the subgroup analyses that could not be conducted in S3 Appendix (under Tables A, B, and C). Minor comments 1. There are many clinical evidences real-world data to support the new treatments of advanced or unresectable HCC. Therefore, the authors have better to revise the introduction “although new treatments are available, the survival benefit is still not optimal and new alternatives are sought”. Thank you for your comment. Although many new treatments showing promising results are available, the quality of the evidence is still not optimal to be very assertive on the matter. We therefore prefer to keep the same phrasing. 2. Citation should be added on each trial in the table 1. The change has been made to Table 1. 3. Y90-TARE seems to yield a significantly longer time to progression in the glass microsphere subgroup. The authors have to discuss this finding well. Thank you for your comment. We modified the first paragraph of the discussion to highlight this finding and we also put this result in context with prior knowledge in the second paragraph of the discussion. REFERENCES: 1. Boutron I, Page MJ, Higgins JPT, Altman DG, Lundh A, Hróbjartsson A. Chapter 7: Considering bias and conflicts of interest among the included studies. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.1 (updated September 2020). Cochrane, 2020. Available from www.training.cochrane.org/handbook. Attachments Attachment Submitted filename: Response To Reviewers.docx https://doi.org/10.1371/journal.pone.0247958.r002
17 Feb 2021 Decision Letter - Yi-Hsiang Huang, Editor Effect of Yttrium-90 transarterial radioembolization in patients with non-surgical hepatocellular carcinoma: a systematic review and meta-analysis PONE-D-20-34186R1 Dear Dr. Lemieux, 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, Yi-Hsiang Huang, M.D., Ph.D. 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? 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 ****** 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? 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 ****** 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 ****** 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: The authors conducted more detailed subgroup analyses and explanation to support the strengths of this study. I have no further 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 https://doi.org/10.1371/journal.pone.0247958.r003
Formally Accepted
22 Feb 2021 Acceptance Letter - Yi-Hsiang Huang, Editor PONE-D-20-34186R1 Effect of Yttrium-90 transarterial radioembolization in patients with non-surgical hepatocellular carcinoma: a systematic review and meta-analysis Dear Dr. Lemieux: 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 Professor Yi-Hsiang Huang Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0247958.r004

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