Comparison of survival times of advanced cancer patients with palliative care at home and in hospital

Jun Hamano; Ayano Takeuchi; Masanori Mori; Yasuhiro Saitou; Takahide Yamaguchi; Nobuyuki Miyata; Masakatsu Shimizu; Ryo Yamamoto; Yousuke Kimura; Yoshiyuki Kamiyama; Yasuyuki Arai; Hiroshi Matsuo; Hideki Shishido; Kazushi Nakano; Tomohiro Nishi; Hiroka Nagaoka; Naosuke Yokomichi; Isseki Maeda; Takashi Yamaguchi; Tatsuya Morita; Takuya Shinjo

doi:10.1371/journal.pone.0284147

Peer Review History

Original SubmissionOctober 28, 2022
15 Dec 2022 Decision Letter - Kenji Fujiwara, Editor PONE-D-22-27287Comparison of survival times of advanced cancer patients with palliative care at home and in hospitalPLOS ONE Dear Dr. Hamano, 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 Jan 29 2023 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. 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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. Please amend your current ethics statement to address the following concerns: a) Did participants provide their written or verbal informed consent to participate in this study? b) If consent was verbal, please explain i) why written consent was not obtained, ii) how you documented participant consent, and iii) whether the ethics committees/IRB approved this consent procedure. 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. Additional Editor Comments: Dear Dr. Jun Hamano. The manuscript is a prospective cohort study about the comparison of palliative care in hospitals and homes. The article was reviewed by two reviewers one recommended major revision and the other recommend rejection. I think the manuscript is eligible to proceed to major revision and re-evaluation after the revision. Best regards, Kenji Fujiwara Academic editor [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: No ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: No ****** 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: No 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: In this secondary data analysis, data from two multicenter, prospective cohort studies of advanced cancer patients was compared regarding survival time. One cohort was home-based, the other hospital-based. A Cox regression analysis with adjusting for some of the potential confounders including symptoms and treatments during the stay was conducted. Thank you for giving me the opportunity to review this interesting paper. I am reviewing this paper from the perspective of a clinician-scientist with clinical as well as scientific experience in home-based palliative care in Germany. Overall, the paper is very interesting, well written and scientifically well conducted. I have to general points of inquiry that need to be addressed in a revised version: 1. From my experience, PC patients with a burden of symptoms that requires visits at home, care more about symptom-control than they care about survival time. Still it is totally acceptable to center this paper on survival time, but it would be strengthened if more comments could be added on the quality of symptom control/burden of suffering (e.g. in the abstract). In my opinion, adequate symptom control and survival time should always be linked in PC and displayed in close connection to each other. 2. The baseline data shows that the timing of enrollment in the two different types of care may differ in a clinically significant way and may therefore have a big influence on “survival time”. Table 1 shows, that patients with a “markedly poor health” are much more frequent in hospital-based PC (13.4% vs. 7.3%) which is also the case for a bad “palliative care prognostic index” (39.0% vs. 19.9%). Most of these factors are controlled for in the cox-regression model, but some are necessarily missing. I was confused though, that the ECOG wasn’t included in the model. Papers that the authors have cited (e.g. Just et al 2021) have shown, that performance status is an important factor connected to survival time. Table 2 shows clinically relevant differences in the ECOG regarding the two cohorts with a much higher burden of disability in the hospital group. I would therefore like to ask the authors to recalculate their model including ECOG upon enrollment/first available time-point as an independent variable. 3. Reasons for a decreased survival time in hospitals over time may be due to “hospitalization hazards” such as hospital acquired infections (e. g. MSRA, ESBL, Noro-Virus, SARS-CoV-2, etc.). Does the data include information on complications during the hospital stay? Reviewer #2: I have reviewed 2 previous versions of this manuscript for another journal. My main concerns about the study remain the same: The main rationale the authors have for the study is that in their previous study comparing home PC clients and hospital PC clients they did not adjust for symptom severity and medical treatments during care. In other words, they want to shift the interest from going from a description of clients of two services to exploring a causal question about whether one of the services (causally) lengthens or shortens survival. That would, after all, be the reason for controlling for potential confounders. I think that, despite the efforts done by the authors in refining some of their analysis compared to an early version of the manuscript, it is impossible to answer this causal question with the data they have. There is so much suspicion of residual confounding and at the same time there is not really a qualitative criterion for causality (eg the Bradford-Hill criteria) that is addressed (plausibility would be a minimum). I just have too much doubt about the contribution this manuscript would make to the state of science (and would even present a misleading message). The analysis perhaps most plausibly shows that those clients referred to home PC are different from those referred to hospital PC, not only in their symptom severity but also in several other characteristics that the study did not measure. Like in other places around the world, referrals to hospital PC most likely just happen later than referrals to home PC. But this manuscript goes way beyond that modest claim and infers a causal effect of the type of service. The authors even claim that their study provides the best possible evidence (with an RCT being impossible). I disagree that the study does. Another comment I made in the previous reviews (as an aside) also remains: while the authors claim that all the variables controlled for in their model are confounders, treatments received during care are a mediator as they would be the result of the care service they are referred to. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0284147.r001
Revision 1
3 Feb 2023 Author Response Response to Review Comments Reviewer #1: 1. From my experience, PC patients with a burden of symptoms that requires visits at home, care more about symptom-control than they care about survival time. Still it is totally acceptable to center this paper on survival time, but it would be strengthened if more comments could be added on the quality of symptom control/burden of suffering (e.g. in the abstract). In my opinion, adequate symptom control and survival time should always be linked in PC and displayed in close connection to each other. Reply#1 We agree with this comment. Although unfortunately, our study could not indicate a clear association between the quality of symptom control or the burden of suffering and survival time. However, we added this fact and possible explanation in the Discussion section. (p.23, l.207 - 210) 2. The baseline data shows that the timing of enrollment in the two different types of care may differ in a clinically significant way and may therefore have a big influence on “survival time”. Table 1 shows, that patients with a “markedly poor health” are much more frequent in hospital-based PC (13.4% vs. 7.3%) which is also the case for a bad “palliative care prognostic index” (39.0% vs. 19.9%). Most of these factors are controlled for in the cox-regression model, but some are necessarily missing. I was confused though, that the ECOG wasn’t included in the model. Papers that the authors have cited (e.g. Just et al 2021) have shown, that performance status is an important factor connected to survival time. Table 2 shows clinically relevant differences in the ECOG regarding the two cohorts with a much higher burden of disability in the hospital group. I would therefore like to ask the authors to recalculate their model including ECOG upon enrollment/first available time-point as an independent variable. Reply#2 As the reviewer pointed out, the timing of enrollment in the two different types of care may differ. Moreover, we agree with the reviewer's comment that the performance status as the independent variable is essential. Since the PiPS-A and Palliative prognostic index include the component of performance status, we exclude the ECOG as the independent variable in terms of multicollinearity. 3. Reasons for a decreased survival time in hospitals over time may be due to “hospitalization hazards” such as hospital acquired infections (e. g. MSRA, ESBL, Noro-Virus, SARS-CoV-2, etc.). Does the data include information on complications during the hospital stay? Reply#3 As the reviewer pointed out, hospital acquired infections and other adverse event in hospital might affect the survival time in hospital. Since, we did not assess the reason of the fever, it is difficult to speculate the “hospitalization hazards”. Therefore, the detailed assessment of the “hospitalization hazards” is important to conduct high quality observational study mentioned in recent article (Hernán, M. A. (2021). Methods of Public Health Research - Strengthening Causal Inference from Observational Data. The New England Journal of Medicine, 385(15), 1345–1348. https://doi.org/10.1056/NEJMP2113319). Reviewer #2 My main concerns about the study remain the same: The main rationale the authors have for the study is that in their previous study comparing home PC clients and hospital PC clients they did not adjust for symptom severity and medical treatments during care. In other words, they want to shift the interest from going from a description of clients of two services to exploring a causal question about whether one of the services (causally) lengthens or shortens survival. That would, after all, be the reason for controlling for potential confounders. I think that, despite the efforts done by the authors in refining some of their analysis compared to an early version of the manuscript, it is impossible to answer this causal question with the data they have. There is so much suspicion of residual confounding and at the same time there is not really a qualitative criterion for causality (eg the Bradford-Hill criteria) that is addressed (plausibility would be a minimum). I just have too much doubt about the contribution this manuscript would make to the state of science (and would even present a misleading message). The analysis perhaps most plausibly shows that those clients referred to home PC are different from those referred to hospital PC, not only in their symptom severity but also in several other characteristics that the study did not measure. Like in other places around the world, referrals to hospital PC most likely just happen later than referrals to home PC. But this manuscript goes way beyond that modest claim and infers a causal effect of the type of service. The authors even claim that their study provides the best possible evidence (with an RCT being impossible). I disagree that the study does. Reply#1 We already mentioned what reviewer concerned in limitation section as “however, we could not conclude a causal relationship or clarify the scientific mechanisms between the type of palliative of care and the survival time of advanced cancer patients in this observational study.” (p.24, l.224 - l.226) In addition, we changed the description of discussion from “our current study was novel in confirming that patients receiving home-based palliative care had longer survival times than those receiving hospital-based palliative care by adjusting for symptoms and treatment factors.” to “our current study was novel to imply that patients receiving home-based palliative care had longer survival times than those receiving hospital-based palliative care by adjusting for symptoms and treatment factors.” (p.22 l.199) Furthermore, we changed the description of discussion from “our large-scale prospective, multicenter study with multifactorial adjustments is considered to be the highest level of evidence available.” to “our large-scale prospective, multicenter study with multifactorial adjustments is considered to be the high level of evidence available. However, RCTs in this area will continue to be ethically challenging, so it is necessary to perform the high-quality observational studies proposed in a recent article38.” We cited new article for this sentence. (Hernán, M. A. (2021). Methods of Public Health Research - Strengthening Causal Inference from Observational Data. The New England Journal of Medicine, 385(15), 1345–1348. https://doi.org/10.1056/NEJMP2113319)) Another comment I made in the previous reviews (as an aside) also remains: while the authors claim that all the variables controlled for in their model are confounders, treatments received during care are a mediator as they would be the result of the care service they are referred to. Reply#2 We already mentioned what reviewer concerned in limitation section as “First, we were unable to adjust for residual confounding factors affecting the choice of the type of palliative care and survival time such as the preferences of patients and their families, family support, the details of dose-response treatment, and spiritual well-being.” (p.23, l.221 – p.24, l.224), and “however, we could not conclude a causal relationship or clarify the scientific mechanisms between the type of palliative of care and the survival time of advanced cancer patients in this observational study.” (p.24, l.224 - l.226) Attachments Attachment Submitted filename: R1_Response to Review Comments_PLOS ONE.docx https://doi.org/10.1371/journal.pone.0284147.r002
7 Mar 2023 Decision Letter - Kenji Fujiwara, Editor PONE-D-22-27287R1Comparison of survival times of advanced cancer patients with palliative care at home and in hospitalPLOS ONE Dear Dr. Hamano, 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. The article is about the comparison of palliative care between at-home and in-hospital. This multi-center prospective study tried to adjust the survival time between two groups with symptoms. The manuscript is controversial among reviewers because the comparison has a risk to neglect some confounders and the disease severity of the two groups does seem not the same. I partly agree with the opinion of previous Reviewer #2 who recommended the rejection, and I think that the conclusion is too strong and the conclusion should be more modest. Please reconsider the conclusion by checking the suggestion from reviewers. Please submit your revised manuscript by Apr 21 2023 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, Kenji Fujiwara, PhD, MD 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: Dear Dr. Hamano. The article is about the comparison of palliative care between at-home and in-hospital. This multi-center prospective study tried to adjust the survival time between two groups with symptoms. The manuscript is controversial among reviewers because the comparison has a risk to neglect some confounders and the disease severity of the two groups does seem not the same. I partly agree with the opinion of previous Reviewer #2 who recommended the rejection, and I think that the conclusion is too strong and the conclusion should be more modest. Please reconsider the conclusion by checking the suggestion from reviewers. On the other hand, this manuscript is a challenging study to compare two treatment styles though not perfect in order to encourage the home-based palliative care that many patients want. I added my minor concerns below. Best regards, Kenji Fujiwara Minor concerns. 1. In the abstract, “at 45 home-based PC” sounds confusing. I recommend using a 45-home-based PC “services”, “centers”, or “units” in order to distinguish from patients' numbers. 2. In the abstract, I found meaningless indention. Please delete it. A total of 2,998 patients were enrolled in both studies and 2,878 patients were analyzed; 988 patients receiving home-based PC and 1,890 receiving hospital-based PC. The survival time of patients receiving home-based PC was significantly longer than that of patients receiving hospital-based PC for the Days Prognosis (estimated median survival time: 10 days [95% CI 8.1 – 11.8] vs. 9 days [95% CI 8.3-10.4], p=0.157), the Weeks prognosis (32 days [95% CI 28.9 -35.4] vs. 22 days [95% CI 20.3-22.9], p < 0.001), and the Months Prognosis, (65 days [95% CI 58.2 – 73.2] vs. 32 days [95% CI 28.9-35.4], p < 0.001). 3. In the Ethics statement in the submission system, please indicate the form of consent obtained (written/oral) or the reason that consent was not obtained (the data were analyzed anonymously) 4. In Figure 1, I could not read the words in the PDF file. Please check whether the high-resolution image was uploaded. [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 #3: (No Response) ******** 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 #3: Partly ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #3: I Don't Know ****** 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: No Reviewer #3: 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 #1: Yes Reviewer #3: 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: Dear Authors, thank you for your comments as well as the revised version. I still have one minor comment regarding the abstract (as this will be the most-read part of the paper). I would suggest to rephrase the comment section as in its current form it may be misunderstood as a generalization of the results that may not be supported by the evidence and its limitations: current version: Conclusion Our study revealed that advanced cancer patients with a Weeks or Months prognosis receiving home-based PC survived longer than those receiving hospital-based PC after adjusting for symptoms and treatments. Suggestion: Conclusion In this cohort of advanced cancer patients with a Weeks or Months prognosis, those receiving home-based PC survived longer than those receiving hospital-based PC after adjusting for symptoms and treatments. Reviewer #3: I agree with the comments of reviewer 1 and 2. Essentially, patients referred to home palliative care services and hospital palliative care services are inherently different. The differences cannot be fully accounted for by statistical adjustment, due to the presence of unmeasurable confounders. While many of the comments from reviewers 1 and 2 have been addressed by including statements in the limitation section, the main text, in my opinion, still overstates the conclusions that can be reasonably drawn from this study. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #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.0284147.r003
Revision 2
17 Mar 2023 Author Response The institutional review boards of all participating services approved this study and main institutional review boards (Come Home study: University of Tsukuba, EASED study: Seirei Mikatahara General Hospital) approved the use of existing EASED data for secondary analysis, and to combine the data for analysis. Japanese law does not require individual informed consent from participants in a non-invasive observational trial such as the present study. Therefore, we used an opt-out method rather than acquiring written or oral informed consent; all patients could receive information on the study through the instructions posted on the ward or institutional website, and they had the opportunity to decline participation. Attachments Attachment Submitted filename: R2_Response to Review Comments_PLOS ONE.docx https://doi.org/10.1371/journal.pone.0284147.r004
27 Mar 2023 Decision Letter - Kenji Fujiwara, Editor Comparison of survival times of advanced cancer patients with palliative care at home and in hospital PONE-D-22-27287R2 Dear Dr. Hamano, 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, Kenji Fujiwara, PhD, MD Academic Editor PLOS ONE Additional Editor Comments (optional): Dr. Hamano. Thank you for re-submitting the manuscript and I appreciate the responses to our suggestions. I think the manuscript is eligible to be accepted. Best regards, Kenji Fujiwara https://doi.org/10.1371/journal.pone.0284147.r005
Formally Accepted
4 Apr 2023 Acceptance Letter - Kenji Fujiwara, Editor PONE-D-22-27287R2 Comparison of survival times of advanced cancer patients with palliative care at home and in hospital Dear Dr. Hamano: 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. Kenji Fujiwara Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0284147.r006

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