PONE-D-21-04718

A retrospective multicenter analysis of conditional survival after radical nephroureterectomy for locally advanced upper tract urothelial carcinoma

PLOS ONE

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PLOS ONE

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Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: Partly

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

Reviewer #1: I Don't Know

Reviewer #2: No

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: In this manuscript, the authors examined comparing the conditional cancer-specific survival (CCSS) between open (ONU) and laparoscopic radical nephroureterectomy (LNU) in patients with locally advanced UTUC from five tertiary centers. They compared the surgical outcomes retrospectively with CCSS in 723 patients with locally advanced UTUC (pT3, pT4, and pN+ without metastasis) who underwent either 439 open RNU or 284 laparoscopic RNU at 5 institutions between 2000 and 2012. The concept of conditional survival is convincing when considering diseases associated with unfavorable prognosis at initial diagnosis or treatment, such as locally advanced UTUC, which suggested that the patients who have already survived for a certain duration after being diagnosed with cancer, will continue to survive for a specified duration.

In general, this report is interesting for the urologists to updated information on the surgical outcome for locally advanced UTUC. However, some points need to be cleared and to be described more in detail.

Major comments:

1. This study showed the existence of different factors affecting prognosis at each annual follow-up and the decreased impact of prognostic pathological features including pN stage and LVI over time until their disappearance in long-term CCSS. This result is similar to ones of previous studies. Ploussard G, et al. in European Urology, 2015 reported that the tumor location, the presence of carcinoma in situ, and the type of bladder cuff excision were continuously predictive for intravesical recurrence-free survival whatever the survivorship. The authors are encouraged to discuss any difference with this paper.

2.The previous study demonstrated the clinical characteristics such as the number of removed nodes, lymph node status (both number of removed nodes and number of positive nodes). Could the authors provide these additional clinical dates to make it clear if it the difference between the previous report or not?

3. Why patients with NAC were excluded in this study?

4. The operation time, bleeding amount, and the transfusion should be considered.

5. Clinical stage as well as pathological stage should be examined. If clinical stage was T3, would you prefer to laparoscopic surgery?

6. Details of AC should be discussed (number of courses, regimens)

7. The significance to demonstrate subset B data is not clear.

8. The method of propensity score matching should be described in detail.

Minor comments:

1.On Table3, number of events should be disclosed for laparo- or open surgery, respectively.

2. Fig2-A. Conditional probability of cancer-specific survival at 5 years should be described.

3. Fig.2-B. Was there significant difference in 3-year conditional probability of cancer-specific survival between LNU and ONU?

Reviewer #2: In this paper the authors performed a multi-center retrospective review of 723 patients who underwent either open or laparoscopic nephu for locally advanced upper tract urothelial carcinoma from 2000-2012. They compared survival between the two surgical approaches and then performed a propensity score matched conditional survival analysis to find that there was no difference in 5 year survival rates between open and laparoscopic approaches. Overall, this paper may be of interest given that it reports on a rarer urologic malignancy and in an Asian population. However, I have several concerns listed below.

Title:

- Doesn’t mention anything about surgical technique and this papers main objective is comparing survival after open vs laparoscopic RNU

Abstract:

- Correct line 51 to state that RNU is the gold-standard treatment for non-metastatic HIGH GRADE UTUC.

- Need to state your definition of locally advanced disease

- Are you measuring cancer specific survival or overall survival?

Introduction:

- Grammatical errors throughout

- Statement on line 80 that lap RNU provides better outcomes needs a reference

- I disagree with the statement on line 83 that most urologists believe ONU is superior to LNU. I think MIS is considered standard at this point and there is plenty of data already to support this. Focus on what makes your paper unique – i.e. multicenter, Asian population, statistical methods

- Again, are you looking at cancer specific or overall survival?

Methods:

- What are the indications for open or lap RNU at the institutions?

- Why did you exclude neoadjuvant chemotherapy? This is now considered standard of care at academic centers

- You state you included pT3 or N+ patients but results show the inclusion of pTa/T1-2 and N0

Results:

- What was the follow up and how complete? Has significant implications on the validity of conditional survival assessments…

- What variables were controlled for in the matching?

- The tables need better labels in the headings i.e. HR (95%CI). Also the tables switch between separate columns for p values in table 1 to separate rows in table 2. Stick with p values in a separate column.

- I think you need to look at more variables if you are doing a survival analysis and stage should be stratified differently as that is the most important predictor. pTa should not be in same group as pT2.

- No data on adjuvant chemotherapy in the results sections.

Discussion:

- There are more limitations that need to be addressed. The real limitation in retrospective series that compare open and MIS surgery is selection bias. I don’t think the propensity score matching can control for this.

- Talk about the limitations of conditional survival analysis. You need to have good long term follow up.

- Patients had surgery from 2000 to 2012. There have been a lot of recent advancements in the management of UTUC including learning curve of MIS, use of adjuvant chemo (POUT trial) and intravesical chemo at the time of surgery. All those factors make the current results not necessarily applicable to modern readers.

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Reviewer #1: No

Reviewer #2: No

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A retrospective multicenter comparison of conditional cancer-specific survival between laparoscopic and open radical nephroureterectomy in locally advanced upper tract urothelial carcinoma

PONE-D-21-04718R1

Dear Dr. Seo,

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Kind regards,

Isaac Yi Kim, MD, PhD

Academic Editor

PLOS ONE

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