Oncologic outcomes of Bacillus Calmette-Guérin therapy in elderly patients with non-muscle-invasive bladder cancer: A meta-analysis

Seyed Mohammad Kazem Aghamir; Fatemeh Khatami; Hossein Farrokhpour; Leonardo Oliveira Reis; Mahin Ahmadi Pishkuhi; Abdolreza Mohammadi

doi:10.1371/journal.pone.0267934

Peer Review History

Original SubmissionMarch 12, 2022
14 Apr 2022 Decision Letter - Giuseppe Lucarelli, Editor PONE-D-22-07135Oncologic Outcomes of Bacillus Calmette-Guérin Therapy in Elderly Patients with Non-Muscle-Invasive Bladder Cancer: A Meta-AnalysisPLOS ONE Dear Dr. Mohammadi, 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 May 29 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Partly Reviewer #4: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes Reviewer #4: 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 Reviewer #3: Yes Reviewer #4: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: No Reviewer #4: 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: Dear authors, I carefully read your paper that I found interesting. The argument is not new but is still debated. It is still difficult finding a correct suggestion about BCG usage in elderly. I believe that the paper can be considered for publication after following some reviews. Please look following suggestions. INTRODUCTION: first sentence, please add a reference. I believe that instead of talking about grades and Cis is more correct talking about high- and super-high risks, in accordance with latest guidelines. Please include the concept of induction and maintenance. MATERIALS&METHODS: please enrich the section about inclusion/exclusion criteria (e.g. primary/recurrent tumors, characteristics, Cis, etc…). DISCUSSION: the first paragraph can be moved to introduction. You can refer to EAU guidelines 2022, they have been realized. I suggest to summarize the part where your repeat results of the studies (there are tables at this regard) while I think that you should improve the discussion of the results. Reviewer #2: Elderly Patients with Non-Muscle-Invasive Bladder Cancer: A Meta-Analysis COMMENTS TO AUTHORS: The aim of this manuscript is to evaluate the efficacy and toxicity of BCG therapy among aged (>70) and younger patients with non-muscle-invasive bladder cancer (NMIBC). The authors concluded the BCG maintenance therapy improved oncological outcomes DFS, CSS, and PFS in elderly patients with NMIBC and had a similar safety profile without moderate and severe complications. I believe that the study has sufficient merit to be considered for publication on Plos One, although major revisions are required. MAJOR COMMENTS - The introduction should be argued. Authors should better discuss the superiority of BCG in preventing tumor recurrence in intermediate-risk and high-risk NMIBC patients compared to a combination of epirubicin and interferon-alpha2b, mitomycin C or epirubicin alone. - Discussion. it will be for the benefit of the reader if the authors add and discuss the role of age (cut-off 70 years) at diagnosis in predicting oncologic behavior of pure carcinoma in situ of the bladder and the response to BCG therapy (doi: 10.1016/j.clgc.2021.12.005 ; PMID 35033480). The authors should also underline that another limitation regarding the studies under consideration is that younger patients were offered intravesical BCG treatment more often than elderly patients, because they are considered physiologically and psychologically different from younger patients. They should discuss the difficulties encountered during the Covid- 19 period as a reduced proportion of patients who underwent BCG therapy (induction + maintenance) after surgery (doi: 10.3390/cancers13215276 ; PMID 34771440). Reviewer #3: Objectives: Authors purposes in this manuscript were to evaluate the efficacy and toxicity of BCG therapy among aged (>70 years) and younger patients with non-muscle-invasive bladder cancer (NMIBC). 1. The second paragraph in the introduction is not intelligible, and I would suggest the authors to rephrase it. 2. If there is an acronym given to a topic I would suggest the authors to use the acronym throughout the manuscript. 3. The following paragraph: “Finally, activation of CD8+ cytotoxic, Natural Killer cells (NK), and shedding of inflammatory molecules like Interferon-gamma (IFNγ), Interleukin-12 (IL-12), and tumor necrosis factor Alfa (TNFα) (2, 3)” does not give a conclusion to the statement. It would be better if the authors will rephrase it. 4. The next phrase: “The medical reaction to intravesical BCG can be linked to the basic immune levels and activating potential which can be influenced by the age of the patient (4) is relatively poor to be understood by the English language readers. It would be better if the authors will rephrase it. 5. The purpose of this review does not provide enough information to raise the interest level for readers. In order for the readers to fully understand the main objectives of the study please provide at the end of the introduction section a more detailed presentation of the analysis that the authors are about to perform bellow. 6. The following phrase: “advanced age was defined differently from 60 to 80 in studies” is lacking probably years for 60 and 80. I would suggest the authors to specify if indeed the authors meant “years”. 7. In the headline of Table 1 on the seventh column is specified Male. Is it the percentage of male patients from each study? I would suggest the authors to clarify this headline. If the authors chose to insert a percentage it would be best to use the unit measure for all studies in the Tabel. This is also available for the sixth column (mention years for each study). 9. In Table “Treatment protocol” second row please correct “installations” 10. In the results section, it would be better for the discussions in the footnote of figures to be inserted in discussion section. It does not belong to results section. 11. The first phrase in the Discussion section should be erased as the intended information has been mentioned in the Introduction section. 12. Any country is written with capital letters. I would invite the authors to correct this. 13. The following phrase: “besides the concerns regarding the safety profile of the BCG, but the studies are conflicting results (8, 16, 45)” is not intelligible. I would suggest the authors to rephrase it. 14. In the discussion section I advise the authors to emphasize the findings of their own systematic review and meta-analysis, to compare the findings with existing relevant literature and to highlight how this study adds new value to the existing evidence. The discussion section in this form does not fulfill the main outcomes of the proposed review. 15. In the introduction and conclusions sections (abstract and manuscript) the authors mentioned the safety profile in elderly NMIBC patients treated with BCG. There is no evidence from the analyzed data from the meta-analysis about safety and toxicity in elderly patients; therefore it should be not mentioned. Reviewer #4: This meta-analysis evaluates the efficacy and toxicity of BCG therapy among aged (>70) and younger patients with non-muscle-invasive bladder cancer. I appreciate this study and suggest to evaluate also 3 recent study in your analysis or in discussion : -Clin Genitourin Cancer. 2022 Apr;20(2):e166-e172. doi: 10.1016/j.clgc.2021.12.005. Epub 2021 Dec 10.Clin Genitourin Cancer. 2022. PMID: 35033480 World Journal of Urology (2019) 37:507–514 https://doi.org/10.1007/s00345-018-2397-1 , see median age of this study ****** 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:** Gian Maria Busetto Reviewer #2: No Reviewer #3: No Reviewer #4: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0267934.r001
Revision 1
18 Apr 2022 Author Response Dear Editor Giuseppe Lucarelli Thanks for the comments to change the manuscript for the better. Following is my point by point my response. Journal Requirements: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf RE: This item was checked and is correct. 2. Thank you for stating the following financial disclosure: RE: The authors received no specific funding for this work. 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. RE: Our data set is available in supplementary file 1. 4. PLOS requires an ORCID iD for the corresponding Author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?=_xcclfuvtxQ RE: The ORCID iD of the corresponding Author is: 0000-0002-0483-2635 5. Please include a separate caption for figure 7 in your manuscript. RE: This caption was added to the manuscript. Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Partly Reviewer #4: Yes ________________________________________ 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes Reviewer #4: 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 Reviewer #3: Yes Reviewer #4: Yes ________________________________________ 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: No Reviewer #4: 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: Dear authors, I carefully read your paper that I found interesting. The argument is not new but is still debated. It is still difficult finding a correct suggestion about BCG usage in elderly. I believe that the paper can be considered for publication after following some reviews. Please look following suggestions. INTRODUCTION: first sentence, please add a reference. I believe that instead of talking about grades and Cis is more correct talking about high- and super-high risks, in accordance with latest guidelines. Please include the concept of induction and maintenance. RE: -The first sentence reference was added to the manuscript -The latest guideline reference added to the manuscript with a focus on high-grade tumor -The concept of the induction and maintenance of BCG therapy was added to the introduction MATERIALS&METHODS: please enrich the section about inclusion/exclusion criteria (e.g., primary/recurrent tumors, characteristics, Cis, etc.…). RE: Inclusion criteria were all patients with a histopathological diagnosis of non-muscle-invasive bladder cancer who received a BCG induction and maintenance therapy. We did not exclude recurrent, multiple, or CIS tumors. DISCUSSION: the first paragraph can be moved to introduction. You can refer to EAU guidelines 2022, they have been realized. I suggest to summarize the part where your repeat results of the studies (there are tables at this regard) while I think that you should improve the discussion of the results. RE: -The first paragraph moved to the introduction -The EAU 2022 referenced and mentioned changes are made ________________________________________ Reviewer #2: Elderly Patients with Non-Muscle-Invasive Bladder Cancer: A Meta-Analysis COMMENTS TO AUTHORS: The aim of this manuscript is to evaluate the efficacy and toxicity of BCG therapy among aged (>70) and younger patients with non-muscle-invasive bladder cancer (NMIBC). The authors concluded the BCG maintenance therapy improved oncological outcomes DFS, CSS, and PFS in elderly patients with NMIBC and had a similar safety profile without moderate and severe complications. I believe that the study has sufficient merit to be considered for publication on Plos One, although major revisions are required. MAJOR COMMENTS - The introduction should be argued. Authors should better discuss the superiority of BCG in preventing tumor recurrence in intermediate-risk and high-risk NMIBC patients compared to a combination of epirubicin and interferon-alpha2b, mitomycin C or epirubicin alone. RE: superiority of BCG in preventing tumor recurrence and its reference was added to the introduction. - Discussion. it will be for the benefit of the reader if the authors add and discuss the role of age (cut-off 70 years) at diagnosis in predicting oncologic behavior of pure carcinoma in situ of the bladder and the response to BCG therapy (doi: 10.1016/j.clgc.2021.12.005 ; PMID 35033480). RE: Thank you so much for the recommendation. The Ferro et al. study was discussed in the discussion The authors should also underline that another limitation regarding the studies under consideration is that younger patients were offered intravesical BCG treatment more often than elderly patients, because they are considered physiologically and psychologically different from younger patients. RE: Thank you so much for the comments; this item was added to the discussion They should discuss the difficulties encountered during the Covid- 19 period as a reduced proportion of Patients who underwent BCG therapy (induction + maintenance) after surgery (doi: 0.3390/cancers13215276 ; PMID 34771440). RE: Thank you so much for the recommendation; this study was added to the discussion ________________________________________ Reviewer #3: Objectives: Authors purposes in this manuscript were to evaluate the efficacy and toxicity of BCG therapy among aged (>70 years) and younger patients with non-muscle-invasive bladder cancer (NMIBC). 1. The second paragraph in the introduction is not intelligible, and I would suggest the authors to rephrase it. RE: this paragraph was rephrased 2. If there is an acronym given to a topic I would suggest the authors to use the acronym throughout the manuscript. RE: The acronyms applied throughout the manuscript. 3. The following paragraph: “Finally, activation of CD8+ cytotoxic, Natural Killer cells (N.K.), and shedding of inflammatory molecules like Interferon-gamma (IFNγ), Interleukin-12 (IL-12), and tumor necrosis factor Alfa (TNFα) (2, 3)” does not give a conclusion to the statement. It would be better if the authors will rephrase it. RE: The consequence of these inflammatory responses added to this paragraph. 4. The next phrase: “The medical reaction to intravesical BCG can be linked to the basic immune levels and activating potential which can be influenced by the age of the patient (4) is relatively poor to be understood by the English language readers. It would be better if the authors will rephrase it. RE: Rephrased item was replaced (The therapeutic response to intravesical BCG is dependent on the response of the innate immune system, influenced by the patient's age). 5. The purpose of this review does not provide enough information to raise the interest level for readers. In order for the readers to fully understand the main objectives of the study please provide at the end of the introduction section a more detailed presentation of the analysis that the authors are about to perform bellow. RE: this item changed, as you mentioned. 6. The following phrase: “advanced age was defined differently from 60 to 80 in studies” is lacking probably years for 60 and 80. I would suggest the authors to specify if indeed the authors meant “years”. RE: The” years” was addad to the mentioned item. 7. In the headline of Table 1 on the seventh column is specified Male. Is it the percentage of male patients from each study? I would suggest the authors to clarify this headline. If the authors chose to insert a percentage it would be best to use the unit measure for all studies in the Tabel. RE: The seventh column was corrected (male=63 patients (75%) ,female= 21 patients(25%) This is also available for the sixth column (mention years for each study). RE: The sixth column was corrected(years). 9. In Table “Treatment protocol” second row please correct “installations” RE: This word was corrected to the instillation 10. In the results section, it would be better for the discussions in the footnote of figures to be inserted in discussion section. It does not belong to results section. RE: This change was made as you mentioned. 11. The first phrase in the Discussion section should be erased as the intended information has been mentioned in the Introduction section. RE: This phrase was removed and added to the introduction. 12. Any country is written with capital letters. I would invite the authors to correct this. RE: It seems that this item is correct in text and tables 13. The following phrase: “besides the concerns regarding the safety profile of the BCG, but the studies are conflicting results (8, 16, 45)” is not intelligible. I would suggest the authors to rephrase it. RE: This item was changed as you wished(One of the continuing concerns regarding the intravesical BCG is its efficacy in elderly patients related to the probable reduced immune response with advanced age; and safety profile). 14. In the discussion section I advise the authors to emphasize the findings of their own systematic review and meta-analysis, to compare the findings with existing relevant literature and to highlight how this study adds new value to the existing evidence. The discussion section in this form does not fulfill the main outcomes of the proposed review. RE: A significant association was observed between the overall H.R. for CSS (1.43; 95% CI: 1.11-1.83) and the overall H.R. for PFS 1.22(95% CI: 1.02-1.46). The noticeable finding of our study compared to other studies is that the BCG therapy did not significantly change the DSF 15. In the introduction and conclusions sections (abstract and manuscript) the authors mentioned the safety profile in elderly NMIBC patients treated with BCG. There is no evidence from the analyzed data from the meta-analysis about safety and toxicity in elderly patients; therefore it should be not mentioned. RE: this item was corrected in the abstract and manuscript. Conclusion: The BCG maintenance therapy improved CSS and PFS oncological outcomes in elderly patients with NMIBC. BCG therapy did not significantly change the DSF ________________________________________ Reviewer #4: This meta-analysis evaluates the efficacy and toxicity of BCG therapy among aged (>70) and younger patients with non-muscle-invasive bladder cancer. I appreciate this study and suggest to evaluate also 3 recent study in your analysis or in discussion : RE: Thank you so much for your recommendations -Clin Genitourin Cancer. 2022 Apr;20(2):e166-e172. doi: 10.1016/j.clgc.2021.12.005. Epub 2021 Dec 10.Clin Genitourin Cancer. 2022. PMID: 35033480 RE: This articles was mentioned in the discussion World Journal of Urology (2019) 37:507–514 https://doi.org/10.1007/s00345-018-2397-1 , see median age of this study RE: The data of this article was added to the discussion. Attachments Attachment Submitted filename: Response to reviewers, BCG, PLOS ONE.doc https://doi.org/10.1371/journal.pone.0267934.r002
20 Apr 2022 Decision Letter - Giuseppe Lucarelli, Editor Oncologic Outcomes of Bacillus Calmette-Guérin Therapy in Elderly Patients with Non-Muscle-Invasive Bladder Cancer: A Meta-Analysis PONE-D-22-07135R1 Dear Dr. Mohammadi, 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, Giuseppe Lucarelli, M.D., Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0267934.r003
Formally Accepted
28 Apr 2022 Acceptance Letter - Giuseppe Lucarelli, Editor PONE-D-22-07135R1 Oncologic Outcomes of Bacillus Calmette-Guérin Therapy in Elderly Patients with Non-Muscle-Invasive Bladder Cancer: A Meta-Analysis Dear Dr. Mohammadi: 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. Giuseppe Lucarelli Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0267934.r004

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