Risk stratification for the prediction of skeletal-related events in patients with castration-resistant prostate cancer with bone metastases

Masanori Hamada; Eiji Nakata; Ryuichi Nakahara; Shinsuke Sugihara; Haruyoshi Katayama; Takuto Itano; Tomohiro Inoue; Shota Takihira; Yoshiteru Akezaki; Toshifumi Ozaki

doi:10.1371/journal.pone.0328792

Peer Review History

Original SubmissionDecember 20, 2024
Decision Letter - Khalid Said Mohammad, Editor Dear Dr. Nakata, 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 May 30 2025 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. 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'. 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If no institutional body is available to respond to requests for your minimal data, please consider if there any institutional representatives who did not collaborate in the study, and are not listed as authors on the manuscript, who would be able to hold the data and respond to external requests for data access? If so, please provide their contact information (i.e., email address). Please also provide details on how you will ensure persistent or long-term data storage and availability. Additional Editor Comments: Based on the reviewer comments, "see below." The manuscript will require major revision before considered for publication [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? Reviewer #1: Partly 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 Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: Masanori Hamada et al developed a risk stratification model to predict skeletal-related events (SREs) in patients with bone metastases from castration-resistant prostate cancer (CRPC), identifying extensive vertebral metastases and visceral/lymph node metastases as key risk factors through multivariate analysis. Patients with the highest-risk group (extensive vertebral plus additional metastases) showed significantly earlier onset of SREs and spinal SREs, reaching 56% and 47% incidence at 12 months, respectively. The findings emphasize close monitoring for high-risk subgroups to prevent SREs and guide personalized management in CRPC patients with bone metastases, ensuring timely interventions and improved patient outcomes. The manuscript provides valuable insights into SREs of CRPC. I will give some comments as follows. 1. The sample size (n=68) was small. While the cohort provided preliminary insights into risk stratification for SREs, future multi-center studies with larger cohorts are needed to validate the generalizability of the proposed model and refine risk subgroup thresholds. 2. Fig. 5 should be revised to improve clarity, including adding detailed information and expanding the figure legend to explicitly define key findings. 3. I will propose validating the findings using datasets specific to advanced CRPC or integrating genomic/transcriptomic data from metastatic biopsies to explore molecular correlates of SRE risk. Reviewer #2: Hamada et al present a study that looks to stratify castrate-resistant prostate cancer patients with bone metastases based on their likelihood of developing skeletal-related events (SRE). The manuscript is clearly laid out and well written. However, I am still unsure of the novelty, impact, and in parts, the experimental design. For instance, a central finding of the manuscript is that patients with a higher count of vertebrae metastases have a higher risk of SRE. Unless I am missing a key detail, this seems intuitive and borderline obvious… In other words, more cancer = more risk of an event… As a result, it is not clear how the findings from this manuscript will add to our clinical understanding or management of the disease. Personally, I think that this is a key point that needs to be addressed before this work can be published. Minor points: Why was 20 picked as a cut off for more or less vertebrae metastases? The patient cohort is 10 – 20 years old and prior to current best practices. Can the authors comment on how this time lag is expected to impact their model? Why was no comparison performed between zoledronic acid and denosumab? I would have thought that this would be a key question given that both agents are used to try and prevent SREs. ****** 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: Xiaofeng Ding 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. 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Revision 1
16 Jun 2025 Author Response Response letter June 1, 2025 Khalid Sail Mohammad Academic Editor PLoS One Dear Editor: We are pleased to submit our revised manuscript, (ID: PONE-D-24-56347), titled “Risk stratification for the prediction of skeletal-related events in patients with castration-resistant prostate cancer with bone metastases.” First, we would like to express our deepest gratitude to the reviewers and you for the constructive and insightful comments. The feedback was invaluable in enhancing the quality and clarity of our research. We have carefully considered each comment and suggestion made by the reviewers and made corresponding revisions to the manuscript, indicated as yellow-highlighted text. Below, we address each comment point-by-point and outline the changes made in the revised manuscript: Reviewer #1: Masanori Hamada et al developed a risk stratification model to predict skeletal-related events (SREs) in patients with bone metastases from castration-resistant prostate cancer (CRPC), identifying extensive vertebral metastases and visceral/lymph node metastases as key risk factors through multivariate analysis. Patients with the highest-risk group (extensive vertebral plus additional metastases) showed significantly earlier onset of SREs and spinal SREs, reaching 56% and 47% incidence at 12 months, respectively. The findings emphasize close monitoring for high-risk subgroups to prevent SREs and guide personalized management in CRPC patients with bone metastases, ensuring timely interventions and improved patient outcomes. The manuscript provides valuable insights into SREs of CRPC. I will give some comments as follows. 1. The sample size (n=68) was small. While the cohort provided preliminary insights into risk stratification for SREs, future multi-center studies with larger cohorts are needed to validate the generalizability of the proposed model and refine risk subgroup thresholds. Response: Thank you for your comments. Indeed, the small sample size was a limitation, and we agree that multi-center studies with larger cohorts are necessary. Accordingly, we have added these points in the limitations sections of the Discussion, as follows. “The study has some limitations. First, this retrospective study was conducted at a single institution and involved a relatively small patient cohort (n=68). Further research encompassing multi-center studies with larger cohorts is needed to validate the generalizability of the proposed model and refine risk subgroup thresholds”(Line 246-249) 2. Fig. 5 should be revised to improve clarity, including adding detailed information and expanding the figure legend to explicitly define key findings. Response: Thank you for your valuable suggestions. Accordingly, we have corrected the legend for Figure 5 to ensure the numbers are accurate (Lines 209-210). We have also added more detailed information to Figure 5 and revised it to make it easier to understand. 3. I will propose validating the findings using datasets specific to advanced CRPC or integrating genomic/transcriptomic data from metastatic biopsies to explore molecular correlates of SRE risk. Response: Indeed, the results of our study need to be validated using a dataset specific to progressive CRPC. In the original paper, we had stated "Additional research is necessary to identify predictors of SREs, and these findings should be confirmed through validation studies using independent datasets.”(Line 264-265) To further emphasize this point, we have added the following test to the Conclusion: “Although it was not possible in the present study, integrating genomic/transcriptomic data from metastatic biopsies and exploring molecular correlates of SRE risk could provide new insights.” (Line 270-272) Reviewer #2: Hamada et al present a study that looks to stratify castrate-resistant prostate cancer patients with bone metastases based on their likelihood of developing skeletal-related events (SRE). The manuscript is clearly laid out and well written. However, I am still unsure of the novelty, impact, and in parts, the experimental design. For instance, a central finding of the manuscript is that patients with a higher count of vertebrae metastases have a higher risk of SRE. Unless I am missing a key detail, this seems intuitive and borderline obvious… In other words, more cancer = more risk of an event… As a result, it is not clear how the findings from this manuscript will add to our clinical understanding or management of the disease. Personally, I think that this is a key point that needs to be addressed before this work can be published. Response: Thank you for your insightful comments. We aimed to develop a metric that could detect hidden metastatic spinal cord compression (MSCC) in patients with castration-resistant prostate cancer (CRPC) and bone metastases. Early detection of hidden MSCC by spinal cord magnetic resonance imaging before neurological symptoms develop could enable rapid intervention and reduce the risk of paralysis. Some studies have suggested that patients with CRPC with visceral, lymph node, or extensive vertebral metastases (more than 20) may be at a higher risk for SRE. However, further studies are needed to identify the predictors of SRE. These findings should be confirmed by validation studies using independent data sets. Minor points: Why was 20 picked as a cut off for more or less vertebrae metastases? Response: Thank you for this question. It is difficult to provide a clear rationale for dividing the number of spinal metastases by 20. In this study, most patients had 10 or fewer spinal metastases and the number of metastases throughout the spine was 24. Of the 60 patients who had spinal metastases at the last observation, 27 had metastases throughout the spine; 29 patients had 20 or more metastases, while 26 had 10 or fewer metastases. Therefore, the number of spinal metastases was set at 20. However, we believe that further research is needed to create a clear rationale; therefore, we have added this following information to the revised manuscript: “However, in this study, the number of spinal metastases was categorized into groups of 20, and there was an insufficient number of cases to allow accurate determination of the number of metastases.” (Line 266-268) The patient cohort is 10 – 20 years old and prior to current best practices. Can the authors comment on how this time lag is expected to impact their model? Response: We appreciate your question. The cohort in this study reflects treatment patterns, survival outcomes, and disease progression characteristics from a time when treatment options were much more limited and treatment criteria were different. Early detection of hidden metastatic spinal cord compression (MSCC) by spinal cord magnetic resonance imaging before the onset of neurological symptoms would allow for rapid intervention and potentially reduce the incidence of paralysis. The aim of this study was to create an index to detect hidden MSCC in patients with castration-resistant prostate cancer patients with bone metastases. Why was no comparison performed between zoledronic acid and denosumab? I would have thought that this would be a key question given that both agents are used to try and prevent SREs. Response: Thank you for your comment. We recognize that comparing zoledronic acid and denosumab is an important clinical issue because healthcare providers widely use both drugs to prevent bone-related events in patients with bone metastases. Several large randomized controlled trials and meta-analyses have been conducted to compare the two drugs directly, showing that denosumab is superior to or equivalent with zoledronic acid in delaying or suppressing skeletal-related events (SREs). We aimed to develop a metric that could detect hidden metastatic spinal cord compression (MSCC) in patients with castration-resistant prostate cancer (CRPC) and bone metastases. The primary objective of this study was not to make a direct comparison between the two drugs. However, we acknowledge the need for more detailed comparisons and subgroup analyses and plan to conduct additional studies with larger patient populations in the future. In conclusion, we believe that these revisions have helped significantly improve our manuscript, making it a valuable contribution to “PLoS One”. We appreciate the opportunity to revise our work and thank the reviewers for their essential role in this process. Thank you for considering our revised manuscript for publication in “PLoS One”. We look forward to your decision. Sincerely, Masanori Hamada, Division of Physical Medicine and Rehabilitation, Okayama University Hospital, 2-5-1, Shikata-cho, Okayama City, Okayama 700-8558, Japan E-mail: pjvy4uc1@okayama-u.ac.jp (EN) Eiji Nakata Department of Orthopedic Surgery, Okayama University Hospital, 2-5-1, Shikata-cho, Okayama City, Okayama 700-8558, Japan E-mail: eijinakata8522@yahoo.co.jp (EN) Attachments Attachment Submitted filename: Response Letter (PONE-D-24-56347).docx https://doi.org/10.1371/journal.pone.0328792.r002
Decision Letter - Khalid Said Mohammad, Editor Risk stratification for the prediction of skeletal-related events in patients with castration-resistant prostate cancer with bone metastases PONE-D-24-56347R1 Dear Dr. Nakata, 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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, Khalid Said Mohammad Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #1: All comments have been addressed Reviewer #2: (No Response) ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> 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 Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: The authors have addressed all concerns raised during the review process, and I agree that the current version of the paper is accepted. Reviewer #2: This manuscript is greatly improved, and I am satisfied with the authors responses. I believe that this is now ready to be published in PLOS One. ****** 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: Xiaofeng Ding Reviewer #2: No ******** https://doi.org/10.1371/journal.pone.0328792.r003
Formally Accepted
Acceptance Letter - Khalid Said Mohammad, Editor PONE-D-24-56347R1 PLOS ONE Dear Dr. Nakata, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, 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 customercare@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. Khalid Said Mohammad Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0328792.r004

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