Advanced radiotherapy technique in hepatocellular carcinoma with portal vein thrombosis: Feasibility and clinical outcomes

Chonlakiet Khorprasert; Kanokphorn Thonglert; Petch Alisanant; Napapat Amornwichet

doi:10.1371/journal.pone.0257556

Peer Review History

Original SubmissionMarch 12, 2021
18 May 2021 Decision Letter - Panagiotis Balermpas, Editor PONE-D-21-07678 Advanced radiotherapy technique in hepatocellular carcinoma with portal vein thrombosis: Feasibility and clinical outcomes PLOS ONE Dear Dr. Amornwichet, 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 02 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. 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). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. 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. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Panagiotis Balermpas Academic Editor PLOS ONE Additional Editor Comments: Dear authors, your manuscript is very interesting, however you will have to address the issues raised by the reviewers, especially the limitations and the discussion of the novelty/importance of your work, before the manuscript is suitable for publication. 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. In your ethics statement in the manuscript and in the online submission form, please ensure that you have discussed whether all data/samples were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data/samples from their medical records used in research, please include this information. 3. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript. 4. Please include a copy of Tables 5-7 which you refer to in your text on pages 12-14. 5. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. [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: Yes Reviewer #2: No ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: No Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: No Reviewer #2: 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: This is a well written and large retrospective overview of HCC/PVTT patients treated with radiotherapy. However, it does have some grammatical failures that should be corrected. Radiotherapy plays an increasingly important role in these patients and is included in the international guidelines as treatment option for Child Pugh A and B patients. SBRT appears to be even better than conventionally fractionated radiotherapy. I have some small remarks: Results: Patients who were treated between 2007 and 2019 were included. Radiotherapy has improved a lot in this period. Did you see any differences in local control, radiotherapy type and OS between patients treated earlier vs. later? Please correct EQD210 to EQD210 Please add the p value (site 10) to median survival comparing tumor size, also add the p value to survival comparing BED (site 11). Did you also know the ECOG-PS of these patients? Discussion: The first paragraph is a copy of your introduction. Please remove in one of the 2 sections, or adapt. Tables 5, 6 and 7 are not uploaded. Please add. A part of your patients were treated with SBRT. Did you see a difference in LC and OS in this subgroup? Were these lesions smaller? Please add some more information on these SBRT patients in your results section. Please compare your data to the newly published SBRT data in the discussion section. Reviewer #2: The manuscript analyses a large HCC cohort with portal vein tumor thrombus retrospectively. As data on this HCC subpopulation are relatively rare, the database is valuable, however the manuscript and data analysis have major issues which have to be fixed before publication. Major remarks: - radiation techniques and different dose-fractionation methods were completely mixed up and this can not be completely compensated by just calculating BED. Please add subgroup analyses of normofractionated and hypo fractionated (SBRT) treatments - what is meant by "advanced" RT technique? Techniques vary extremely from 3DCRT, IMRT, SBRT. Probably a subgroup analysis would bring more light to the data (eg group 1, SBRT; group 2, IMRT/VMAT/3DCRT with BED> a threshold and under this threshold - statistical analysis: which software has been used? This info is missing from M&M - please provide local control and competing-risk adjusted local. recurrence rates. - toxicity part is very short. Please add non-hepatic toxicity (gastrointestinal, eg stomach, duodenum) which usually can happen by liver SBRT. How about central hepatobiliary toxicity, cholestasis, etc. - table 1: some numbers do not seem to be correct/ do not add on to 100%. there were 160 Patients, but some data are not provided for all of them eg CP-score only for 157, tumor size only for 159...). For TNM, even 165 M0 stages are reported (but only 160 patients). Please check, and provide information on missing data - figure 2. probably the caption is mixed up. BED <10 cm????? - figure 3. please add to the Kaplan Meier analysis a competing-risk adjusted local recurrence rate. probably we have. a survival time bias here with a lot of patients dying before local relapse. Minor remarks: - abstract: please explain "10"m do you mean alpa-beta ratio? - do not begin a sentence with "and" - it is not usual to name the treating center in the abstract, please remove - follow-up instead of follows-up -what is meant bei EQD210? probably EQD2- for alpha-beta 10? ****** 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.0257556.r001
Revision 1
5 Jul 2021 Author Response Dear Editor, Thank you for inviting us to submit a revised draft of our manuscript entitled, "Advanced radiotherapy technique in Hepatocellular carcinoma with Portal Vein Thrombosis: Feasibility and clinical outcomes" to PLOS ONE. We also appreciate the time and effort you and each of the reviewers have dedicated to providing insightful feedback on ways to strengthen our paper. Thus, it is with great pleasure that we resubmit our article for further consideration. We have incorporated changes that reflect the detailed suggestions you have graciously provided. We also hope that our edits and the responses we provide below satisfactorily address all the issues and concerns you and the reviewers have noted. To facilitate your review of our revisions, the following is a point-by-point response to the questions and comments delivered in your letter. All modifications in the manuscript have been highlighted in yellow. EDITOR SUGGESTIONS: 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 • Thank you for your careful consideration. We have been thoroughly checked and corrected in accordance with PLOS ONE's style guidelines. 2. In your ethics statement in the manuscript and in the online submission form, please ensure that you have discussed whether all data/samples were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data/samples from their medical records used in research, please include this information. • As a response of your recommendation, we acknowledged your concern and addressed the ethical issue in the materials and methods section. 3. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript. • As a response of your recommendation, we acknowledged your concern and addressed the ethical issue in the materials and methods section. 4. Please include a copy of Tables 5-7 which you refer to in your text on pages 12-14. • We regret for the errors. They have been corrected. 5. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. • We adjusted the caption of the supplement material based on your recommendation. REVIEWER 1 COMMENTS: 1. This is a well written and large retrospective overview of HCC/PVTT patients treated with radiotherapy. However, it does have some grammatical failures that should be corrected. Radiotherapy plays an increasingly important role in these patients and is included in the international guidelines as treatment option for Child Pugh A and B patients. SBRT appears to be even better than conventionally fractionated radiotherapy. • Thank you so much for recognizing the importance of our work. We appreciate your efforts to enhance our work. Please accept an apology for any grammatical problems in the paper. We revised the manuscript with a stronger emphasis on the English language. 2. Patients who were treated between 2007 and 2019 were included. Radiotherapy has improved a lot in this period. Did you see any differences in local control, radiotherapy type and OS between patients treated earlier vs. later? • We conducted more analysis focused on your advice and chose 2015 as a cut point. Because our advanced SBRT machines were installed that year. Table 1 and p11 lines 148-152 contained the data. • 3. Please correct EQD210 to EQD210 • We have fixed the error. 4. Please add the p value (site 10) to median survival comparing tumor size, also add the p value to survival comparing BED (site 11). • As per your advice, we have included p-value. 5. Did you also know the ECOG-PS of these patients? • We agreed that the important factor is ECOG-PS. ECOG-PS data were partially missing from medical records. We did our best to investigate the additional note and acquire the ECOG-PS data. Additionally, we do uni and multivariate analyses, which include the ECOG-PS. Tables 1 and 2 contain data. 6. Discussion: The first paragraph is a copy of your introduction. Please remove in one of the 2 sections or adapt. • The first paragraph has been removed from the discussion section. We recognized your issue and agreed that they shared a common meaning. 7. Tables 5, 6 and 7 are not uploaded. Please add. • We regret for the errors. They have been corrected. 8. A part of your patients were treated with SBRT. Did you see a difference in LC and OS in this subgroup? Were these lesions smaller? Please add some more information on these SBRT patients in your results section. • SBRT is becoming more widely employed and has a larger role in hepatocellular cancer. We conducted and summarized an analysis concentrating on SBRT patients. The data are included in the discussion section on page 19 line 291-296, as well as in the S3, S4 Table, and S1 Fig. 9. Please compare your data to the newly published SBRT data in the discussion section. • We reviewed publications utilizing SBRT in HCC with PVTT. Our study demonstrated a comparable response rate and outcome. Page 19 line 297-300 and S5 Table provide the data. REVIEWER 2 COMMENTS: 1. The manuscript analyses a large HCC cohort with portal vein tumor thrombus retrospectively. As data on this HCC subpopulation are relatively rare, the database is valuable, however the manuscript and data analysis have major issues which have to be fixed before publication. • We appreciate your time and effort in providing us with suggestions to improve the quality of our study. 2. Radiation techniques and different dose-fractionation methods were completely mixed up and this can not be completely compensated by just calculating BED. Please add subgroup analyses of normofractionated and hypo fractionated (SBRT) treatments • We conducted and presented an analysis focusing on SBRT patients and comparing them to the non-SBRT group, which includes hypo- and normofrationation patients. The data are given in the discussion section beginning on page 19 line 291-296, as well as in the S3, S4 Table, and S1 Fig. 3. What is meant by "advanced" RT technique? Techniques vary extremely from 3DCRT, IMRT, SBRT. Probably a subgroup analysis would bring more light to the data (eg group 1, SBRT; group 2, IMRT/VMAT/3DCRT with BED> a threshold and under this threshold • We apologize for the confusion caused by the mix-up. What we are attempting to demonstrate is that the radiation approach used in the majority of this study, IMRT/VMAT, could spare liver tissue and can be safely delivered to HCC patients with PVTT who have a poor prognosis and limited treatment options. • After thoughtful consideration, we chose to do a subgroup analysis between SBRT and Non-SBRT, which includes normofractionation and hypofractionation utilizing 3D-CRT or IMRT/VMAT. However, the number of SBRT patients was insufficient to detect a significant difference in outcomes. 4. Statistical analysis: which software has been used? This info is missing from M&M • They are now included on page 8 line 136. 5. Please provide local control and competing-risk adjusted local. recurrence rates. • Competing risk analyses of local recurrence and associated factors have been conducted and are now presented on page 13 line 193-200 and in Table 3. 6. Toxicity part is very short. Please add non-hepatic toxicity (gastrointestinal, eg stomach, duodenum) which usually can happen by liver SBRT. How about central hepatobiliary toxicity, cholestasis, etc. • We have included a section on gastrointestinal toxicity. However, our dataset did not include any grade 3-4 acute or late gastrointestinal adverse events. The cholestasis was not clearly identified. Although there were 10.3 percent grade 3 and 3.8 percent grade 4 increases in total bilirubin, the causes could have been liver decompensation, tumor development, or cholestasis. Table 6 contains the data. 7. Table 1: some numbers do not seem to be correct/ do not add on to 100%. there were 160 Patients, but some data are not provided for all of them eg CP-score only for 157, tumor size only for 159...).For TNM, even 165 M0 stages are reported (but only 160 patients).Please check, and provide information on missing data • As a result of your feedback, we recalculated and included the missing data rows in Table 1. 8. Figure 2. probably the caption is mixed up. BED <10 cm????? • We apologize for the error, which has now been corrected. 9. Figure 3. please add to the Kaplan Meier analysis a competing-risk adjusted local recurrence rate. probably we have. a survival time bias here with a lot of patients dying before local relapse. • We present a competing-risk analysis of local relapse in Figure 5 and a comparison figure between patients who responded to radiation and those who did not, which was determined to be an unfavorable factor in Figure 6. • Regretfully, due to limitations in statistical software, we were unable to include the number at risk beneath the figures. 10. Abstract: please explain "10"m do you mean alpha-beta ratio? • It is the alpha/beta ratio used in calculation of BED. The further explanation is now included in the abstract. 11. Do not begin a sentence with "and" • We acknowledged and corrected all of them. 12. It is not usual to name the treating center in the abstract, please remove. • We removed it on your recommendation. 13. Follow-up instead of follows-up. • We have changed it in accordance with your recommendation. 14. What is meant by EQD210? probably EQD2- for alpha-beta 10? • Yes, it is. It was our error not to subscript 10 after the EQD2. All of them have been fixed, and further explanations have been added to the materials and methods section. Again, we appreciate you providing us with the opportunity to improve our manuscript through your insightful comments and queries. We have made a concerted effort to incorporate your suggestions. We hope that these adjustments will allow our manuscript to be published in PLOS ONE. Yours Sincerely, Chonlakiet Khorprasert M.D. (First author) Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Chulalongkorn University, Pathumwan, Bangkok, Thailand. Contact address: 1873, Rama 4 Rd., Pathumwan, Bangkok, Thailand 10330 Email: Chonlakiet.k@chula.ac.th Napapat Amornwichet M.D., Ph.D. (Corresponding author) Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Chulalongkorn University, Pathumwan, Bangkok, Thailand. Contact address: 1873, Rama 4 Rd., Pathumwan, Bangkok, Thailand 10330 Email: Napapat.a@chula.ac.th, Napapat.amornwichet@gmail.com Attachments Attachment Submitted filename: Response to reviewer.docx https://doi.org/10.1371/journal.pone.0257556.r002
6 Sep 2021 Decision Letter - Panagiotis Balermpas, Editor Advanced radiotherapy technique in hepatocellular carcinoma with portal vein thrombosis: Feasibility and clinical outcomes PONE-D-21-07678R1 Dear Dr. Amornwichet, 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, Panagiotis Balermpas 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 #3: 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 #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #3: 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 #3: No ****** 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 #3: No ****** 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: (No Response) Reviewer #3: All reviewer comments have been addressed. Some English errors are still present ( sentences still begin with "and", eg page 12, line 150. ****** 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 #3: No https://doi.org/10.1371/journal.pone.0257556.r003
Formally Accepted
14 Sep 2021 Acceptance Letter - Panagiotis Balermpas, Editor PONE-D-21-07678R1 Advanced radiotherapy technique in hepatocellular carcinoma with portal vein thrombosis: Feasibility and clinical outcomes Dear Dr. Amornwichet: 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. Panagiotis Balermpas Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0257556.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 .