Prognostic value of SUVmax on 18F-fluorodeoxyglucose PET/CT scan in patients with malignant pleural mesothelioma

Jun Hyeok Lim; Joon Young Choi; Yunjoo Im; Hongseok Yoo; Byung Woo Jhun; Byeong-Ho Jeong; Hye Yun Park; Kyungjong Lee; Hojoong Kim; O Jung Kwon; Joungho Han; Myung-Ju Ahn; Jhingook Kim; Sang-Won Um

doi:10.1371/journal.pone.0229299

Peer Review History

Original SubmissionSeptember 28, 2019
11 Nov 2019 Decision Letter - Andrea S. Wolf, Editor PONE-D-19-27290 Prognostic value of SUVmax on 18F-fluorodeoxyglucose PET/CT scan in patients with malignant pleural mesothelioma PLOS ONE Dear Dr. Um, 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. ============================== There are fairly few but important considerations expressed by the reviewers that will help improve this manuscript. Overall, it is a well-written paper describing a well-designed study. It is small and this limits some of the conclusions that can be drawn but it is interesting and merits publication. Please revise taking into account the recommended revisions. With regard to Reviewer 2's concerns about the references for surgical candidacy, consider citing papers that actually discuss these issues (the ones you cite only describe the two operations not the evaluation for them and/or which to perform). One such paper is Wolf, Flores, Thorac Surg Clin. 2016 Aug;26(3):359-75. The major issue with this study is that it is severely underpowered to detect differences and the reliability of the model is low as demonstrated by the large confidence intervals. This likely reflects overfitting with too many covariates and too few events/small sample size. I would consider redoing the analysis using propensity scores instead of a multivariable regression with so many covariates and only 54 patients. Please also expand the limitations section as clearly there are additional limitations (some of which are described by the reviewers, but others that exist, including the single-institution, small sample size, short follow-up, limited number events that may invalidate the stability of the multivariable model, missing data with regard to asbestos exposure,among others) that should be described. Moreover, there should be some discussion about how the limitations might impact the results or why they are not as relevant as one might expect. ============================== We would appreciate receiving your revised manuscript by November 30, 2019. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. We look forward to receiving your revised manuscript. Kind regards, Andrea S. Wolf, M.D. Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 1. In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records used in your retrospective study, including: a) whether all data were fully anonymized before you accessed them; b) the date range (month and year) during which patients' medical records were accessed. [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: 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: No ****** 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: Please comment on how many patients had undergone talc or chemical pleurodesis? Pleurodesis can affect the SUV max. Please provide the number and how was analysis done accounting for those with and without pleurodesis . Other than that the paper is well written and the results and discussion are well written Reviewer #2: Dr. Um and colleagues have retrospectively evaluated the prognostic value of SUVmax on PET scans. This is an interesting exercise, especially to help differentiate within histologic subtypes. 1) The Zellos reference is outdated as it preceded the use of pemetrexed based therapy. Additionally, the survival referenced for multimodality therapy is not accurate. 2) The statement that no other agents have proven effective to treat mesothelioma is not accurate. Several other agents, including checkpoint inhibitors, vinorelbine and gemcitabine are active in mesothelioma. 3) It is inconsistent to state that trials of immunotherapies are underway and then cite references of completed and published clinical trials. Additionally, what does it mean that optimal candidates need to be selected and in what way do these references address that? 4) I am troubled by the suggestion that there may not be a relationship between SUV and prognosis in non-epithelioid histology. With so few patients, not finding an association does not provide meaningful data that a relationship does not exist, especially when other studies have demonstrated different results. 5) The discussion of Klabatsa and Lee is unclear. Did those studies account for subtypes within epithelioid histology. Please clarify the contrast between the two studies and Kadota study. 6) The use of terminology such as cutoff is unclear. For example, when stating that the cutoff value for death was 10.1, what does that mean? Did people below this level not die? Or is that a level at which the risk of death changes substantially? Or is it in reference to death within a certain time frame? Such comments must be clarified throughout the manuscript. 7) End of 1st paragraph says precious instead of previous. ****** 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: Ritu R Gill Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0229299.r001
Revision 1
10 Jan 2020 Author Response Point-to-point responses to the editor and reviewers’ comments; Editor There are fairly few but important considerations expressed by the reviewers that will help improve this manuscript. Overall, it is a well-written paper describing a well-designed study. It is small and this limits some of the conclusions that can be drawn but it is interesting and merits publication. C1: Please revise taking into account the recommended revisions. With regard to Reviewer 2's concerns about the references for surgical candidacy, consider citing papers that actually discuss these issues (the ones you cite only describe the two operations not the evaluation for them and/or which to perform). One such paper is Wolf, Flores, Thorac Surg Clin. 2016 Aug;26(3):359-75. R1: We have added the reference in the revised manuscript. C2: The major issue with this study is that it is severely underpowered to detect differences and the reliability of the model is low as demonstrated by the large confidence intervals. This likely reflects overfitting with too many covariates and too few events/small sample size. I would consider redoing the analysis using propensity scores instead of a multivariable regression with so many covariates and only 54 patients. R2: We performed propensity score adjustment for histology subtype, stage and chemotherapy to validate the prognostic significance of SUVmax instead of the multivariable regression analysis as the editor recommended. The hazard ratios (95% confidence interval) for total, epithelioid, and non-epithelioid histology were 1.83 (0.86-3.87; P=0.114), 2.53 (0.83-7.67; P=0.101), and 1.84 (0.59-5.75; P=0.295), respectively. The hazard ratios of SUVmax after propensity score adjustment showed similar trends with the multivariable regression analysis but all the results from the propensity score adjustment were not statistically significant. We have added this point as a limitation of this study to the Discussion section as follows; “First, relatively small sample size and limited number of events may invalidate the stability of the multivariable regression model in this study. The generalization of our results might potentially be limited by its retrospective nature and single-institution population. We also performed propensity score adjustment for histology subtype, stage and chemotherapy to validate the prognostic significance of SUVmax instead of the multivariable regression analysis. The hazard ratios (95% confidence interval) for total, epithelioid, and non-epithelioid histology were 1.83 (0.86-3.87; P=0.114), 2.53 (0.83-7.67; P=0.101), and 1.84 (0.59-5.75; P=0.295), respectively. The hazard ratios of SUVmax after propensity score adjustment showed similar trends with the multivariable regression model but all the results from the propensity score adjustment were not statistically significant. Therefore, the results of current study from the multivariable model should be interpreted conservatively. Although there was no association between SUVmax and overall survival in non-epithelioid histology, a further prospective study using the multivariable model or propensity score adjustment is needed for the larger population in the future to elucidate the association between SUVmax and prognosis in epithelioid and non-epithelioid histology.” C3: Please also expand the limitations section as clearly there are additional limitations (some of which are described by the reviewers, but others that exist, including the single-institution, small sample size, short follow-up, limited number events that may invalidate the stability of the multivariable model, missing data with regard to asbestos exposure, among others) that should be described. Moreover, there should be some discussion about how the limitations might impact the results or why they are not as relevant as one might expect. R3: We have modified the limitations of the study in the Discussion section as follows; Original: “The present study had several limitations. First, the results of the study should be interpreted conservatively due to its retrospective nature and relatively small sample size. Second, the histologic subtypes of the study subjects were not specifically defined in seven subjects who also underwent surgery.” Revised: “The present study had several limitations. First, relatively small sample size and limited number of events may invalidate the stability of the multivariable regression model in this study. The generalization of our results might potentially be limited by its retrospective nature and single-institution population. We also performed propensity score adjustment for histology subtype, stage and chemotherapy to validate the prognostic significance of SUVmax instead of the multivariable regression analysis. The hazard ratios (95% confidence interval) for total, epithelioid, and non-epithelioid histology were 1.83 (0.86-3.87; P=0.114), 2.53 (0.83-7.67; P=0.101), and 1.84 (0.59-5.75; P=0.295), respectively. The hazard ratios of SUVmax after propensity score adjustment showed similar trends with the multivariable regression model but all the results from the propensity score adjustment were not statistically significant. Therefore, the results of current study from the multivariable model should be interpreted conservatively. Although there was no association between SUVmax and overall survival in non-epithelioid histology, a further prospective study using the multivariable model or propensity score adjustment is needed for the larger population in the future to elucidate the association between SUVmax and prognosis in epithelioid and non-epithelioid histology. Second, the histologic subtypes of the study subjects were not specifically defined in seven subjects who also underwent surgery. Finally, there were insufficient data on exposure to asbestos in 19 patients (35.2%).” Reviewer #1 C4: Please comment on how many patients had undergone talc or chemical pleurodesis? Pleurodesis can affect the SUV max. Please provide the number and how was analysis done accounting for those with and without pleurodesis. Other than that the paper is well written and the results and discussion are well written R4: Five patients had undergone talc or chemical pleurodesis before PET/CT scan. All 5 patients had epithelioid subtype of MPM. There was no statistically significant differences in the SUVmax between 5 patients who underwent pleurodesis (5.1 [3.5-14.7]) and 49 patients who did not undergo pleurodesis (10.0 [4.5-13.5]; P=0.662). Reviewer #2 Dr. Um and colleagues have retrospectively evaluated the prognostic value of SUVmax on PET scans. This is an interesting exercise, especially to help differentiate within histologic subtypes. C5: 1) The Zellos reference is outdated as it preceded the use of pemetrexed based therapy. Additionally, the survival referenced for multimodality therapy is not accurate. 2) The statement that no other agents have proven effective to treat mesothelioma is not accurate. Several other agents, including checkpoint inhibitors, vinorelbine and gemcitabine are active in mesothelioma. 3) It is inconsistent to state that trials of immunotherapies are underway and then cite references of completed and published clinical trials. Additionally, what does it mean that optimal candidates need to be selected and in what way do these references address that? R5: Thank you so much for the comments. We have removed the Zellos reference and have modified the Introduction section as the reviewer #2 recommended: Original: “Malignant pleural mesothelioma (MPM) is a rare but aggressive tumor that arises from pleural mesothelial cells. The prognosis of patients with MPM is poor, with median survival of 9–12 months despite multimodal therapy including surgery, chemotherapy, and radiotherapy [1]. Surgical methods (e.g., extra-pleural pneumonectomy [EPP] or pleurectomy/decortication) should be selected in accordance with the patient's condition [2, 3]. Among chemotherapeutic agents, a pemetrexed and platinum-based regimen has been recommended as a first-line agent because of its proven ability to improve the survival rate, but no other chemotherapeutic agents have been proven to effectively treat MPM [4]. In addition, clinical trials of new immunotherapeutic agents, such as pembrolizumab and nivolumab, are in progress, and it is important to select optimal candidates for these new agents [5-7].” Revised: “Malignant pleural mesothelioma (MPM) is a rare but aggressive tumor that arises from pleural mesothelial cells. The prognosis of patients with MPM is poor, with a median survival of 20–29 months despite tri-modality treatment including surgery, chemotherapy, and radiotherapy [1, 2]. Surgical methods (e.g., extra-pleural pneumonectomy [EPP] or pleurectomy/decortication) should be selected in accordance with the patient's condition [3-4]. Among chemotherapeutic agents, a pemetrexed and platinum-based regimen has been recommended as a first-line treatment because of its proven ability to improve the survival rate [5, 6]. Immune checkpoint inhibitors, vinorelbine and gemcitabine are recommended as subsequent systemic therapy in the most recent guideline [6]. Pembrolizumab or nivolumab with (or without) ipilimumab showed promising results in recent clinical trials [7, 8, 9].” References: 1. Krug LM, et al. Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma. J Clin Oncol 2009; 27:3007-3013. 2. Thieke C, et al. Long-term results in malignant pleural mesothelioma treated with neoadjuvant chemotherapy, extrapleural pneumonectomy and intensity-modulated radiotherapy. Radiat Oncol 2015: 10: 267. 3. Treasure T, et al. Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study. The lancet oncology. 2011;12(8):763-72. 4. Wolf AS, Flores RM. Current treatment of mesothelioma: extrapleural pneumonectomy versus pleurectomy/decortication. Thoracic surgery clinics. 2016;26(3):359-75. 5. Vogelzang NJ, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. Journal of clinical oncology. 2003;21(14):2636-44. 6. Network NCC. NCCN malignant pleural mesothelioma guidelines, version 1.2020 Nov 27, 2019. Available from: https://www.nccn.org/professionals/physician_gls/pdf/mpm.pdf. 7. Scherpereel A, et al. Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial. Lancet Oncol. 2019; 20(2): 239–253. 8. Disselhorst MJ, et al. Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma (INITIATE): results of a prospective, single-arm, phase 2 trial. Lancet Respir Med. 2019; 7(3): 260– 270. 9. Alley EW, et al. Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol. 2017; 18(5): 623–630 C6: 4) I am troubled by the suggestion that there may not be a relationship between SUV and prognosis in non-epithelioid histology. With so few patients, not finding an association does not provide meaningful data that a relationship does not exist, especially when other studies have demonstrated different results. R6: We also agree with the reviewer’s opinion. We have added following sentences as a limitation of this study to the Discussion section. “Although there was no association between SUVmax and overall survival in non-epithelioid histology, a further prospective study using the multivariable model or propensity score adjustment is needed for the larger population in the future to elucidate the association between SUVmax and prognosis in epithelioid and non-epithelioid histology.” C7: 5) The discussion of Klabatsa and Lee is unclear. Did those studies account for subtypes within epithelioid histology. Please clarify the contrast between the two studies and Kadota study. R7: In Kadota's study, pleomorphic subtype of epithelioid histology showed higher SUVmax than epithelioid non-pleomorphic subtype and was similar to non-epithelioid histology. However, in Klabatsa and Lee's studies, there was no significant difference in SUVmax between epithelioid and non-epithelioid subtypes. We have modified the manuscript to clarify the differences of previous studies as follows; Original: “Kadota et al. showed that SUVmax in MPM with epithelioid nonpleomorphic subtype was lower than that in MPM with epithelioid pleomorphic subtype and that in MPM with non-epithelioid subtype [14]. In contrast, two studies reported no statistically significant differences in PET parameters between MPM patients with epithelioid and non-epithelioid subtypes [16, 19].” Revised: “Kadota et al. showed that pleomorphic subtype of epithelioid histology showed higher SUVmax than epithelioid non-pleomorphic subtype and was similar to non-epithelioid histology [14]. However, two studies reported no statistically significant differences in SUVmax between epithelioid and non-epithelioid subtypes in patients with MPM [16, 19].” C8: 6) The use of terminology such as cutoff is unclear. For example, when stating that the cutoff value for death was 10.1, what does that mean? Did people below this level not die? Or is that a level at which the risk of death changes substantially? Or is it in reference to death within a certain time frame? Such comments must be clarified throughout the manuscript. R8: As the reviewer pointed out, we have clarified the meaning of the cutoff value in the Materials and Methods section (Statistical analysis) as follows; Original: “Receiver operating characteristic (ROC) curves of the SUVmax for the prediction of mortality were generated to determine the cutoff value that yielded optimal sensitivity and specificity.” Revised: “Receiver operating characteristic (ROC) curves were plotted to determine the optimal cutoff values of SUVmax that yielded the maximal sensitivity plus specificity of predicting the overall survival. The patient population was subdivided using the cutoff values of SUVmax from the ROC curves, and the duration of overall survival was compared between groups.” C9: 7) End of 1st paragraph says precious instead of previous. R9: We have corrected the typo. Attachments Attachment Submitted filename: R1_point-to-point_responses.docx https://doi.org/10.1371/journal.pone.0229299.r002
4 Feb 2020 Decision Letter - Andrea S. Wolf, Editor Prognostic value of SUVmax on 18F-fluorodeoxyglucose PET/CT scan in patients with malignant pleural mesothelioma PONE-D-19-27290R1 Dear Dr. Um, We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements. Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication. Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. With kind regards, Andrea S. Wolf, M.D. Academic Editor PLOS ONE Additional Editor Comments (optional): The authors have performed additional analysis and made substantial revisions that clarify the significance of this work. This manuscript should be published. Reviewers' comments: https://doi.org/10.1371/journal.pone.0229299.r003
Formally Accepted
6 Feb 2020 Acceptance Letter - Andrea S. Wolf, Editor PONE-D-19-27290R1 Prognostic value of SUVmax on 18F-fluorodeoxyglucose PET/CT scan in patients with malignant pleural mesothelioma Dear Dr. Um: I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. For any other questions or concerns, please email plosone@plos.org. Thank you for submitting your work to PLOS ONE. With kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Andrea S. Wolf Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0229299.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 .