Elderly patients with cancer admitted to intensive care unit: A multicenter study in a middle-income country

Antonio Paulo Nassar Junior; Mariane da Silva Trevisani; Barbara Beltrame Bettim; Fernando Godinho Zampieri; José Albani Carvalho Jr.; Amilton Silva Jr.; Flávio Geraldo Rezende de Freitas; Jorge Eduardo da Silva Soares Pinto; Edson Romano; Silvia Regina Ramos; Guilherme Brenande Alves Faria; Ulysses V. Andrade e Silva; Robson Correa Santos; Edmundo de Oliveira Tommasi; Ana Paula Pierre de Moraes; Bruno Azevedo da Cruz; Fernando Augusto Bozza; Pedro Caruso; Jorge Ibrahin Figueira Salluh; Marcio Soares

doi:10.1371/journal.pone.0238124

Peer Review History

Original SubmissionFebruary 28, 2020
18 May 2020 Decision Letter - Valérie Pittet, Editor PONE-D-20-05881 Very old patients with cancer admitted to intensive care unit: A multicenter study in a middle-income country PLOS ONE Dear Mr. Nassar Junior, 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. We would appreciate receiving your revised manuscript by Jul 02 2020 11:59PM. When you are 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. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. 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Reviewer #1: No Reviewer #2: Partly Reviewer #3: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No Reviewer #2: Yes Reviewer #3: 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 ****** 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 ****** 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: This is indeed an interesting question in the cancer setting. However, I have two major issues with the statistical analyses performed, and hence the discussion and conclusion. 1) If the outcome is mortality, why did you do logistic regression? Why did you not consider Cox regression and time to death? 2) The variables in the model may suffer from collinearity and hence it is recommended to create a directed acyclic graph to identify which variables should go into the model and how to estimate their independent effects on the outcome of interest. Reviewer #2: This is an interesting piece of work with a few areas which could benefit from additional clarification; How representative of the population as a whole is the population which is served by the two centres included in this study. Are the results scalable? It is not entirely clear from the methods how confident the authors were with the completeness of variables such as cancer status which were used to identify the cohort. How was the reason for admission to ICU defined? There is no mention in the methods as to whether patients were on active treatment for their cancer at the time of admission to ICU, and if they were, what that was. This may be significantly impacting on the results of the study. The message of the paper becomes a little confused in the discussion, the final paragraph of the paper is unclear. The focus appears to switch from being the impact of age on ICU mortality to being the impact of cancer on mortality in the very elderly. This could be made much stronger. Reviewer #3: Very old patients with cancer admitted to intensive care unit: A multicentre study in a middle-income country. The authors have performed a study aiming to describe clinical characteristics and identify factors associated with hospital mortality in a cohort of very old patients with cancer admitted to intensive care units. The analyses are well performed and the only thing that makes me hesitate to recommend this paper for publication is the lack of information about the selection of patients to the study. On page 3 line 78 the authors mention that cancer “is still considered a condition predisposing denial of ICU admission…”. What kind of patients are in this study? They have cancer, but it’s hard to tell from the information given in the paper what cancer patients that are denied ICU admission. What are the characteristics for patients in the ICU without cancer? Some of the cancers presented in Table2 (at least prostate cancer detected with a PSA-test) can be associated with a better health status than the background population https://zerocancer.org/learn/about-prostate-cancer/facts-statistics/. If a screening program for breast cancer is present in Brazil, the same argument can be applied for breast cancer. Why did the authors compare these patients to patients of similar age but without cancer? ****** 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 Reviewer #3: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.] 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 us at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0238124.r001
Revision 1
15 Jul 2020 Author Response Reviewer #1: This is indeed an interesting question in the cancer setting. However, I have two major issues with the statistical analyses performed, and hence the discussion and conclusion. Dear reviewer, Thank you for your time spent on peer-review. 1) If the outcome is mortality, why did you do logistic regression? Why did you not consider Cox regression and time to death? We chose logistic regression because our aim was to evaluate factors associated with a specific event (i.e., hospital mortality). We did not intend to study a time to event outcome. Additionally, a Cox regression model would not be appropriate for this study because some of the predefined variables (type of cancer, use of vasopressors and renal replacement therapy) included in the model did not respect the proportion hazards assumption according to the Schoenfeld residuals method, as can be seen in the figure in the attached file. Therefore, in order to verify the association of the predefined covariates with the hospital mortality, we believe it would be more appropriate to perform a logistic regression model. 2) The variables in the model may suffer from collinearity and hence it is recommended to create a directed acyclic graph to identify which variables should go into the model and how to estimate their independent effects on the outcome of interest. We agree with the reviewer about collinearity. In the revised manuscript, We evaluated collinearity among the variables included in the models by calculating the Variation Inflation Factor (VIF). Arbitrarily, we considered, in a conservative approach, a VIF ≥ 2 as a diagnostic of multicollinearity. We added a sentence in Methods: “We evaluated collinearity among the variables included in the models by calculating the Variation Inflation Factor (VIF). Arbitrarily, we considered VIF ≥ 2 as a diagnostic of multicollinearity.” We also added the results of multicollinearity assessment in Results: “There was no multicollinearity among the predefined variables to be included in the logistic regression model (Table 3). Table 3. Variation inflation index of the selected variables to be included in the logistic regression model Variable VIF Type of admission 1.018 Type of cancer 1.096 Performance status 1.008 Mechanical ventilation 1.374 Vasopressors 1.387 Renal replacement therapy 1.097 Modified CCI 1.112 CCI: Charlson Comorbidity Index. VIF: Variation Inflation Index.” Reviewer #2: This is an interesting piece of work with a few areas which could benefit from additional clarification; Dear reviewer, Thank you for your time spent on peer-review. How representative of the population as a whole is the population which is served by the two centres included in this study. Are the results scalable? Actually, this study was carried out with data from 56 centers. One of the databases is from a multicenter study with 55 hospitals (Orchestra study) and the other from a single large cancer center (A.C. Camargo Cancer Center). We believe the results are representative of Brazilian hospitals dedicated to care of patients with cancer. It is not entirely clear from the methods how confident the authors were with the completeness of variables such as cancer status which were used to identify the cohort. We agree with the reviewer that this information was not entirely clear. In the revised manuscript, we included the sentences: “There was no missing data on the outcome. Information on performance status was absent for 193 patients (4.2%). There was minimal (<1%) missing data on mechanical ventilation, vasopressors and renal replacement use. There was no missing data on type of cancer, type of admission and CCI. We did not perform any imputation on these missing data and performed complete-case analysis.” How was the reason for admission to ICU defined? In Orchestra database, reason for admission is extracted from a form fulfilled by a nurse or physician from the included ICU. In A.C. Camargo database, reason for admission is extracted from medical charts. The reason for admission is fulfilled by the intensivist in charge of the patient at the time of admission. In both databases, diagnoses are further categorized as sepsis, trauma or a disorder in an organ/system (neurologic, cardiovascular, respiratory, renal, gastrointestinal, surgical and others). There is no mention in the methods as to whether patients were on active treatment for their cancer at the time of admission to ICU, and if they were, what that was. This may be significantly impacting on the results of the study. It was an inclusion criteria for the study that patients were on active treatment for their cancer (In Methods, Patients, we highlighted this status in the revised manuscript: “We included all patients aged 80 years or older with active cancer who were admitted to the participant ICUs during the study period. We excluded patients admitted after elective surgeries.”). However, we don’t have, in neither database which were the treatment patients were on (for example, chemotherapy, target therapies, radiotherapy, etc). The message of the paper becomes a little confused in the discussion, the final paragraph of the paper is unclear. The focus appears to switch from being the impact of age on ICU mortality to being the impact of cancer on mortality in the very elderly. This could be made much stronger. We agree with the reviewer and apologize for not being clear. We believe we have two main messages. We have tried to emphasize both in the revised manuscript: 1. Short-term mortality of elderly critically ill patients with cancer was not worse than that from elderly critically ill patients without cancer. Thus, in the second paragraph of discussion, we have written: “Our study suggests elderly critically ill patients with cancer had a similar hospital mortality to those without cancer reported in previous studies [5, 7]. Additionally, in conclusion, we have written “elderly critically ill patients with cancer have comparable short-term outcomes after ICU admission to those of elderly patients without cancer reported in literature.” 2. Type of cancer is associated with short-term mortality in elderly critically ill patients with cancer, what has not been consistently shown in previous studies in critically ill patients with cancer. In the fourth paragraph of discussion, we have written: “One specific finding of our study was that metastatic solid cancer and hematologic cancer were also associated with increased hospital mortality. Previous studies in critically ill patients with cancer have not consistently shown that type of cancer had such an impact[21]. (…) Our study suggests that, in a different manner from their younger counterparts, type of cancer has an impact on short-term outcomes of elderly critically ill patients.” Additionally, in conclusion, we have writen: “In a different manner from their younger counterparts, metastatic solid cancer and hematologic cancer are associated with increased mortality in elderly critically ill patients and should be taken into consideration when planning care of these patients.” Reviewer #3: Very old patients with cancer admitted to intensive care unit: A multicentre study in a middle-income country. The authors have performed a study aiming to describe clinical characteristics and identify factors associated with hospital mortality in a cohort of very old patients with cancer admitted to intensive care units. Dear reviewer, Thank you for your time spent on peer-review. The analyses are well performed and the only thing that makes me hesitate to recommend this paper for publication is the lack of information about the selection of patients to the study. On page 3 line 78 the authors mention that cancer “is still considered a condition predisposing denial of ICU admission…”. What kind of patients are in this study? They have cancer, but it’s hard to tell from the information given in the paper what cancer patients that are denied ICU admission. What are the characteristics for patients in the ICU without cancer? Thank you for the consideration. In the sentence mentioned previously, we had just tried to contextualize our study in the previous knowledge of critically ill patients. The study by Guidet et al (Guidet B, Leblanc G, Simon T, Woimant M, Quenot JP, Ganansia O, et al. Effect of Systematic Intensive Care Unit Triage on Long-term Mortality Among Critically Ill Elderly Patients in France: A Randomized Clinical Trial. Jama. 2017;318(15):1450-9.), which we cite after this sentence, aimed to evaluate whether a liberal ICU admission policy in elderly critically ill patients could reduce long-term mortality. However, elderly patients with cancer were excluded from this trial, possibly because it may be common sense that elderly patients with active cancer wouldn’t benefit from liberal ICU admission policies. Unfortunately, because of both databases are from patients ultimately admitted to ICU, we don’t have data on critically ill patients which ICU admission was denied or simply not considered. Some of the cancers presented in Table2 (at least prostate cancer detected with a PSA-test) can be associated with a better health status than the background population https://zerocancer.org/learn/about-prostate-cancer/facts-statistics/. If a screening program for breast cancer is present in Brazil, the same argument can be applied for breast cancer. Why did the authors compare these patients to patients of similar age but without cancer? We agree with the reviewer. In Brazil, we have a screening program for breast cancer too and maybe patients identified in screening programs may be associated with better health status. Anyway, our main aim was to describe a population of elderly critically ill patients with any type of cancer. Although patients with different types of cancer may have different long-term outcomes, we believe most healthcare personnel who take care of critically ill patients still see cancer as a unique variable. Additionally, unfortunately, we don’t have data on elderly patients without cancer from this study and can’t make such comparison. Attachments Attachment Submitted filename: Response to reviewers_R1.docx https://doi.org/10.1371/journal.pone.0238124.r002
11 Aug 2020 Decision Letter - Valérie Pittet, Editor Elderly patients with cancer admitted to intensive care unit: A multicenter study in a middle-income country PONE-D-20-05881R1 Dear Dr. Nassar Junior, 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, Valérie Pittet, PhD Academic Editor PLOS ONE 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 #3: 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 #2: Yes Reviewer #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: Yes Reviewer #3: 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 #2: Yes Reviewer #3: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #2: Yes Reviewer #3: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #2: (No Response) Reviewer #3: My concerns are satisfyingly addressed although it’s the problem of generalizability is still a concern. The potential reader of the paper has been presented with enough information to judge the generalizability. The paper is OK for publication. ****** 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 #3: No https://doi.org/10.1371/journal.pone.0238124.r003

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