Highlights
- •Radical nephroureterectomy is the standard for upper tract urothelial carcinoma.
- •Overall survival (OS) after radical nephroureterectomy (RNU) is still poor.
- •Intermediate clinical endpoints (ICE) help expediting approval of novel treatments.
- •We aimed to identify the most informative ICE for predicting OS after RNU.
- •Metastasis within 3-years from RNU is the most informative ICE for predicting OS.
Abstract
Introduction
The only phase III trial that evaluated the role of adjuvant chemotherapy following
radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) was terminated
early. Thus, eventual overall survival (OS) surrogacy, as per Prentice, cannot be
assessed in this setting. We aimed to identify an intermediate clinical endpoint (ICE)
that could serve as an OS surrogate after RNU for UTUC.
Patients and Methods
We retrospectively analyzed 823 high-grade UTUC patients treated with RNU at 8 tertiary
referral centers. We explored the role of any recurrence (aR), defined as recurrence
in the urinary tract or in the resection bed as well the presence of distant metastasis
(DM), defined as metastatic disease outside the urinary tract and regional lymph nodes,
on OS through a time-varying Cox regression analyses fitted at the landmark points
of 1, 2, 3, and 4 years from RNU. Models’ discrimination was assessed using Harrell's
c index, after internal validation.
Results
Median follow-up for survivors was 5.6 years (interquartile range: 2.0-8.8). Overall,
391 and 212 patients experienced aR and DM, respectively. In a time-varying model,
aR and DM were predictors of OS: hazard ratio [HR]:1.20, 95% confidence interval [CI]:
1.13-1.28 (P < .001) and HR:1.26, 95% CI: 1.18-1.34 (P < .001), respectively. Progression to DM within 3 years from RNU was the most informative
ICE for predicting OS (c index: 0.81; HR: 4.40; 95%CI: 2.45-7.92; P < .001), compared to DM within 1, 2, and 4 years (c indexes: 0.74, 0.76, and 0.78, respectively). Progression to DM within 3 years from
RNU was further found superior for predicting OS compared to aR at any landmark points.
Conclusions
Progression to DM within 3 years represents a potential OS surrogate for surgically-treated
UTUC. This information could help in patient counseling, future study design and expedite
results release of ongoing randomized controlled trials.
Keywords
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Article info
Publication history
Published online: March 09, 2022
Accepted:
March 6,
2022
Received in revised form:
February 20,
2022
Received:
August 22,
2021
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
