Management of de novo metastatic hormone-sensitive prostate cancer: A comprehensive report of a single-center experience

Sunny Guin; Bobby K. Liaw; Tomi Jun; Kristin Ayers; Bonny Patel; Timmy O’Connell; Matthew Deitz; Michael Klein; Tommy Mullaney; Tony Prentice; Scott Newman; Marc Fink; Xiang Zhou; Eric E. Schadt; Rong Chen; William K. Oh

doi:10.1371/journal.pone.0264800

Peer Review History

Original SubmissionFebruary 15, 2022
14 Jun 2022 Decision Letter - Isaac Yi Kim, Editor PONE-D-22-04683Management of de novo metastatic hormone-sensitive prostate cancer: a comprehensive report of a single-center experiencePLOS ONE Dear Dr. Guin, 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 29 2022 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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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 ******** 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: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The authors conducted a database survey to identify risk factors among mCSPC patients treated with upfront chemotherapy or NHA. The primary end-point was TTNT. I have some comments as below. 1. Were there any neuroendocrine tumor in origin included in this study? 2. The statistical power is low because of the small study number. 3. The study design and the manuscript wring is robust. Reviewer #2: The authors present a retrospective analysis of real world data from their institution - comparing outcomes for patients with metastatic castration-sensitive prostate cancer treated either with docetaxel or novel hormonal agents. The question the authors are trying to address is relevant and timely since this clinical scenario is common and there is limited data to guide the decision of proceeding with docetaxel, NHA, or now with triplet therapy (both docetaxel and NHA). They report a longer time to next treatment (TTNT) for patients treated with docetaxel compared to NHA therapy but no difference in survival. The authors are using an automated abstraction platform, and data to demonstrate accuracy of this platform would be useful to ensure soundness of their conclusions. They refer to the figures in the supplement and say that a subset was reviewed manually for quality assurance but I would like more data regarding the accuracy of their platform. Some caveats are required related to the interpretation of their data, which the authors also acknowledge in their discussion: 1) there may be selection bias where patients offered docetaxel have more aggressive disease than those offered NHA. Although visceral/metastatic burden variables were reported to be similar, there seems to be a difference in Gleason between the two groups and there may be other differences that were not measured. Patients offered NHA may also be less fit (fewer ECOG 0) and thus oncologists may be slower to offer more intense therapies, or slower to change therapy. 2) indication for next line of therapy may be different for patients offered docetaxel vs NHA. For example, patients with PSA progression after docetaxel may be offered NHA; while patients with PSA progression on NHA may be monitored until radiographic progression to start docetaxel. The authors state that the PSA was higher in the NHA group than the docetaxel group. The authors also mention that toxicity is different between the two types of treatment and was more often a reason for discontinuation/change of therapy in the docetaxel group. for these reasons, the clinical significance of their endpoint is unclear to me - even if TTNT is shorter in docetaxel group, it is not necessarily a reason to favor NHA over docetaxel, especially since OS is the same in their analysis. The authors state that patients started on a next line of therapy before PSA progression were excluded - how many patients and what types of therapies? Were there more in the docetaxel vs the NHA group? Were there differences in subsequent lines of therapy for docetaxel vs NHA? Some other comments: line 51 in abstract - clarify that this is PSA nadir line 74 - would add STAMPEDE to body of evidence supporting treatment intensification in mHSPC. In Table 1: why is PSA being reported as log10PSA? Why is Gleason 10 presented before 7, 8, and 9? It is somewhat unusual to present both mean and categories of variables such as age and Gleason in Table 1; or mean plus log10 as for PSA. Line 389 - needs attention to correct grammar ****** 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. 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Revision 1
21 Jul 2022 Author Response Isaac Yi Kim, MD, PhD, MBA Academic Editor PLOS ONE July 20th 2022 Dear Dr. Kim, Thank you for the feedback and insightful comments from the editorial office and the reviewers. We appreciate the opportunity to revise the manuscript. We accordingly revised the text, figures and tables, and supplementary content. We have made changes to the manuscript per PLOS ONE style requirement. Changes in the main text are highlighted. Below are the detailed point-by-point responses to the reviewers’ comments. Reviewer 1 Comment 1: Were there any neuroendocrine tumor in origin included in this study? Answer: None of the patients in the final cohort had neuroendocrine histology. Comment 2: The statistical power is low because of the small study number. Answer: We understand the reviewer concern. We have been rigorous with our methods and have highlighted limitations of our study including sample size. Comment 3: The study design and the manuscript wring is robust. Answer: We thank the reviewer for appreciating our study design and manuscript writing. Reviewer 2: Comment 1: The authors present a retrospective analysis of real world data from their institution - comparing outcomes for patients with metastatic castration-sensitive prostate cancer treated either with docetaxel or novel hormonal agents. The question the authors are trying to address is relevant and timely since this clinical scenario is common and there is limited data to guide the decision of proceeding with docetaxel, NHA, or now with triplet therapy (both docetaxel and NHA). They report a longer time to next treatment (TTNT) for patients treated with docetaxel compared to NHA therapy but no difference in survival. The authors are using an automated abstraction platform, and data to demonstrate accuracy of this platform would be useful to ensure soundness of their conclusions. They refer to the figures in the supplement and say that a subset was reviewed manually for quality assurance but I would like more data regarding the accuracy of their platform. Answer: We understand the reviewer concern. We have referred to a recently presented abstract in American Medical Informatics Association (AMIA) Informatics Summit in 2022 highlights the efficiency of diagnosis extraction by the abstraction platform highlighted in Supplemental Figure 1. Besides, once a cohort is selected for a study, we carry out manual chart review of patient records to improve on automated abstraction for final analysis. It is clearly stated in Methods subsection “Patient Cohort Identification” in the text- “After the cohorts were identified, chart review was carried out to confirm duration of upfront docetaxel or NHA therapy, adverse events, identification of 2nd line therapy, and start date of 2nd line therapy. Additional clinical and demographic variables such as PSA values, age, sex, race, performance status, Gleason score, and metastasis burden at time of diagnosis were also evaluated.” Comment 2: there may be selection bias where patients offered docetaxel have more aggressive disease than those offered NHA. Although visceral/metastatic burden variables were reported to be similar, there seems to be a difference in Gleason between the two groups and there may be other differences that were not measured. Patients offered NHA may also be less fit (fewer ECOG 0) and thus oncologists may be slower to offer more intense therapies, or slower to change therapy. Answer: We understand the reviewer concern. We agree treatment change in real world scenario can be attributed to several factors. We explain the reasons for the difference in time to next treatment in Discussion in the text “Time to next treatment was shorter with docetaxel than NHAs. Several factors may have contributed to this observation. First, more docetaxel-treated patients changed therapy due to toxicity (6 vs. 0, p = 0.022). Second, there appeared to be a lower clinical threshold for docetaxel-treated patients to be initiated on a 2nd line therapy compared to NHA-treated patients. For example, 14 docetaxel-treated patients were started on a 2nd line therapy before meeting formal criteria for PSA progression, compared to only 4 of NHA-treated patients (p=0.03). In addition, the median increase in PSA from nadir at the time of 2nd line treatment initiation was 0.68 ng/ml among docetaxel-treated patients compared to 1.58 ng/ml among NHA treated patients; this difference was not statistically significant (p=0.55), but suggests that clinicians were more inclined to initiate 2nd line therapy in docetaxel-treated patients than NHA-treated patients. The fact that docetaxel treatment is limited to 6 cycles whereas NHAs are taken on an ongoing basis may influence clinicians’ response to rising PSA levels.” Moreover, we are not claiming one treatment is better than the other. We are reporting on the treatment patterns observed in patients and try to understand the underlying reason for the observations made. Comment 3: indication for next line of therapy may be different for patients offered docetaxel vs NHA. For example, patients with PSA progression after docetaxel may be offered NHA; while patients with PSA progression on NHA may be monitored until radiographic progression to start docetaxel. The authors state that the PSA was higher in the NHA group than the docetaxel group. The authors also mention that toxicity is different between the two types of treatment and was more often a reason for discontinuation/change of therapy in the docetaxel group. for these reasons, the clinical significance of their endpoint is unclear to me - even if TTNT is shorter in docetaxel group, it is not necessarily a reason to favor NHA over docetaxel, especially since OS is the same in their analysis. Answer: We understand the reviewer concern. We do not make a claim that one treatment is better than the other. We report on real treatment patterns for mHSPC patients and found that time on treatment is shorter on docetaxel than NHA however there is no change in OS. We acknowledge time on treatment can be influenced by many factors as discussed in the Discussion section and highlighted above. We hope this study help clinicians council patients on what to expect when put on docetaxel vs NHA for mHSPC on subsequent treatments and journey in disease management. Comment 4: The authors state that patients started on a next line of therapy before PSA progression were excluded - how many patients and what types of therapies? Were there more in the docetaxel vs the NHA group? Answer: The patients who were put on next line of therapy before meeting the PCWG criteria for PSA progression were excluded from the PSA Progression Free Survival Analysis. 14 patients receiving docetaxel were moved to next treatment before meeting PSA progression guideline compared to 4 in NHA group. This is noted in Results, subsection “PSA progression” “Among evaluable patients, we found that those treated with docetaxel were more likely to start a subsequent therapy in the context of rising PSA levels prior to meeting PCWG criteria for PSA progression (14/45 vs. 4/42, p=0.02).” Comment 5: Were there differences in subsequent lines of therapy for docetaxel vs NHA? Answer: Supplemental Table 2 and 4 list the subsequent line of therapy after docetaxel or NHA. The findings are described in Results under subsection “Docetaxel Treatment Course” and “Novel Hormonal Agent Treatment Course”. NHA were the most common drugs used after docetaxel or NHA. Comment 6: line 51 in abstract - clarify that this is PSA nadir Answer: Thank you for the suggestion. We have clarified this in the Abstract now by adding- “lower post-treatment PSA levels (PSA nadir)”. Comment 7: line 74 - would add STAMPEDE to body of evidence supporting treatment intensification in mHSPC. Answer: Line 74 talks about the two landmark trials CHAATED and LATIDUTE that lead to use of docetaxel and abiraterone to standard of care for mHSPC patients in USA. Since STAMPEDE do not fit that criterion, it is not discussed in the Introduction. However, we discuss results from STAMPEDE trials extensively in Discussion. Comment 8: In Table 1: why is PSA being reported as log10PSA? Why is Gleason 10 presented before 7, 8, and 9? It is somewhat unusual to present both mean and categories of variables such as age and Gleason in Table 1; or mean plus log10 as for PSA. Answer: Thank you for this comment. We have reported log10PSA because absolute PSA values have a heavy right tail containing outliers with very large values which can skew the mean and the results in regression models. Taking the log changes the distribution to more closely resemble a normal distribution. Moreover, we have used mean and categories for same variables as age; mean and log10 for PSA to analyze the variables in detail to understand how they match between cohorts. Sometimes two cohorts can have a similar mean for a continuous variable but the categories can be distributed quite differently. We have fixed the order of Gleason scores in Table 1. Comment 9: Line 389 - needs attention to correct grammar Answer: We corrected the grammar. The sentence reads- “this study will help clinicians….” Sincerely, William Oh, MD Attachments Attachment Submitted filename: Response to Reviewer final.docx https://doi.org/10.1371/journal.pone.0264800.r002
4 Aug 2022 Decision Letter - Isaac Yi Kim, Editor Management of de novo metastatic hormone-sensitive prostate cancer: a comprehensive report of a single-center experience PONE-D-22-04683R1 Dear Dr. Oh, 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, Isaac Yi Kim, MD, PhD, MBA Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0264800.r003
Formally Accepted
11 Aug 2022 Acceptance Letter - Isaac Yi Kim, Editor PONE-D-22-04683R1 Management of de novo metastatic hormone-sensitive prostate cancer: a comprehensive report of a single-center experience Dear Dr. Oh: 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. Isaac Yi Kim Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0264800.r004

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