Intravesical Instillation of Chemotherapy Before Radical Surgery for Upper Urinary Tract Urothelial Carcinoma: The REBACARE Trial

Thomas van Doeveren; Sebastiaan Remmers; Egbert R Boevé; Erik B Cornel; Antoine G van der Heijden; Kees Hendricksen; Evelyne C C Cauberg; Rens Jacobs; Bin K Kroon; Annemarie M Leliveld; Richard P Meijer; Harm van Melick; Bob Merks; Jorg R Oddens; Benjamin Pradere; Luc A J Roelofs; Diederik M Somford; Peter de Vries; Bart Wijsman; Willemijn A K M Windt; Marit Yska; Peter J Zwaan; Katja K H Aben; Pim J van Leeuwen; Joost L Boormans

doi:10.1016/j.eururo.2024.12.006

Intravesical Instillation of Chemotherapy Before Radical Surgery for Upper Urinary Tract Urothelial Carcinoma: The REBACARE Trial

Eur Urol. 2025 Jan 21:S0302-2838(24)02759-3. doi: 10.1016/j.eururo.2024.12.006. Online ahead of print.

Authors

Thomas van Doeveren¹, Sebastiaan Remmers², Egbert R Boevé³, Erik B Cornel⁴, Antoine G van der Heijden⁵, Kees Hendricksen⁶, Evelyne C C Cauberg⁷, Rens Jacobs⁸, Bin K Kroon⁹, Annemarie M Leliveld¹⁰, Richard P Meijer¹¹, Harm van Melick¹², Bob Merks¹³, Jorg R Oddens¹⁴, Benjamin Pradere¹⁵, Luc A J Roelofs¹⁶, Diederik M Somford¹⁷, Peter de Vries⁸, Bart Wijsman¹⁸, Willemijn A K M Windt¹⁹, Marit Yska²⁰, Peter J Zwaan²¹, Katja K H Aben²², Pim J van Leeuwen⁶, Joost L Boormans²

Affiliations

¹ Department of Urology Erasmus MC Cancer Institute University Medical Center Rotterdam Rotterdam The Netherlands. Electronic address: [email protected].
² Department of Urology Erasmus MC Cancer Institute University Medical Center Rotterdam Rotterdam The Netherlands.
³ Department of Urology Franciscus Gasthuis en Vlietland Rotterdam The Netherlands.
⁴ Department of Urology Ziekenhuis Groep Twente Hengelo The Netherlands.
⁵ Department of Urology Radboud University Medical Center Nijmegen The Netherlands.
⁶ Department of Urology Netherlands Cancer Institute Amsterdam The Netherlands.
⁷ Department of Urology Isala Medical Center Zwolle The Netherlands.
⁸ Department of Urology Zuyderland Medical Center Heerlen The Netherlands.
⁹ Department of Urology Rijnstate Medical Center Arnhem The Netherlands.
¹⁰ Department of Urology University Medical Center Groningen Groningen The Netherlands.
¹¹ Department of Oncological Urology University Medical Center Utrecht Utrecht The Netherlands.
¹² Department of Urology St. Antonius Ziekenhuis Nieuwegein The Netherlands.
¹³ Department of Urology Haaglanden Medical Center Leidschendam The Netherlands.
¹⁴ Department of Urology Amsterdam UMC University of Amsterdam Amsterdam The Netherlands.
¹⁵ Department of Urology La Croix du Sud Hospital Quint-Fonsegrives France.
¹⁶ Department of Urology Treant Zorggroep Emmen The Netherlands.
¹⁷ Department of Urology Canisius Wilhelmina Ziekenhuis Nijmegen The Netherlands.
¹⁸ Department of Urology Elisabeth-Tweesteden Medical Center Tilburg The Netherlands.
¹⁹ Department of Urology Martini Ziekenhuis Groningen The Netherlands.
²⁰ Department of Urology Maasstad Ziekenhuis Rotterdam The Netherlands.
²¹ Department of Urology Gelre Ziekenhuis Apeldoorn The Netherlands.
²² Department of Research and Development Netherlands Comprehensive Cancer Organization Utrecht The Netherlands; IQ Health Science Department Radboud University Medical Center Nijmegen The Netherlands.

PMID: 39843302
DOI: 10.1016/j.eururo.2024.12.006

Abstract

Background and objective: Intravesical instillation of chemotherapy (IIC) after radical surgery for upper urinary tract urothelial carcinoma (UTUC) reduces the risk of intravesical recurrence (IVR). However, compliance is low because of possible extravesical leakage after bladder cuff excision. The aim of this study was to evaluate the efficacy of preoperative IIC in reducing the risk of IVR.

Methods: In this prospective, single-arm, multi-institutional, phase 2 clinical trial, 190 chemonaïve patients with primary UTUC without prior or concurrent bladder cancer received a single intravesical instillation of mitomycin C for 1-2 hr within 3 h before surgery. The primary endpoint was the 2-yr histologically confirmed IVR rate, with a target reduction of >40% (from 33.2% according to literature data to <20%). A historical cohort of 247 patients with UTUC who did not receive perioperative IIC served as the reference. Secondary endpoints included compliance, toxicity, and IVR-free survival, which was analyzed via multivariable Cox regression and stratified by previous diagnostic ureteroscopy (d-URS).

Key findings and limitations: The 2-yr IVR rate was 24% (95% confidence interval [CI] 18-31%) on intention-to-treat analysis and 23% (95% CI 13-32%) on per-protocol analysis. Multivariable analysis revealed that d-URS was associated with higher IVR risk. In the REBACARE cohort, patients without d-URS had threefold lower IVR risk (hazard ratio 0.33, 95% CI 0.12-0.87) in comparison to the reference cohort. Compliance with preoperative instillation was 96% and no grade >2 toxicity occurred.

Conclusions and clinical implications: Preoperative IIC with mitomycin C was feasible and well tolerated and significantly reduced IVR risk for patients without d-URS. These findings suggest that preoperative IIC is a viable strategy for this subset of UTUC patients and that d-URS should be performed judiciously.

Keywords: Diagnostic ureteroscopy; Intravesical instillation; Intravesical recurrence; Phase 2 trial; Treatment; Upper urinary tract urothelial carcinoma.