Experiences of participants in a clinical trial of a novel radioactive treatment for advanced prostate cancer: A nested, qualitative longitudinal study

Bianca Viljoen; Michael S. Hofman; Suzanne K. Chambers; Jeff Dunn; Haryana M. Dhillon; Ian D. Davis; Nicholas Ralph

doi:10.1371/journal.pone.0276063

Peer Review History

Original SubmissionApril 7, 2022
27 May 2022 Decision Letter - Randall J. Kimple, Editor PONE-D-22-10351Experiences of participants in a clinical trial of a novel radioactive treatment for advanced prostate cancer: A nested, qualitative longitudinal studyPLOS ONE Dear Dr. Ralph, 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. In particular please focus on comments raised by reviewers 2 and 3, below. Please submit your revised manuscript by Jul 11 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. 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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: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Randall J. Kimple Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf. 2. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section. 3. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability. Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized. Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. We will update your Data Availability statement to reflect the information you provide in your cover letter. 4. Thank you for stating the following in your Competing Interests section: [The authors declare there are no competing interests.] Please complete your Competing Interests on the online submission form to state any Competing Interests. If you have no competing interests, please state "The authors have declared that no competing interests exist.", as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now This information should be included in your cover letter; we will change the online submission form on your behalf. [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: Yes Reviewer #3: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: N/A Reviewer #3: N/A ****** 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 Reviewer #3: 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 Reviewer #3: 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: Nicely written manuscript reporting on patient experiences as participants in a clinical trial. Important to report on such perspectives especially with novel therapeutic agents, including the radiopharmaceutical agent 177Lu-PSMA-617. Accept as is. Reviewer #2: The authors report the results of a qualitative study nested within the TheraP clinical trial. The authors should be applauded for this approach and congratulated on this manuscript. There are a few points to consider that may improve the manuscript for readers, and expand upon some of the limitations and implications of this study. 1) Please consider shortening the introduction, making the background information more concise. 2) The potential financial impacts of participating in a trial are not addressed in the introduction, but were included in the interviews. 3) Figure 1 and Table 2: Although the randomization of this trial was 1:1, the participants in this study were 2:1 overrepresented in the Lutetium arm. Please comment on this in the study limitations or elsewhere. 4) Figure 1: Should the arrow for "Refused" go above the "Potential Participants" box? 4) Table 2: Could any data on the ethnic or socioeconomic makeup of the participants be included, beyond education and occupation? 5) Table 3: Under the "Mental changes" section, it appears all the included quotes are from patients who received cabazitaxel. Could any sample quotes from patients who received lutetium be included? 6) Did financial hardship emerge as a theme? It is grouped under the "Practical circumstances" sub-section (line 334). Access to Lutetium PSMA therapy and the financial cost to patients is a significant concern among healthcare providers in the US. It may be worthwhile expanding on this a bit more either within the results or discussion, if the results from the interviews would support such a discussion. 7) Under "Strengths and Limitations" it may be worth further expanding upon the limitation that "this study may not be generalizable to other socioeconomic and cultural contexts". Additional socioeconomic information in table 3 may help provide perspective for this point. 8) Another point to consider including is that patient experiences obtained from qualitative studies could help inform the design and review of future clinical trials. Reviewer #3: Abstract: Results section is very short. Although this is meant to be a qualitative analysis, it seems that a few summary statistics would be helpful. For example, could the author’s add the percent of men whose experience included each of the 3 ‘identified themes’? Also, could they include some mention of how these evolved over time as mentioned in the objective? The patients included in this study are a small proportion of the patients included in the larger trial. The conclusions of the paper are targeted to the broader population of patients represented in the larger trial. It would be helpful to include in the results some comparison of characteristics of these 15 patients to all patients on the randomized trial. Are they similar age, … This could be added to Table 2. ****** 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:** Freddy E Escorcia Reviewer #2: No Reviewer #3: 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.0276063.r001
Revision 1
18 Jul 2022 Author Response Response to Reviewer 1 Thank you for your review of our paper. We have answered each of your comments below: Reviewer Comments Authors Response Nicely written manuscript reporting on patient experiences as participants in a clinical trial. Important to report on such perspectives especially with novel therapeutic agents, including the radiopharmaceutical agent 177Lu-PSMA-617. Accept as is. Thank you for the comment. Response to Reviewer 2 Thank you for your review of our paper. We have answered each of your comments below: Reviewer Comments Authors Response The authors report the results of a qualitative study nested within the TheraP clinical trial. The authors should be applauded for this approach and congratulated on this manuscript. There are a few points to consider that may improve the manuscript for readers and expand upon some of the limitations and implications of this study. 1) Please consider shortening the introduction, making the background information more concise. Thank you for the comment. The authors have reduced the length of the introduction with the aim of making the background information more succinct (Line 74-75 sentences removed, next paragraph moved up from line 78 to 77, line 117- 118, and line 124-126 sentences removed). 2) The potential financial impacts of participating in a trial are not addressed in the introduction but were included in the interviews. The financial impact of participation was only minimally identified by participants in this study. To support the statement in the results (line 339) under the subheading ‘Practical Circumstances’, a comment has been added to line 103 of the introduction. The included references support this. 3) Figure 1 and Table 2: Although the randomization of this trial was 1:1, the participants in this study were 2:1 overrepresented in the Lutetium arm. Please comment on this in the study limitations or elsewhere. This is a reasonable comment however the authors feel that with the variance of four men it is unlikely to be significant for qualitative research outcomes. 4) Figure 1: Should the arrow for "Refused" go above the "Potential Participants" box? We agree with this comment. Figure 1 has been amended to show that out of the 22 total referrals, 2 refused, resulting in 20 potential and consenting participants. Table 2: Could any data on the ethnic or socioeconomic makeup of the participants be included, beyond education and occupation? During the consent and interview process, the ethnicity or socioeconomic make up of participants was not asked or obtained in detail. This data point was not collected as part of the main trial either and has not been standard practice in Australian and New Zealand trials (beyond Indigenous status). This information can therefore not be included in the research paper. We have included a comment in the “Strengths and Limitations” (line 430-432) to address this. 5) Table 3: Under the "Mental changes" section, it appears all the included quotes are from patients who received cabazitaxel. Could any sample quotes from patients who received lutetium be included? Participants who received LuPSMA experienced fewer side-effects and were less anxious about receiving treatment compared to those who received cabazitaxel. Therefore, the only quotes identifying any mental changes from those who received LuPSMA were included in the results under the sub-heading “coping with changes to mental health” (line 303 – 319). A greater number of participants who received cabazitaxel expressed a range of negative emotions. Consequently, more quotes were available and included in the results section and in Table 3. 6) Did financial hardship emerge as a theme? It is grouped under the "Practical circumstances" sub-section (line 334). Access to Lutetium PSMA therapy and the financial cost to patients is a significant concern among healthcare providers in the US. It may be worthwhile expanding on this a bit more either within the results or discussion, if the results from the interviews would support such a discussion. Financial impact was not identified strongly enough as a theme. Therefore, it was not included in the discussion. All considerable and identified themes are concentrated on and included in the discussion and conclusion. 7) Under "Strengths and Limitations" it may be worth further expanding upon the limitation that "this study may not be generalizable to other socioeconomic and cultural contexts". Additional socioeconomic information in table 3 may help provide perspective for this point. During the consent and interview process, the ethnicity or socioeconomic make up of participants was not asked or obtained in detail. We have included a comment in the “Strengths and Limitations” (line 430-433) to address this. 8) Another point to consider including is that patient experiences obtained from qualitative studies could help inform the design and review of future clinical trials. We agree with the reviewers comment. A statement has been added to the end of the Conclusion (Page 23, line 440). Response to Reviewer 3 Thank you for your review of our paper. We have answered each of your comments below: Reviewer Comments Authors Response Abstract: Results section is very short. Although this is meant to be a qualitative analysis, it seems that a few summary statistics would be helpful. For example, could the author’s add the percent of men whose experience included each of the 3 ‘identified themes’? Also, could they include some mention of how these evolved over time as mentioned in the objective? The focus of this study was to describe the lived experiences of men with advanced prostate cancer who participated in the TheraP clinical trial using qualitative analysis. The purpose and execution of qualitative studies is to provide rich data to understand the phenomenon under study; in this instance, clinical trial participation. The authors feel that due to the qualitative design and small number of participants numbers, it does not permit quantitative conclusions. The patients included in this study are a small proportion of the patients included in the larger trial. The conclusions of the paper are targeted to the broader population of patients represented in the larger trial. It would be helpful to include in the results some comparison of characteristics of these 15 patients to all patients on the randomized trial. Are they similar age, … This could be added to Table 2. Specific data from participants in the larger trial can unfortunately not be included in the paper for comparison. Generalisation of qualitative research via meta-synthesis or narrative in a setting where evidence for improving practice is held in high esteem, warrants careful attention by both qualitative and quantitative researchers (Polit & Beck 2010). Qualitative studies presenting an in-depth understanding of human experience, may also pursue theoretical generalisability (Carminati, 2018). In regards to the conclusions of the paper, we feel that producing explanations which are particular to the limited empirical parameters of the study is not enough and that our qualitative research should produce explanations which are generalisable, or which have a wider resonance. With the small sample of participants, this has yielded unique insights by revealing symmetries that may be overlooked in large sample studies. As stated in the book ‘Interpreting Qualitative Data’ by David Silverman (2019), good deductions articulate that the data gathered are significant beyond the particular cases, individuals or sites studied. Response from Academic Editor Thank you for your review of our paper. We have answered each of your comments below: Editor Comments Authors Response When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE’s style requirements, including those for file naming. PLOS ONE style requirements have been adhered to. Amendments to the authors affiliations, main body and file naming have been made. 2. Please note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section. Funding support was received from an ANZUP Below the Belt Research Grant (QualTheraP: A nested, multi-perspective longitudinal qualitative study of participants). There is no associated grant number. 3. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability. Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized. Interview data, in the form of audio recordings and de-identified transcripts are stored in secure, password protected USQ cloud storage. Only authors on this paper have access to transcript and audio files. Any raw qualitative data will not be made publicly available. Although de-identified it may contain detailed information about a person that could be recognisable to another when read in full. Data is available on request to authors. 4. Thank you for stating the following in your Competing Interests section: [The authors declare there are no competing interests.] Please complete your Competing Interests on the online submission form to state any Competing Interests. If you have no competing interests, please state "The authors have declared that no competing interests exist.", as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now This information should be included in your cover letter; we will change the online submission form on your behalf The authors have declared that no competing interests exists. The statement has been included in the cover letter. https://doi.org/10.1371/journal.pone.0276063.r002
17 Aug 2022 Decision Letter - Randall J. Kimple, Editor PONE-D-22-10351R1Experiences of participants in a clinical trial of a novel radioactive treatment for advanced prostate cancer: A nested, qualitative longitudinal studyPLOS ONE Dear Dr. Ralph, 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 make the minor edits suggested by reviewers 1-3. If you wish to address the comment of reviewer 4 you may do so, but it is not necessary. Please submit your revised manuscript by Oct 01 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. 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: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Randall J. Kimple Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments: Thank you for your patience as this manuscript underwent revision and your clear responses to reviewer comments. [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 Reviewer #3: (No Response) Reviewer #4: 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 Reviewer #3: Partly Reviewer #4: Partly ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: N/A Reviewer #3: N/A Reviewer #4: No ****** 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: Yes Reviewer #3: No Reviewer #4: 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 Reviewer #3: Yes Reviewer #4: 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: Manuscript remains a very valuable report on a generally overlooked theme in clinical trials and would be of broad interest to the readership of PLoS One Minor: Page 5, line 118: Did authors mean “deprivation” instead of “detection” Reviewer #2: Small editorial correction: Introduction, page 4: "androgen detection therapy" should be "androgen deprivation therapy". Reviewer #3: I previously suggested that the authors 'include in the results some comparison of characteristics of these 15 patients to all patients on the randomized trial. Are they similar age, … '. The authors have responded that 'Specific data from participants in the larger trial can unfortunately not be included in the paper for comparison.' It is not clear to me why this is? Are you not allowed to give the mean age of all patients enrolled on the larger trial? Is this not already published? Reviewer #4: This qualitative study describes the lived experiences of men with advanced prostate cancer participating in the TheraP trial; an open-label randomised trial of 177Lu-PSMA-617 compared with cabazitaxel chemotherapy. An interpretative phenomenological approach was used, and interviews analysed using thematic analysis. The current manuscript reports the results from the mid-point, conclusion and follow up interviews, focusing specifically on participants’ experiences of trial participation. 1) The current manuscript identifies three representative themes from the participants. As an open-label trial, it is disappointing the authors didn’t try to identify the differences, if there is any, of the participants between the two arms, which can be very interesting. Since all the materials are available, please dig into it more, and present the findings, even if it’s null. ****** 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: Yes: Freddy E Escorcia Reviewer #2: No Reviewer #3: No Reviewer #4: 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.0276063.r003
Revision 2
19 Sep 2022 Author Response Comments to the Author We have answered each of these comments below: Comments Authors Response 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #4: No We are unsure why there is a comment about the rigour of statistical analyses in a qualitative paper. An interpretative phenomenological approach was used, and interviews analysed using thematic analysis. The current manuscript reports the results from the mid-point, conclusion and follow up interviews, focusing specifically on participants’ experiences of trial participation. Comments Authors Response 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. The data should be provided as part of the manuscript or its supporting information or deposited to a public repository. Reviewer #3: No Reviewer #4: No All data underlying the findings described in the manuscript have been made available to PLOS ONE as supplementary files. Participants information has been kept confidential. Response to Reviewer 1 Thank you for your review of our paper. We have answered your comment below: Reviewer Comments Authors Response Minor: Page 5, line 118: Did authors mean “deprivation” instead of “detection”. The word has been amended to state ‘deprivation’. Response to Reviewer 2 Thank you for your review of our paper. We have answered your comment below: Reviewer Comments Authors Response Small editorial correction: Introduction, page 4: “androgen detection therapy” should be “androgen deprivation therapy”. The word has been amended to state ‘deprivation’. Response to Reviewer 3 Thank you for your review of our paper. We have answered your comment below: Reviewer Comments Authors Response I previously suggested that the authors ‘include in the results some comparison of characteristics of these 15 patients to all patients on the randomized trial. Are they similar age, …’. The authors have responded that ‘Specific data from participants in the larger trial can unfortunately not be included in the paper for comparison’. It is not clear to me why this is? Are you not allowed to give the mean age of all patients enrolled on the larger trial? Is this not already published? The mean (SD) age of participants in the larger TheraP trial have been included in Table 2. Furthermore, the total participants allocated to the LuPSMA and Cabazitaxel arms have also been included, as published in the Lancet: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00237-3/fulltext We wish to make the distinction that the language used to draw conclusions does not necessarily relate to the broader population of trial patients in the TheraP trial. Response to Reviewer 4 Thank you for your review of our paper. We have answered your comment below: Reviewer Comments Authors Response This qualitative study describes the lived experiences of men with advanced prostate cancer participating in the TheraP trial; an open-label randomised trial of 177Lu-PSMA-617 compared with cabazitaxel chemotherapy. An interpretative phenomenological approach was used, and interviews analysed using thematic analysis. The current manuscript reports the results from the mid-point, conclusion and follow up interviews, focusing specifically on participants’ experiences of trial participation. 1) The current manuscript identifies three representative themes from the participants. As an open-label trial, it is disappointing the authors didn’t try to identify the differences, if there is any, of the participants between the two arms, which can be very interesting. Since all the materials are available, please dig into it more, and present the findings, even if it’s null. The results of the study identify the overall lived experiences of men with advanced prostate cancer participating in the TheraP trial. The authors believe that the similarities and differences in experiences are shown in the results through the inclusion of participants perspectives and selected quotations from participants in both the LuPSMA and Cabazitaxel treatment arms. Some changes have been made to the results to try and emphasise the comparison even more (page 14, line 210; page 15 line 232 and 250). Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0276063.r004
28 Sep 2022 Decision Letter - Randall J. Kimple, Editor Experiences of participants in a clinical trial of a novel radioactive treatment for advanced prostate cancer: A nested, qualitative longitudinal study PONE-D-22-10351R2 Dear Dr. Ralph, 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, Randall J. Kimple Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #4: 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 #4: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #4: N/A ****** 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 #4: Yes ****** 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 #4: 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 #4: My comments have been addressed. I have no further critique. My comments have been addressed. I have no further critique. ****** 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 #4: No ******** https://doi.org/10.1371/journal.pone.0276063.r005
Formally Accepted
14 Oct 2022 Acceptance Letter - Randall J. Kimple, Editor PONE-D-22-10351R2 Experiences of participants in a clinical trial of a novel radioactive treatment for advanced prostate cancer: A nested, qualitative longitudinal study Dear Dr. Ralph: 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. Randall J. Kimple Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0276063.r006

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