Personal approach for cancer treatment: A meta-analysis of Phase II clinical trials

Mikhail B. Potievskiy; Elena P. Zharova; Lidia A. Nekrasova; Airat I. Garifullin; Ivan V. Korobov; Nikita E. Shevchenko; Anastasia A. Zabolotneva; Dmitriy N. Atochin; Andrei D. Kaprin; Peter V. Shegai

doi:10.1371/journal.pone.0332599

Peer Review History

Original SubmissionOctober 15, 2024
15 Oct 2024 Author Response Transfer Alert This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present. https://doi.org/10.1371/journal.pone.0332599.r001
23 Jan 2025 Decision Letter - Norikatsu Miyoshi, Editor -->PONE-D-24-46559-->-->Personal Approach for Cancer Treatment: a Meta-Analysis of Phase II Clinical Trials-->-->PLOS ONE Dear Dr. Potievskiy, 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 Mar 09 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. 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If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references.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 If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [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: Partly ******** -->2. Has the statistical analysis been performed appropriately and rigorously? --> Reviewer #1: Yes Reviewer #2: I Don't Know ****** -->3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.--> Reviewer #1: Yes Reviewer #2: Yes ****** -->4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.--> Reviewer #1: Yes Reviewer #2: Yes ****** -->5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)--> Reviewer #1: The manuscript provides a comprehensive and well-structured analysis of the impact of personalized genomics-based cancer treatments compared to non-personalized approaches. The combination of a systematic review and meta-analysis, grounded in PRISMA guidelines, enhances the robustness and transparency of the findings. The data-driven approach, including proportional meta-analysis and meta-regression, supports the study's conclusions about the significant benefits of personalized therapy in improving key clinical outcomes such as response rate, progression-free survival, and overall survival. The inclusion of 46 studies spanning 81 arms and over 6,500 patients demonstrates the extensive effort to capture a wide range of clinical trials and provides a strong foundation for the conclusions drawn. The significant positive results, particularly the association of personalized treatment with improved response rates and survival metrics, are timely and relevant for advancing oncology research and clinical practice. Moreover, the meticulous methodology, including independent data extraction and cross-checking by multiple reviewers, adds credibility to the results. The article highlights the promise of genomics-based approaches for tailoring cancer therapies, underscoring their potential for enhancing patient outcomes. Minor Revisions Suggested Clarify the methodology regarding the selection criteria for included studies, particularly how studies with mixed treatment types were handled. Expand on the limitations of the study, especially concerning the heterogeneity of included trials and the potential variability in genetic markers across studies. Consider a brief discussion on the implications of journal impact factor, even if found non-significant, as this adds context to the study design evaluation. Include additional details on the statistical tests used (e.g., assumptions for the Mann-Whitney test) to ensure reproducibility. In summary, this work makes a valuable contribution to the field of oncology by providing compelling evidence for the clinical benefits of personalization in cancer treatment. Upon addressing the minor revisions suggested, I strongly recommend its acceptance for publication, as it will likely inspire further research and have a meaningful impact on both clinical and research communities. Reviewer #2: This study presents a meta-analysis of Phase II clinical trials, showing that genomics-based personalized cancer treatments significantly enhance response rates, progression-free survival, and overall survival compared to non-personalized therapies. To make the article more informative, we suggest addressing the following points: First, the study reports considerable heterogeneity across key outcomes (RR, PFS, OS). Conducting subgroup analyses (e.g., by cancer type, treatment modality, or geographical region) and sensitivity analyses could help identify and address potential sources of heterogeneity. Second, the data collection is restricted to PubMed, which may lead to the exclusion of relevant studies. Expanding the search to include additional databases, such as EMBASE or Cochrane Library, would ensure a more comprehensive literature review. Lastly, as the analysis focuses exclusively on Phase II trials, the clinical applicability of the findings may be limited. Including Phase III trial data or real-world evidence, along with an assessment of cost-effectiveness and quality-of-life outcomes, could significantly enhance the practical relevance and impact of the study's conclusions. ****** -->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: Mohamed ABDELKARIM 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.0332599.r002
Revision 1
5 Apr 2025 Author Response We thank the reviewers and the editor for the crucial comments that will improve our manuscript. The supplements were revised and corrected following the journal’s data availability policy. We added additional information on the Risk of bias evaluation and provided the reasons for exclusion for all the selected trials. We also added supportive information on the data extraction process (names of the reviewers and date of extraction). The dataset and the information on excluded and included studies were revised and corrected following the journal's requirements (S4 Dataset, S5 File https://www.doi.org/10.5281/zenodo.10966214). The results of the certainty of evidence assessment (GRADE approach) are provided in S3 Table, and the method description is included on p.7. Please find below our detailed responses to each point raised by reviewers. Responses to Reviewer 1. Reviewer 1 commented: “Clarify the methodology regarding the selection criteria for included studies, particularly how studies with mixed treatment types were handled”. Response: We added additional information in the Methodology section to clarify the selection criteria, especially for mixed studies: The corrections were made in the 1st paragraphs of the “Eligibility Criteria and Study Selection Strategy” section on p.5 (“Studies of chemotherapy, immunotherapy, targeted therapy, and multi-agent trials, including various treatments, were selected.”) and the “Data Synthesis and Statistics” section on p.7 (“We considered multi-agent therapy as targeted or immune-oncological treatment if those were appointed in combination with other treatments.”). Reviewer 1 suggested: “Expand on the limitations of the study, especially concerning the heterogeneity of included trials and the potential variability in genetic markers across studies”. Response: The study limitations section was extended with a focus on study heterogeneity on page 15 (Only phase II clinical trial data collected from the PubMed database is a limitation of the study. The studies varied in genomic markers and demonstrated a high level of heterogeneity across RR, OS, and PFS. Oncological diseases are quite heterogeneous in general; RR, OS, and PFS depend on cancer type, disease stage, and treatment. Future analysis may include Phase III clinical trials, collected from various databases with an extended subgroup analysis and an assessment of cost-effectiveness and quality-of-life outcomes.”). Reviewer 1: “Consider a brief discussion on the implications of journal impact factor, even if found non-significant, as this adds context to the study design evaluation”. Response: We included a discussion on the implications of the journal impact factor on page 14 (IF was evaluated as an additional parameter to assess study variability and quality. The non-significant results of the meta-regression and subgroup analysis suggest comparable RR, OS, and PFS outcomes across studies published in both high-impact and other journals. These findings indicate that the ability of genomics-based personalization to improve treatment outcomes is consistently reported, regardless of journal impact.”. Reviewer 1 commented: “Include additional details on the statistical tests used (e.g., assumptions for the Mann-Whitney test) to ensure reproducibility”. Response: We added additional information on the statistical tests and clarified the conditions for their use on page 7 (“We compared the effects using the Chi-square test for categorical variables and employed the t-test or Mann-Whitney test based on the type of distribution (normal or non-normal) for continuous variables (RR, OS, and PFS), with a significance level set at p<0.05.”). Responses to Reviewer 2 Reviewer 2 commented: “First, the study reports considerable heterogeneity across key outcomes (RR, PFS, OS). Conducting subgroup analyses (e.g., by cancer type, treatment modality, or geographical region) and sensitivity analyses could help identify and address potential sources of heterogeneity.” Response: We agreed that high heterogeneity is a limitation of the study and included several sentences to highlight it in the 2nd paragraph of page 15 (“The studies varied in genomic markers and demonstrated a high level of heterogeneity across RR, OS, and PFS.”). Thank you for the suggestion that potential reasons for such results may be associated with various cancer types and treatments. Oncological diseases are quite heterogeneous in general; RR, OS, and PFS depend on cancer type, disease stage, and treatment. We described this topic in the discussion section, extending the limitations on page 15 (“Oncological diseases are quite heterogeneous in general; RR, OS, and PFS depend on cancer type, disease stage, and treatment.”). We also enhanced the explanation of heterogeneity on page 10 (“High heterogeneity rates may be associated with different response absolute metrics of outcomes for various cancers, disease stages, and treatments.”). Reviewer 2 commented: “Second, the data collection is restricted to PubMed, which may lead to the exclusion of relevant studies. Expanding the search to include additional databases, such as EMBASE or Cochrane Library, would ensure a more comprehensive literature review.” Response: We underlined such study limitations as PubMed and Phase II clinical trial restricted data search on page 15 (“Only Phase II clinical trial data collected from the PubMed database is a limitation of the study.”). Reviewer 2 commented: “Lastly, as the analysis focuses exclusively on Phase II trials, the clinical applicability of the findings may be limited. Including Phase III trial data or real-world evidence, along with an assessment of cost-effectiveness and quality-of-life outcomes, could significantly enhance the practical relevance and impact of the study's conclusions”. Response: We agree that the recommendations provided will make the study more informative and impactful, however, it will require reorganization of the manuscript after full re-analysis in accordance with the PRISMA workflow. This manuscript is the first step in genomics-based personalization analysis, and our current research includes the extended analysis suggested by the reviewer. A consideration of future research was included in the revised version of the manuscript on page 15 (“Future analysis may include Phase III clinical trials, collected from various databases with an extended subgroup analysis and an assessment of cost-effectiveness and quality-of-life outcomes.”). Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0332599.r003
2 Sep 2025 Decision Letter - Satyajeet Rath, Editor Personal Approach for Cancer Treatment: a Meta-Analysis of Phase II Clinical Trials PONE-D-24-46559R1 Dear Dr. Potievskiy, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support . 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, Satyajeet Rath Academic Editor PLOS ONE Additional Editor Comments: Thank you for making the desired corrections. We are happy to inform you that the article have been accepted for publication. https://doi.org/10.1371/journal.pone.0332599.r004
Formally Accepted
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