Prediction of radiation pneumonitis using dose-volume histogram parameters with high attenuation in two types of cancer: A retrospective study

Yasuki Uchida; Takuya Tsugawa; Sachiko Tanaka-Mizuno; Kazuo Noma; Ken Aoki; Kentaro Fukunaga; Hiroaki Nakagawa; Daisuke Kinose; Masafumi Yamaguchi; Makoto Osawa; Taishi Nagao; Emiko Ogawa; Yasutaka Nakano

doi:10.1371/journal.pone.0244143

Peer Review History

Original SubmissionJune 2, 2020
18 Aug 2020 Decision Letter - Dandan Zheng, Editor PONE-D-20-14886 Prediction of radiation pneumonitis using dose-volume histogram parameters with high attenuation in two types of cancer: A retrospective study PLOS ONE Dear Dr. Nakano, 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 Oct 02 2020 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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Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests 4. Please amend your list of authors on the manuscript to ensure that each author is linked to an affiliation. 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Reviewer #1: No Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No 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: General comments The concept of segmenting the lung volume into low density and high density regions, and ignoring the low density is interesting. It is reasonable to expect a differential in the metrics vs clinical outcomes after subtracting out the low density volumes. It does seem, however, that this is a small improvement on current metrics. The paper requires several major additions to more clearly and definitively show that these differences are meaningful. Major things Choice of CT number Please expand on the choice of -856 HU, why this value? could other choices be made? Ideally one would perform your LAV segmented analysis for a range HU and find the HU number cut-off with the largest improvement in over the non-segmented metrics. Direct comparison of the of new segmented HAV metrics to corresponding traditional V metrics The data suggests that the percentage of low attenuation volume is roughly 10% or less of the total lung volume. Doesn’t this mean that the segmentation is only a small (roughly 10% or less) correction compared to standard analyses without the LAV segmentation? Please directly compare and comment on the statistical significance of the differences between segmented and non-segmented metrics g.g. HAV20% = 33.7 and V20% = 35.2 for lung cancer. Total patients is 77. Is this segmented HAV20% really a significant improvement on the V20%? My quick visual comparison suggests that most the “V” metrics give very similar results to their HAV counterparts. Same also for the ROC results: e.g HAV10% = 0.869 vs V10%=0.849 in the esophageal ROC figure. Is this difference significant? Important missing technical details If possible, also give the mass density or electron densities that the -856 HU threshold value corresponds to for your CT scanner (or at least give a density range). Please specify the dose calculation algorithms used? This may be particularly significant as simpler algorithms such as Varian’s AAA algorithm, is known to overestimate dose to low density lung volumes compared to Boltsmann-solver or Monte-Carlo algorithms such as accuros. Please specify the breathing phase of the CT scan (inspiration breathhold , free breathing,4$D CT at a given phase etc). Note that you may want to add to the discussion that for inspiration-breathold scans which are commonly used for SBRT lung radiotherapy treatments would have larger LAV% and hence larger differential between the segmented and non-segmented metrics. Please also discuss the margins and motion management during treatment (presumably no gating, no breathold was used on these treatments?). Smaller things line 49 “have set vague cut-off values for” strongly suggest to remove word “vague” as the metrics themselves are not vague. Use of “cut-off” is unusual. Suggest to replace “cut-off” with “constraints” as the constraints can be one of a number of metrics such as: volume that gets at least a given dose, mean dose, max dose. Line 50-51 “lung volume receiving 20 Gy or more (V20%) (30−40%) to reduce the risk of RP” Terminology as given is confusing: We need both Dose in Gy and volume in % to define the “V” metrics. Normally the first number (eg V20) is the dose in Gy, not % dose nor % volume. E.g. V20 < 30% means the volume that receives at least 20 Gy should be less than 30% of the lung volume. Here by writing V20% you are implying that the 20 refers to a %, where it normally refers to the dose in Gy. Please correct the your “V20%” notation to the more standard notation “V20 <20%” and complete notation defining both the dose and the volume. For example see the RTOG 0937 protocol where this constraint originated: https://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?action=openFile&FileID=13697 Line 52 For clarity suggest to explain or expand on “low attenuation” and “high attenuation” straightaway eg consider “volumes of low attenuation in CT imaging” Suggest to also apply to abstract. Line 52 It is technically wrong to say “areas of low attenuation” you mean “volumes of low attenuation” Line 80 “using the threshold limit of −856 HU” Replace with “using the upper threshold limit of −856 HU” Line 106 please specify more clearly and consistent with standard notation Replace “V2%, V5%, V10%, V20%, and V30%,” with presumed meaning: “V20 Gy < 2%, 5%, 10%, 20%, 30%” Please also clearly specify that it is the volume of both lungs if that is the case. Tables I find the extreme-spaced tables impossible to digest. E.g table 1 is only 3 data columns but spans 3 pages. data too spread out to meaningfully digest. Please specify the resolution, or at least range of resolutions / slice thickness settings used for the CT scans. E.g. voxel size can effect the segmented volumes if the resolution is too course. e.g a voxel that is 4/5 with air 1/5 dense tumor tissue will represented by approx -800HU Reviewer #2: The manuscript was well written and the analysis was properly done to support the conclusion. There are a few suggestions for author to consider: 1. It's not very clear in the manuscript how the MU threshold of “- 856” was determined. Was there any systematic analysis done? As you have presented in the manuscript, by setting such a threshold it will impact the selection of optimal dose evaluation criteria and corresponding volume threshold. It's probably a good idea to address this issue to ensure that the difference in dose evaluation was not caused by the uncertainty of the chosen threshold. 2. As what I have noticed that only a small portion of plans were done with IMRT technique, this can potentially introduce bias since static IMRT or VMAT plans can have higher, if not much higher, low dose contribution to the treatment. That means if the portion of the IMRT plan increases, one may see the optimal dose evaluation criteria shift towards low dose. 3. For conventional lung radiation therapy, I can imagine the fractional dose would be similar. However, it would be clearer to include the fractional dose information rather than just the total dose > 30Gy when demonstrating the patient selection criteria. ****** 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.0244143.r001
Revision 1
2 Oct 2020 Author Response Response to Reviewer #1: Thank you very much for providing us with important insights. We are delighted to hear that you think our work will spark debate in our field. In the following sections, you will find our responses to each of your points and suggestions. We are grateful for the time and energy you expended in reviewing this work. Major things Choice of CT number Please expand on the choice of -856 HU, why this value? could other choices be made? Ideally one would perform your LAV segmented analysis for a range HU and find the HU number cut-off with the largest improvement in over the non-segmented metrics. Response: In general, most studies on COPD have used a CT cut-off value of -950 HU for inspiration and -856 HU for expiration as the cut-off value for emphysematous lesions. Because the regions suggesting an emphysematous lesion in the free-breathing CT images used in this study is close to the images taken during expiration, we used -856HU, which is commonly used during expiration. To further verify the validity of this cutoff value, we previously validated the association between CT under free breathing and the inspiratory CT performed within 45 days after free breathing CT. Inspiratory CT was performed using Toshiba Aquillion ONE (Toshiba Medical Systems Corp., Otawara, Tochigi, Japan) and LAV was analyzed using the Aquarius iNtuitionTM software ver.4.4.12 (TeraRecon Inc., San Mateo, Calif) and evaluated using the threshold limit of -950 HU. We found that the LAV in inspiratory CT was highly correlated with the LAV in CT under free breathing. This detail can be found in reference #9. We've added these details on lines 87-91. Direct comparison of the of new segmented HAV metrics to corresponding traditional V metrics The data suggests that the percentage of low attenuation volume is roughly 10% or less of the total lung volume. Doesn’t this mean that the segmentation is only a small (roughly 10% or less) correction compared to standard analyses without the LAV segmentation? Response: This correction may seem trivial. However, there were differences between individual patients, even if the overall rate was 10%. Some patients had more emphysematous lesions and others had less, and differences appeared between those with larger and smaller corrections. An error in the unit of values for the lung cancer population has been corrected. Please directly compare and comment on the statistical significance of the differences between segmented and non-segmented metrics g.g. HAV20% = 33.7 and V20% = 35.2 for lung cancer. Total patients is 77. Is this segmented HAV20% really a significant improvement on the V20%? My quick visual comparison suggests that most the “V” metrics give very similar results to their HAV counterparts. Same also for the ROC results: e.g HAV10% = 0.869 vs V10%=0.849 in the esophageal ROC figure. Is this difference significant? Response: We agree that you are making a fair point. The AUC was used as a measure of accuracy in this study. In our previous study, we have assessed the AUC, as well as other indices such as NRI (net reclassification improvement) and IDI (integrated discrimination improvement). Although we did not present significant differences in individual values, the main purpose of this study was to compare cut-off values from a highly accurate index to ascertain universality. The purpose was not to compare significant differences in individual values. Important missing technical details If possible, also give the mass density or electron densities that the -856 HU threshold value corresponds to for your CT scanner (or at least give a density range). Response: Regarding relative electron density, −856HU was 0.1488. We have added these details on lines 92-93. Please specify the dose calculation algorithms used? This may be particularly significant as simpler algorithms such as Varian’s AAA algorithm, is known to overestimate dose to low density lung volumes compared to Boltsmann-solver or Monte-Carlo algorithms such as accuros. Response: correction-based algorithm AAA (version 13.6.23) and the calculation grid was 2.5 mm for the lung. (lines 80-81) Please specify the breathing phase of the CT scan (inspiration breathhold , free breathing,4$D CT at a given phase etc). Note that you may want to add to the discussion that for inspiration-breathold scans which are commonly used for SBRT lung radiotherapy treatments would have larger LAV% and hence larger differential between the segmented and non-segmented metrics. Response: We have added it on line 84 and 244-246. Please also discuss the margins and motion management during treatment (presumably no gating, no breathold was used on these treatments?). Response: Gating and breath-hold were not used, as you pointed out. We have included this information in the manuscript. Smaller things line 49 “have set vague cut-off values for” strongly suggest to remove word “vague” as the metrics themselves are not vague. Use of “cut-off” is unusual. Suggest to replace “cut-off” with “constraints” as the constraints can be one of a number of metrics such as: volume that gets at least a given dose, mean dose, max dose. Response: We have removed the word “vague” and replaced “cut-off” with “constraints.” Line 50-51 “lung volume receiving 20 Gy or more (V20%) (30−40%) to reduce the risk of RP” Terminology as given is confusing: We need both Dose in Gy and volume in % to define the “V” metrics. Normally the first number (eg V20) is the dose in Gy, not % dose nor % volume. E.g. V20 < 30% means the volume that receives at least 20 Gy should be less than 30% of the lung volume. Here by writing V20% you are implying that the 20 refers to a %, where it normally refers to the dose in Gy. Please correct the your “V20%” notation to the more standard notation “V20 <20%” and complete notation defining both the dose and the volume. For example see the RTOG 0937 protocol where this constraint originated: https://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?action=openFile&FileID=13697 Response: Thank you for your comment. We have removed "%." Line 52 For clarity suggest to explain or expand on “low attenuation” and “high attenuation” straightaway eg consider “volumes of low attenuation in CT imaging” Suggest to also apply to abstract. Response: Thank you for pointing this out. Your recommendation has been followed, the abstract inclusive. Line 52 It is technically wrong to say “areas of low attenuation” you mean “volumes of low attenuation” Response: We have replaced with "volumes," as suggested. Line 80 “using the threshold limit of −856 HU” Replace with “using the upper threshold limit of −856 HU” Response: Following your recommendation, we have added "upper" to the phrase. Line 106 please specify more clearly and consistent with standard notation Replace “V2%, V5%, V10%, V20%, and V30%,” with presumed meaning: “V20 Gy < 2%, 5%, 10%, 20%, 30%” Please also clearly specify that it is the volume of both lungs if that is the case. Response: Thank you for your comment. We have removed "%." Tables I find the extreme-spaced tables impossible to digest. E.g table 1 is only 3 data columns but spans 3 pages. data too spread out to meaningfully digest. Response: Thank you for your comment. We have revised the tables for clarity. Please specify the resolution, or at least range of resolutions / slice thickness settings used for the CT scans. E.g. voxel size can effect the segmented volumes if the resolution is too course. e.g a voxel that is 4/5 with air 1/5 dense tumor tissue will represented by approx -800HU Response: Thank you for your comment. We have included this information on lines 82-82. Reviewer #2: The manuscript was well written and the analysis was properly done to support the conclusion. There are a few suggestions for author to consider: 1. It's not very clear in the manuscript how the MU threshold of “- 856” was determined. Was there any systematic analysis done? As you have presented in the manuscript, by setting such a threshold it will impact the selection of optimal dose evaluation criteria and corresponding volume threshold. It's probably a good idea to address this issue to ensure that the difference in dose evaluation was not caused by the uncertainty of the chosen threshold. Response: In general, most studies on COPD have used a CT cut-off value of -950 HU for inspiration and -856 HU for expiration as the cut-off value for emphysematous lesions. Because the regions suggesting an emphysematous lesion in the free-breathing CT images used in this study is close to the images taken during expiration, we used -856HU, which is commonly used during expiration. To further verify the validity of this cutoff value, we previously validated the association between CT under free breathing and the inspiratory CT performed within 45 days after free breathing CT. Inspiratory CT was performed using Toshiba Aquillion ONE (Toshiba Medical Systems Corp., Otawara, Tochigi, Japan) and LAV was analyzed using the Aquarius iNtuitionTM software ver.4.4.12 (TeraRecon Inc., San Mateo, Calif) and evaluated using the threshold limit of -950 HU. We found that the LAV in inspiratory CT was highly correlated with the LAV in CT under free breathing. This detail can be found in reference #9. 2. As what I have noticed that only a small portion of plans were done with IMRT technique, this can potentially introduce bias since static IMRT or VMAT plans can have higher, if not much higher, low dose contribution to the treatment. That means if the portion of the IMRT plan increases, one may see the optimal dose evaluation criteria shift towards low dose. Response: Thank you for pointing this out. We have included information regarding this on lines 246-249 3. For conventional lung radiation therapy, I can imagine the fractional dose would be similar. However, it would be clearer to include the fractional dose information rather than just the total dose > 30Gy when demonstrating the patient selection criteria. Response: The fraction dose is 1.8–3.0 Gy. We have included this in the manuscri Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0244143.r002
29 Oct 2020 Decision Letter - Dandan Zheng, Editor PONE-D-20-14886R1 Prediction of radiation pneumonitis using dose-volume histogram parameters with high attenuation in two types of cancer: A retrospective study PLOS ONE Dear Dr. Nakano, 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. ============================== ACADEMIC EDITOR: The revision is much improved with only minor issues remaining. Please revise accordingly. ============================== Please submit your revised manuscript by Dec 13 2020 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 We look forward to receiving your revised manuscript. Kind regards, Dandan Zheng, PhD Academic Editor PLOS ONE [Note: HTML markup is below. Please do not edit.] 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: 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 #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: The revised version of the manuscript fully addresses all my concerns. Thank you for your corrections. Reviewer #2: Line 225 - This suggestion may not be appropriate for two reasons: 1. As you have mentioned HAV30% is not the most sensitive predictor of RP for esophagus cases, therefore it’s necessary to have multiple/other predictors in order to reach a useful sensitivity. 2. HAV30% is not the most sensitive predictor for a reason. It’s unlikely that HAV30%/V30 from esophagus will be as high as that in lung cases simply because of the anatomies and beam arrangements (i.e. unlikely you will see an APPA treatment for esophagus as what you have shown as an example for lung). Therefore, the onset of RP could be dominated by the low dose to lung for esophagus cases, which was suggested by the shift of most sensitive predictors from HAV30% in lung to HAV10% and HAV5% in esophagus cases. Therefore, suggesting using HAV30% for both sites can be misleading and may not be clinically useful. I would also suggest author to generate bar plots of each DVH parameter side by side for the two sites so that it’s clear how the distribution of those parameters different from each other, and compare the calculated thresholds with the 75% percentile of each parameter to see if using that specific predictor is meaningful. For example if the 75% percentile of HAV30% for esophagus cases is 5% and the HAV30% threshold is 11%, it would not be useful to suggest HAV30% as a RP predictor for esophagus cases. ****** 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 [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.0244143.r003
Revision 2
24 Nov 2020 Author Response Response to Reviewer #2: Thank you very much for providing us with important insights. We are delighted to hear that you think our work will spark debate in our field. In the following sections, you will find our responses to each of your points and suggestions. We are grateful for the time and energy you expended in reviewing this work. Line 225 - This suggestion may not be appropriate for two reasons: 1. As you have mentioned HAV30% is not the most sensitive predictor of RP for esophagus cases, therefore it’s necessary to have multiple/other predictors in order to reach a useful sensitivity. 2. HAV30% is not the most sensitive predictor for a reason. It’s unlikely that HAV30%/V30 from esophagus will be as high as that in lung cases simply because of the anatomies and beam arrangements (i.e. unlikely you will see an APPA treatment for esophagus as what you have shown as an example for lung). Therefore, the onset of RP could be dominated by the low dose to lung for esophagus cases, which was suggested by the shift of most sensitive predictors from HAV30% in lung to HAV10% and HAV5% in esophagus cases. Therefore, suggesting using HAV30% for both sites can be misleading and may not be clinically useful. Response: We deleted this sentence. I would also suggest author to generate bar plots of each DVH parameter side by side for the two sites so that it’s clear how the distribution of those parameters different from each other, and compare the calculated thresholds with the 75% percentile of each parameter to see if using that specific predictor is meaningful. For example if the 75% percentile of HAV30% for esophagus cases is 5% and the HAV30% threshold is 11%, it would not be useful to suggest HAV30% as a RP predictor for esophagus cases. Response: We created box plots instead of bar blots to clarify the 75% percentile (S4 Figure). As you pointed out, the 75% percentile of HAV20% and V20 and V5 in esophageal cancer were lower than threshold. Therefor this point was added as the Limitation to Discussion. Attachments Attachment Submitted filename: Response to Reviwers.docx https://doi.org/10.1371/journal.pone.0244143.r004
4 Dec 2020 Decision Letter - Dandan Zheng, Editor Prediction of radiation pneumonitis using dose-volume histogram parameters with high attenuation in two types of cancer: A retrospective study PONE-D-20-14886R2 Dear Dr. Nakano, 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, Dandan Zheng, PhD Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0244143.r005
Formally Accepted
8 Dec 2020 Acceptance Letter - Dandan Zheng, Editor PONE-D-20-14886R2 Prediction of radiation pneumonitis using dose-volume histogram parameters with high attenuation in two types of cancer: A retrospective study Dear Dr. Nakano: 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. Dandan Zheng Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0244143.r006

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