Beta-blocker and survival in patients with lung cancer: A meta-analysis

Zhen Lei; Weiyi Yang; Ying Zuo

doi:10.1371/journal.pone.0245773

Peer Review History

Original SubmissionMay 1, 2020
8 Oct 2020 Decision Letter - Richard Hodge, Editor PONE-D-20-11931 Beta-blocker and survival in patients with lung cancer: a meta-analysis PLOS ONE Dear Dr. Zuo, 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. Specifically, the reviewer raised concerns about the reporting of the statistical methodology in the manuscript. Please submit your revised manuscript by Nov 21 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The authors conducts a meta-analysis of 10 studies in order to assess whether there is an association between use of beta blockers and survival in patients with lung cancer. Previous research has hypothesized that use of beta-blockers may be protective for lung cancer patients, but results have been inconsistent. This manuscript aimed to synthesize available studies to provide an updated analysis, including a broader set of studies than prior analyses. Major Comments: 1. The authors mention multiple other meta analyses looking at this same topic, but there is no discussion of whether the results from this study were consistent with previous meta analyses. Additionally, in the discussion, the authors say that previous meta analyses did not focus on lung cancer. If so, that should be highlighted when discussing how this study is different from prior ones. 2. The authors focused their analysis on survival, however the search terms include outcomes of recurrence, metastasis, progression, surgery, and operation. Please explain why these outcomes were included in the search terms and whether analyses of these outcomes was undertaken. 3. In the section about “Data extracting and quality evaluation”, the authors mention covariates included in the adjustment of RRs. Please clarify whether the outcomes reported were reported as risk ratios or hazard ratios. 4. The methods suggest that included studies needed to have a minimum follow up of one year, however, Table 2 indicates that not all studies had a sufficiently long follow up. Please clarify. 5. Are the authors defining BB use as before or after diagnosis of lung cancer to mean when they started using beta-blockers? Otherwise, it would seem that in figure 4, these are not mutually exclusive categories (ie: patients could have started taking BB before diagnosis, and continued after diagnosis). 6. The results suggest that there may be a benefit to BB in stage III cancers, and those without surgical resection. As surgical resection is not generally considered standard of care for later stage patients (but is for earlier stage patients), the interaction of other therapies besides surgery BB may be an interesting discussion point. 7. Patients taking beta blockers prior to their lung cancer diagnosis likely have other comorb conditions that may put them at higher risk of mortality. This may confound the relationship between beta-blockers and survival in these patients. This should be more clearly defined and discussed. 8. In the discussion of promising studies (page 14-15): why were these studies were not included in the meta analysis? Minor Comments: 1. The paper could benefit from English language editing 2. Please include a footnote in the tables for abbreviations used 3. It may be beneficial to split figures 3 and 4, as they are almost impossible to read without zooming in. Reviewer #2: As author concluded that BB failed to show OS in lung cancer patients, I would encourage author to have specific data on patients regarding smoking history, family history of lung cancer prevalence, environmental effect of subgroup of patients and more importantly genetic background such as mutation analysis data which could support the claim in sub groups. ****** 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. 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Revision 1
8 Dec 2020 Author Response Response to Reviewer 1 Major Comments: 1. The authors mention multiple other meta analyses looking at this same topic, but there is no discussion of whether the results from this study were consistent with previous meta analyses. Additionally, in the discussion, the authors say that previous meta analyses did not focus on lung cancer. If so, that should be highlighted when discussing how this study is different from prior ones. Authors’ response: Thanks for your comments. We have compared results of current meta-analysis with those of previous meta-analyses. Moreover, the strengths of current meta-analysis, compared to the previous ones, have also been discussed in the second paragraph of Discussion section of the revised manuscript. 2. The authors focused their analysis on survival, however the search terms include outcomes of recurrence, metastasis, progression, surgery, and operation. Please explain why these outcomes were included in the search terms and whether analyses of these outcomes was undertaken. Authors’ response: Thanks for your comments. We expanded the search terms regarding the outcomes of the patients to avoid missing of potential related studies. This has been clarified in the revised methods section. Analyses regarding these outcomes were not performed because this meta-analysis focused on the survival outcomes. 3. In the section about “Data extracting and quality evaluation”, the authors mention covariates included in the adjustment of RRs. Please clarify whether the outcomes reported were reported as risk ratios or hazard ratios. Authors’ response: Thanks for your comments. It should be “HR”, which has been corrected in the revised manuscript. We apologize for the typo. 4. The methods suggest that included studies needed to have a minimum follow up of one year, however, Table 2 indicates that not all studies had a sufficiently long follow up. Please clarify. Authors’ response: Thanks for your comments. We have noticed the error in Table 2. We defined adequate follow up as a minimum of one year, and all of the included studies met this criterion. Table 2 has been revised according. 5. Are the authors defining BB use as before or after diagnosis of lung cancer to mean when they started using beta-blockers? Otherwise, it would seem that in figure 4, these are not mutually exclusive categories (ie: patients could have started taking BB before diagnosis, and continued after diagnosis). Authors’ response: Thanks for your comments. Indeed, we defined BB use as before or after diagnosis of lung cancer according to the time when the patients started using of the medication. This has been clarified in the revised method section. 6. The results suggest that there may be a benefit to BB in stage III cancers, and those without surgical resection. As surgical resection is not generally considered standard of care for later stage patients (but is for earlier stage patients), the interaction of other therapies besides surgery with BB may be an interesting discussion point. Authors’ response: Thanks for your comments. We have added some discussion regarding these subgroup analyses in the revised manuscript as “Since surgical resection is not generally considered as standard of care for later stage patients with lung cancer, results of these subgroup analyses may reflect the potential adverse interaction of BB with treatment strategies other than surgery in these patients. Indeed, an early study including 107 patients with metastatic NSCLC receiving chemotherapy showed that BB use was associated with improved progression-free survival [1]. In addition, a recent retrospective study also showed that BB use was associated with improved prognosis in NSCLC patients that received immune checkpoint inhibitors [2]”. 7. Patients taking beta blockers prior to their lung cancer diagnosis likely have other comorbid conditions that may put them at higher risk of mortality. This may confound the relationship between beta-blockers and survival in these patients. This should be more clearly defined and discussed. Authors’ response: Thanks for your comments. We have discussed this in the limitation section of the revised manuscript as “Secondly, patients taking beta blockers prior to their lung cancer diagnosis were likely to have other comorbid conditions that may increase their mortality risks. Typically, BBs are prescribed for patients with cardiovascular disorders, who may also have concurrent medications such as statins, which have also been suggested to favorably affect the survival in patients with lung cancer [3]. Although comorbidities and concurrent medications have been generally adjusted among the included studies, these factors may confound the relationship between BB and survival in these patients”. 8. In the discussion of promising studies (page 14-15): why were these studies were not included in the meta analysis? Authors’ response: Thanks for your comments. These studies were not included because they were univariate-analysis studies or did not report HR for overall survival. Minor Comments: 1. The paper could benefit from English language editing Authors’ response: Thanks for your comments. Our revised manuscript has been proofread by the Medjaden Bioscience Limited, a professional agency for language editing of scientific research paper, to improve English writing. 2. Please include a footnote in the tables for abbreviations used Authors’ response: Thanks for your comments. A footnote for abbreviations has been embedded for Table 1, but not for Table 2 because there was not any abbreviations in Table 2. 3. It may be beneficial to split figures 3 and 4, as they are almost impossible to read without zooming in. Authors’ response: Thanks for your comments. Figure 3 and 4 has been split accordingly as Figure 3-8 in the revised manuscript. Reviewer #2: As author concluded that BB failed to show OS in lung cancer patients, I would encourage author to have specific data on patients regarding smoking history, family history of lung cancer prevalence, environmental effect of subgroup of patients and more importantly genetic background such as mutation analysis data which could support the claim in sub groups. Authors’ response: Thanks for your comments. In fact, we have performed subgroup analyses according to the adjustment of smoking status in Figure 8 of the revised manuscript, which showed that BB use was not significantly associated with improved OS of lung cancer in studies with and without the adjustment of smoking status of the patients. Since of our study is a meta-analysis based on study level, we were unable to provide subgroup data based on smoking history, family history of lung cancer prevalence, or genetic background of individually included patients. We have acknowledged these as potential limitations, which should be considered in designing of future studies. These contents have been added in the limitation section of the revised manuscript. References 1. Aydiner A, Ciftci R, Karabulut S, Kilic L. Does beta-blocker therapy improve the survival of patients with metastatic non-small cell lung cancer? Asian Pac J Cancer Prev. 2013;14(10):6109-14. Epub 2013/12/03. doi: 10.7314/apjcp.2013.14.10.6109. PubMed PMID: 24289634. 2. Oh MS, Guzner A, Wainwright DA, Mohindra NA, Chae YK, Behdad A, et al. The Impact of Beta Blockers on Survival Outcomes in Patients With Non-small-cell Lung Cancer Treated With Immune Checkpoint Inhibitors. Clin Lung Cancer. 2020. Epub 2020/09/10. doi: S1525-7304(20)30238-2 [pii] 10.1016/j.cllc.2020.07.016. PubMed PMID: 32900613. 3. Xia DK, Hu ZG, Tian YF, Zeng FJ. Statin use and prognosis of lung cancer: a systematic review and meta-analysis of observational studies and randomized controlled trials. Drug Des Devel Ther. 2019;13:405-22. Epub 2019/02/19. doi: 10.2147/DDDT.S187690 dddt-13-405 [pii]. PubMed PMID: 30774306; PubMed Central PMCID: PMC6350654. https://doi.org/10.1371/journal.pone.0245773.r002
8 Jan 2021 Decision Letter - Jianxin Xue, Editor Beta-blocker and survival in patients with lung cancer: a meta-analysis PONE-D-20-11931R1 Dear Dr. Zuo, 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. 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Reviewer #1: (No Response) Reviewer #2: 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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 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 ****** 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 ****** 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: I would like to thank the authors for this revised submission. I have a few additional comments. 1. Table 1 indicates that some studies reported disease free survival, in addition to overall survival. Were these survival outcomes used at all, or was the analysis limited to overall survival. In some places it seems like OS is the only outcome analyzed, but in some places, the authors refer to general “survival outcomes”. If only OS was extracted and analyzed, please specify. If other types of survival were included, please describe how those outcomes were combined. 2. Please define what is meant by selective and non-selective use of beta blockers. 3. Given the large number of subgroup analyses, please address the possibility of false positive/negative results. 4. Where the authors write “Since surgical resection is not generally considered as standard of care for later stage patients with lung cancer, results of these subgroup analyses may reflect the potential adverse interaction of BB with treatment strategies other than surgery in these patients”, please confirm whether adverse interaction is what is meant? The results about those without surgery, along with the next sentence seem to say that research has shown BB to be associated with improved survival in people who receive no surgery/other therapies, not worse survival. Minor Comments: 1. Figure 2 is listed in the figure legends as the funnel plot, but in the text, it is referred to as Figure 9. Reviewer #2: Thank you for the response. For future studies please try to underline the patient genetic and environmental factors. ****** 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 #2: No https://doi.org/10.1371/journal.pone.0245773.r003
Formally Accepted
2 Feb 2021 Acceptance Letter - Jianxin Xue, Editor PONE-D-20-11931R1 Beta-blocker and survival in patients with lung cancer: a meta-analysis Dear Dr. Zuo: 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. Jianxin Xue Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0245773.r004

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