PONE-D-20-01946

The impact of low- versus high-intensity surveillance cystoscopy on surgical care and cancer outcomes in patients with high-risk non-muscle-invasive bladder cancer (NMIBC)

PLOS ONE

Dear Dr. Rezaee,

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Both reviewers concur that the topic is important and the issue raised is not settled. They also concur that such an important question will not be answered conclusively by a retrospective study. 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. You should respond to all the comments of the referees providing the requested information and should tone down your conclusions by taking into consideration the limitations derived from the study design and the possible imbalances in the two study groups.

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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: Partly

Reviewer #2: Partly

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

Reviewer #1: Yes

Reviewer #2: 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

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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

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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: This is a retrospective study on a specific database of patients with high-risk non-muscle-infiltrating bladder cancer. This database also provides reliable follow-up (only 195 lost for follow-up of a total of more than 2100 patients). In this database, the diagnostic profitability and oncological results of establishing a narrow cystoscopic follow-up (one cystoscopy every 4 months minimum) or more lax (less than one cystoscopy every 4 months) are studied, finding that there are no differences between the two follow-ups.

It is an attractive study, with results that push to a more lax follow up, and tries to fill a real world clinical gap. However, the work has the following limitations:

- The exclusion of patients deceased by bladder cancer during the first two years of follow-up must be better explained. It is likely that these patients were part of a closer follow-up and more tumor resections were performed. I would propose to include those patients who died from bladder cancer who had undergone a review with at least one cystoscopy without tumor recurrence. In this way, an attempt is made to exclude patients in whom a non-infiltrating bladder tumor was mistakenly diagnosed in the beginning. To know in which group they are placed, the number of cystoscopies performed is divided into the time spent from initial resection to the diagnosis of the tumor (less than 3 cystoscopies/year or more than 3c/year)

- As the authors point out, the number of tumors is not reflected, which can be an important confounding factor in the cystoscopy rhythm and the results obtained.

- It is not specified whether the follow-up was replaced by other means (ultrasound, CAT Scan…) or if other urothelial tumors (upper urinary tract) were detected during the follow up. These results may influence the results presented.

- The percentage of patients over 80 years in the low intensity group is higher, and that may have influenced in not performing resection of asymptomatic tumors detected.

- Also, it has to be said that some low risk tumours may have been detected, but not operated or biopsied. This may influence the results presented.

- The grouping between non-infiltrating tumors (Ta) and CIS is not correct: High grade Ta may have around a 10% risk of progression, while the CIS can reach 50% (figure 3). This analysis should be reconsidered only with Ta vs T1 if the number of patients with CIS is too small.

Reviewer #2: The authors have assessed the association of low- vs. guideline-recommended high-intensity

cystoscopic surveillance with outcomes among patients with high-risk NMIBC analyzing a retrospective cohort study of Veterans Affairs patients (> 75) diagnosed with high-risk disease between 2005 and 2011 with follow-up through 2014

They found that patients with high-risk NMIBC undergoing low- vs. high-intensity cystoscopic surveillance underwent fewer transurethral resections, but did not experience an increased risk of progression or bladder cancer death

General comments

The evidence behind the frequency of cystoscopies in the follow-up of NMIBC is particularly poor and not supported by any level one evidence. Numerous studies including a previous one by the same group of authors (but mainly in low grade disease) have clearly outlined a major risk of overuse for various reasons.

Therefore the attempt to correlate the frequency of cystoscopic examinations by the authors should be commended and addresses a real unmet need.

Although the results are nicely presented and the authors have done their very best to honestly analyze and criticize their findings nevertheless the reader is left with the impression that the low and high frequency groups may not have been similar, therefore weakening any robust conclusions.

1.The confounder and possible bias is patients with low intensity might have had a better prognosis and less recurrences (even the high risk NMIBC group is heterogenous as outlined by the authors in their discussion); so the treating urologist might have had the tendency to space follow-up.

2. After propensity score adjustment, patients who underwent low-intensity surveillance had almost 3-times fewer transurethral resections compared to those who underwent high-intensity surveillance: In high grade NMIBC, especially given the fact that these patients usually receive BCG leading to bladder inflammation, it is reasonable to assume that more frequent cystos led to a higher chance that the urologists would see something she/he didn't like, decided to err on side of caution and therefore resect, isn't it?

3.The surveillance window tended to be longer among patients who underwent low-intensity surveillance,

because a lower proportion of them experienced a recurrence within the first 2 years (69

of 520 (13.3%) vs 655 of 1022 patients (64.1%); p<0.001).

This is honestly difficult to reconcile and grasp. It seems that despite the matching, groups were imbalanced in terms of risk of recurrence/progression.

4.Among patients with non-invasive disease (high grade Ta/CIS), low-intensity surveillance was associated with decreased risk of progression to invasive disease (T1 or T2) or bladder cancer death (CIn 19.3% vs. 31.4% at 5 years, p=0.002, Figure Panel 3B)- This is again very difficult to understand?? Why would any lower surveillance be associated with decreased risk of progression unless low intensity surveillance was performed in lower risk populations - the authors acknowledge that it is possible that urologists

managed certain high-risk NMIBC patients with low-intensity surveillance based on intra-operative and patient characteristics not measured in their study.Urologists may have followed solitary or small high-risk lesions less intensely compared to multi-focal or larger tumors

In conclusion, this is a nicely written paper on an important topic but the conclusions are not fully supported by the data presented and would benefit from being tempered.

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Reviewer #1: No

Reviewer #2: No

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The impact of low- versus high-intensity surveillance cystoscopy on surgical care and cancer outcomes in patients with high-risk non-muscle-invasive bladder cancer (NMIBC)

PONE-D-20-01946R1

Dear Dr. Rezaee,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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With kind regards,

Francisco X. Real

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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 #1: All comments have been addressed

Reviewer #2: (No Response)

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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 #1: Yes

Reviewer #2: (No Response)

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

Reviewer #1: Yes

Reviewer #2: (No Response)

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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 #1: Yes

Reviewer #2: (No Response)

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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 #1: Yes

Reviewer #2: (No Response)

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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 #1: After reading the new manuscript, all my comments addressed and adequately changed. I have no objection for publication.

Reviewer #2: (No Response)

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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 #1: No

Reviewer #2: No