PONE-D-24-43910Comparative Impact of Integrated Palliative Care vs. Standard Care on the Quality of Life in Cancer Patients: A Global Systematic Review and Meta-Analysis of Randomized Controlled TrialsPLOS ONE

Dear Dr. Getie,

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.

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We look forward to receiving your revised manuscript.

Kind regards,

Usama Waqar, M.B.B.S

Academic Editor

PLOS ONE

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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: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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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: No

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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

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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 have conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) assessing the Impact of integrated palliative care (IPC) in comparison to standard care (SC) on the quality of life (QoL) of different cancer patients across different stage and settings. The authors have reported that IPC is statistically associated with improved QoL, especially among lung cancer patients, patients from Africa, and newly diagnosed patients.

I have the following comments:

1. The authors emphasize the need for this study due to the lack of high-quality evidence supporting the integration of integrated palliative care (IPC) in cancer management, despite varying findings across studies. However, a literature search reveals a study by Xu S. et al., titled “The effects of integrated palliative care on quality of life and psychological distress in patients with advanced cancer: a systematic review and meta-analysis.” This study highlights the positive effects of IPC on patients' quality of life (QoL) and psychological well-being. It also examines multiple types of cancer, including hematological malignancies, similar to the author’s study. Additionally, it addresses variations in QoL improvement across different IPC models. The authors should acknowledge this evidence and clearly define the specific gap in the literature that their study aims to address.

2. The authors have mentioned in their “search strategy” that only articles published in English will be included. However, “eligibility criteria” mentions that there will be no restrictions on language. Similarly, authors mention in their “search strategy” that articles from inception will be included, while in “data collection and quality assessment” study mentions RCTs published in last ten years will be included. The authors need to address these inconsistencies.

3. The authors need to add definitions and explicit details to strengthen their study:

a. The authors need to clearly state the definition of IPC and SC which they used for their inclusion along with the IPC model they accepted.

b. The authors should also define the threshold they used to define high, moderate, or low risk of bias.

c. The authors need to define how they determined the advanced stage of cancer or if they accepted included study authors’ definition. Moreover, the authors have written “all” as the site of cancer in table 1 but did not explain clearly with a footnote that “all” defines as cancer involving lung, gastrointestinal, breast, and reproductive organs.

4. The authors need to add more details in table 1 to improve it including the phase of the RCT and the QoL tool(s) used by it.

5. While authors have explained their screening process along with two independent reviewer policy to reduce bias, the authors have failed to mention if a software, such as Covidence, was used for this process.

6. While the study methodology mentions the plan for risk of bias and quality assessment of included studies, the authors have not conducted and represented the quality assessment in results, explained them in discussion, or conducted associated analysis after excluding low quality RCTs.

7. Figure 3 represents USA’s standard mean difference (SMD) as significant with value of 4.84 [2.49-7.19]. However, authors have not represented this finding in their results or explained it in their discussion. Moreover, authors have not represented studies from Asia in their figure 3.

8. The authors have mentioned, “The studies consistently showed a positive impact of IPC on patient satisfaction, symptom management, and overall quality of life, especially in advanced cancer stages”. However, later it is mentioned, “These findings suggest that the integration of palliative care has a more pronounced impact on patients from Africa, those with lung cancer, and newly diagnosed individuals.” The authors should explain this finding in more detail.

9. The authors explain that African patients showed most benefit for IPC on QoL with other evidence also supporting more pronounced effects of palliative care in low-resource settings. However, this explanation is refuted by authors’ own positive finding for USA. The authors should highlight this and explain their findings.

10. The authors find that lung cancer is significantly associated with improved outcomes with evidence showing such trend among advanced lung cancer patients. However, the included RCT included newly diagnosed patients. The authors should highlight this difference. Moreover, they can cite a systematic review by Kochovska S et al. (PMID: 32953543) which also IPC use early in lung cancer.

Reviewer #2: Summary:

This manuscript provides a well-conducted systematic review and meta-analysis by analyzing RCTs across various geographic regions and cancer types. It provides a comprehensive and globally relevant perspective on IPC's benefits, specially in resource-limited settings. The study is methodologically rigorous and provides a valuable contribution to evidence-based practice in palliative oncology.

Revision:

1. While the authors conduct subgroup and sensitivity analyses to account for heterogeneity, a more detailed discussion on the variables leading to high heterogeneity (I² = 82.94%) could strengthen the interpretation, particularly around the variability in IPC implementation and patient demographics.

2. To improve clarity, explicitly define each subgroup for example patient categories (e.g., newly diagnosed vs. advanced) and summarize findings for each subgroup analysis.

3. Expand the limitations section to acknowledge that variations in healthcare settings and IPC implementation could limit generalizability of results

4. Proof read the manuscript for few minor grammatical errors and clarity

5. Suggest directions for future RCTs for example using a standardized IPC protocol to reduce variability and explore specific IPC components which has the greatest impact on QoL.

Reviewer #3: The authors conducted a systematic review and meta-analysis comparing the impact of integrated palliative care vs. standard care on the quality of life in cancer patients. The authors 9 randomized controlled trials showcasing an increase in quality of life with integrated palliative care. Stratified analysis by continent, patient population, and cancer type demonstrated consistency of the results. The authors concluded that through integrating palliative care, quality of life for all cancer patients can be improved significantly. I congratulate the authors on a well conducted study.

I have a few comments:

1. Authors should provide rationale for choosing only RCTs for their systematic review and meta-analysis.

2. Page 3, 3rd para of introduction, the authors mention that some studies show benefit of IPC while others do not. The reference of this statement is a single student showing benefit.

The authors have explained the knowledge gap and created the need for a systematic review. However, there is a need to cite studies showing no benefit of IPC considering the statement.

3. Several lines in the first para of discussion lack citations.

4. 2nd line of 2nd para of discussion citing a study by Davis et al. lacks a citation.

5. The authors should attempt to explain why low resource settings have a greater impact of integrated palliative care in the discussion section.

6. Similarly, in the para on page 10 explaining the impact of IPC on lung cancer should be expanded to talk briefly about the reasons behind this finding.

7. The authors should expand on the discussion section’s recommendation paragraph on future implications. How can the results of this study be used for policy making or improving cancer care guidelines? This has been briefly mentioned at the end of the manuscript but needs further elaboration.

8. The authors reported that the impact of IPC was more pronounced in Africa. There is only 1 study from Africa included in this review. Could this have influenced the results? Please include this in limitations section.

9. The authors should replace the word USA with North America if they are trying to compare continents (as mentioned in the manuscript several times)

10. The authors show a comparison of newly diagnosed vs. advanced cancer patients in figure 5. Would any of these newly diagnosed patients be considered advanced if they have Stage IV disease? This categorization needs rewording.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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PONE-D-24-43910R1Comparative Impact of Integrated Palliative Care vs. Standard Care on the Quality of Life in Cancer Patients: A Global Systematic Review and Meta-Analysis of Randomized Controlled Trials

PLOS ONE

Dear Dr. Getie,

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 address the editorial comment on the follow-up intervals for QoL assessment in included studies.

Please submit your revised manuscript by Apr 16 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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,

Usama Waqar, M.B.B.S

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:

The mentioned outcome is QoL. Different studies may have measured QoL at different follow-up intervals. Did you focus on QoL at a specific follow-up interval after IPC vs. SC? How did you pool QoL data from multiple studies with different follow-up intervals in your meta-analyses? Please address in the Methods section in the Outcome heading or the statistical analysis plan.

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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 #2: All comments have been addressed

Reviewer #4: All comments have been addressed

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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 #2: Yes

Reviewer #4: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #4: Yes

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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 #2: Yes

Reviewer #4: Yes

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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 #2: Yes

Reviewer #4: Yes

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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 #2: (No Response)

Reviewer #4: I applaud the authors on their rigorous edits, which have satisfied any concerns that I may have had. I believe this manuscript makes a valuable contribution to the literature.

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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 #2: No

Reviewer #4: No

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[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.

PONE-D-24-43910R2Comparative Impact of Integrated Palliative Care vs. Standard Care on the Quality of Life in Cancer Patients: A Global Systematic Review and Meta-Analysis of Randomized Controlled TrialsPLOS ONE

Dear Dr. Getie,

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 address the editorial comment.

Please submit your revised manuscript by Apr 19 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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,

Usama Waqar, M.B.B.S

Academic Editor

PLOS ONE

Additional Editor Comments:

Random effects model only accounts for heterogeniety, which refers to differences in effects, i.e., odds ratios, risk ratios, etc, being estimated in the different studies included in a meta-analysis. It does not account for differences in follow-up intervals of individual studies.

Please see the following text from the Cochrane Handbook: 9.5.4 Incorporating heterogeneity into random-effects models.

"A random-effects meta-analysis model involves an assumption that the effects being estimated in the different studies are not identical, but follow some distribution. The model represents our lack of knowledge about why real, or apparent, intervention effects differ by considering the differences as if they were random. The centre of this distribution describes the average of the effects, while its width describes the degree of heterogeneity."

If the authors have not accounted for differences in follow up interval, this is a substantial error with the study design. Studies with short-term follow up may underestimate impact of different modalities on QoL; they cannot be merged with studies assessing QoL at larger intervals straight up. The authors should report follow up intervals at which QoL was assessed by individual studies in their Characteristics of Included Studies Table, then perform either of the following approach that aligns mostly with the variations in follow up intervals in the included studies (cannot directly assess as the authors have not provided this data:

1. Stratified analysis by follow-up duration

2. Meta-regression incorporating follow-up interval as an effect size

3. Sensitivity analyses excluding studies with very short or very long follow up intervals and pooling data from studies with similar follow-up intervals.

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[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.

Comparative Impact of Integrated Palliative Care vs. Standard Care on the Quality of Life in Cancer Patients: A Global Systematic Review and Meta-Analysis of Randomized Controlled Trials

PONE-D-24-43910R3

Dear Dr. Getie,

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.

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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,

Usama Waqar, M.B.B.S

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: