TY - JOUR
T1 - Metastasis Within Three Years from Radical Nephroureterectomy as a Potential Surrogate for Overall Survival
AU - the European Association of Urology - Young Academic Urologists (EAU-YAU): Urothelial Carcinoma Working Group.
AU - Martini, Alberto
AU - Lonati, Chiara
AU - Necchi, Andrea
AU - Galsky, Matthew D.
AU - Ploussard, Guillaume
AU - Fallara, Giuseppe
AU - Pellegrino, Antony
AU - Simeone, Claudio
AU - Suardi, Nazareno
AU - Zamboni, Stefania
AU - Krajewski, Wojciech
AU - Simone, Giuseppe
AU - Briganti, Alberto
AU - Montorsi, Francesco
AU - Mattei, Agostino
AU - Shariat, Shahrokh F.
AU - Moschini, Marco
N1 - Funding Information:
A. Necchi reports Honoraria from Roche, Merck, Astra- Zeneca, Janssen Pharmaceuticals, has served as consultant or advisor for Merck Sharp & Dohme, Roche, Bayer, Astra- Zeneca, Clovis Oncology, Janssen Pharmaceuticals, Incyte, BioClin Therapeutics, Seattle Genetics, Astellas Pharma, has received research funding from Merck Sharp & Dohme (Inst), AstraZeneca (Inst) and Travel funding from Roche, Merck Sharp & Dohme, AstraZeneca, Janssen Pharmaceuticals, outside the submitted work. M.D. Galsky has served as consultant for BioMotiv, Janssen, Merk, Dendreon, Glax- oSmithKline, Lilly, Astellas, Genetech, BMS, Novartis, Pfizer, EMD Serono, AZ, Seattle Genetics, Incyte, Aileron Therapeutics, Dracen, Inovio Pharmaceuticals, NuMab, has received research funding from Janssen, Merk, Dendreon, Novartis, BMS, AZ, Genentech/Roche and owns stock of Rappta Therapeutics, outside the submitted work. The other authors have no conflict.
Publisher Copyright:
© 2022
PY - 2022/8
Y1 - 2022/8
N2 - 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.
AB - 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.
KW - Intermediate clinical endpoints
KW - Metastasis
KW - Overall survival
KW - Urothelial carcinoma
UR - http://www.scopus.com/inward/record.url?scp=85128339670&partnerID=8YFLogxK
U2 - 10.1016/j.clgc.2022.03.007
DO - 10.1016/j.clgc.2022.03.007
M3 - Article
C2 - 35383003
AN - SCOPUS:85128339670
VL - 20
SP - 389.e1-389.e7
JO - Clinical Genitourinary Cancer
JF - Clinical Genitourinary Cancer
SN - 1558-7673
IS - 4
ER -