Metastasis Within Three Years from Radical Nephroureterectomy as a Potential Surrogate for Overall Survival

Published:March 09, 2022DOI:


      • 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.



      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.


      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.


      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.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Genitourinary Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Deuker M
        • Stolzenbach LF
        • Collà Ruvolo C
        • et al.
        Upper Urinary tract tumors: variant histology versus urothelial carcinoma.
        Clin Genitourin Cancer. 2021; 19: 117-124
        • Lwin AA
        • Hsu CH
        • Chipollini J.
        Urothelial carcinoma of the renal pelvis and ureter: does location make a difference?.
        Clin Genitourin Cancer. 2020; 18: 45-49.e1
        • Almås B
        • Halvorsen OJ
        • Johannesen TB
        • Beisland C.
        Higher than expected and significantly increasing incidence of upper tract urothelial carcinoma. A population based study.
        World J Urol. 2021; (0123456789): 1-7
        • Rouprêt M
        • Babjuk M
        • Burger M
        • et al.
        European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma : 2020 Update.
        Eur Urol. 2021; 9: 80-81
        • Veccia A
        • Antonelli A
        • Checcucci E
        • et al.
        Segmental ureterectomy for upper tract urothelial carcinoma: a systematic review and meta-analysis of comparative studies.
        Clin Genitourin Cancer. 2020; 18: e10-e20
        • Kenigsberg AP
        • Meng X
        • Ghandour R
        • Margulis V.
        Oncologic outcomes of radical nephroureterectomy (RNU).
        Transl Androl Urol. 2020; 9: 1841-1852
        • Powles T
        • Assaf ZJ
        • Davarpanah N
        • et al.
        ctDNA guiding adjuvant immunotherapy in urothelial carcinoma.
        Nature. 2021; 595: 432-437
        • Birtle A
        • Johnson M
        • Chester J
        • et al.
        Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial.
        Lancet. 2020; 395: 1268-1277
        • Prentice RL.
        Surrogate endpoints in clinical trials: definition and operational criteria.
        Stat Med. 1989; 3
        • Martini A
        • Daza J
        • Poltiyelova E
        • et al.
        Pathological downstaging as a novel endpoint for the development of neoadjuvant chemotherapy for upper tract urothelial carcinoma.
        BJU Int. 2019; : 665-671
        • Singla N
        • Christie A
        • Freifeld Y
        • et al.
        Pathologic stage as a surrogate for oncologic outcomes after receipt of neoadjuvant chemotherapy for high-grade upper tract urothelial carcinoma.
        Urol Oncol Semin Orig Investig. 2020; 38: 933.e7-933.e12
        • Bajorin DF
        • Witjes JA
        • Gschwend J
        • Schenker M.
        First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab vs placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC).
        J Clin Oncol. 2021; 39: 391
        • Humphrey PA
        • Moch H
        • Cubilla AL
        • Ulbright TM
        • Reuter VE.
        The 2016 WHO classification of tumours of the urinary system and male genital organs-Part B: prostate and bladder tumours.
        Eur Urol. 2016; 70: 106-119
        • Kuroiwa K
        • Inokuchi J
        • Nishiyama H
        • et al.
        Impact of previous, simultaneous or subsequent bladder cancer on prognosis after radical nephroureterectomy for upper urinary tract urothelial carcinoma.
        J Urol. 2019; 202: 1127-1135
        • Owens WD
        • Felts JA
        • Spitznagel EL.
        ASA Physical status classifications: a study of consistency of ratings.
        Anesthesiology. 1978; 49: 239-243
        • Paner GP
        • Stadler WM
        • Hansel DE
        • Montironi R
        • Lin DW
        • Amin MB.
        Updates in the Eighth Edition of the Tumor-Node-Metastasis Staging Classification for Urologic Cancers.
        Eur Urol. 2018; 73: 560-569
        • Moch H
        • Cubilla AL
        • Humphrey PA
        • Reuter VE
        • Ulbright TM.
        The 2016 WHO Classification of tumours of the urinary system and male genital organs—Part A: Renal, penile, and testicular tumours.
        Eur Urol. 2016; 70: 93-105
        • Novara G
        • Matsumoto K
        • Kassouf W
        • et al.
        Prognostic role of lymphovascular invasion in patients with urothelial carcinoma of the upper urinary tract : an international validation study.
        Eur Urol. 2010; 57: 1064-1071
        • Colin P
        • Ouzzane A
        • Yates DR
        • et al.
        Influence of positive surgical margin status after radical nephroureterectomy on upper urinary tract urothelial carcinoma survival.
        Ann Surg Oncol. 2012; 19: 3613-3620
        • Kamat AM
        • Sylvester RJ
        • Böhle A
        • et al.
        Definitions, end points, and clinical trial designs for non–muscle-invasive bladder cancer: recommendations from the international bladder cancer group.
        J Clin Oncol. 2016; 34: 1935-1944
        • Chen EY
        • Joshi SK
        • Tran A
        • Prasad V.
        Estimation of study time reduction using surrogate end points rather than overall survival in oncology clinical trials.
        JAMA Intern Med. 2019; 179: 642-647
        • Martini A
        • D M
        • Falagario UG
        • et al.
        Neoadjuvant versus adjuvant chemotherapy for upper tract urothelial carcinoma.
        Urol Oncol Semin Orig Investig. 2020; 38: 684.e9-684.e15
        • Martini A
        • Pfail J
        • Montorsi F
        • Galsky MD
        • Oh WK.
        Surrogate endpoints for overall survival for patients with metastatic hormone-sensitive prostate cancer in the CHAARTED trial.
        Prostate Cancer Prostatic Dis. 2020; 23: 638-645
        • Xie W
        • Regan MM
        • Buyse M
        • et al.
        Metastasis-free survival is a strong Surrogate of overall survival in localized prostate cancer.
        J Clin Oncol. 2017; 35: 3097-3104
        • Haslam A
        • Hey SP
        • Gill J
        • Prasad V.
        A systematic review of trial-level meta-analyses measuring the strength of association between surrogate end-points and overall survival in oncology.
        Eur J Cancer. 2019; 106: 196-211
        • Craig Hall M
        • Womack S
        • Sagalowsky AI
        • Carmody T
        • Erickstad MD
        • Roehrborn CG
        Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: A 30-year experience in 252 patients.
        Urology. 1998; 52: 594-601
        • Cosentino M
        • Palou J
        • Gaya JM
        • Breda A
        • Rodriguez-Faba O
        • Villavicencio-Mavrich H.
        Upper urinary tract urothelial cell carcinoma: location as a predictive factor for concomitant bladder carcinoma.
        World J Urol. 2013; 31: 141-145
        • Xylinas E
        • Rink M
        • Margulis V
        • Shariat SF.
        Multifocal carcinoma in situ of the upper tract is associated with high risk of bladder cancer recurrence.
        Eur Urol. 2012; (Published online)
        • Li WM
        • Shen JT
        • Li CC
        • et al.
        Oncologic outcomes following three different approaches to the distal ureter and bladder cuff in nephroureterectomy for primary upper urinary tract urothelial carcinoma.
        Eur Urol. 2010; 57: 963-969
        • Martini A
        • Lonati C
        • Montorsi F
        • et al.
        The role of prior bladder cancer on recurrence in patients treated with radical nephroureterectomy.
        Clin Genitourin Cancer. 2021; : S15
        • Rouprêt M
        • Babjuk M
        • Compérat E
        • et al.
        European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2017 Update.
        Eur Urol. 2018; 73: 111-122
        • Liao RS
        • Gupta M
        • Schwen ZR
        • et al.
        Comparison of pathological stage in patients treated with and without neoadjuvant chemotherapy for high risk upper tract urothelial carcinoma.
        J Urol. 2018; 200: 68-73
        • Meng X
        • Chao B
        • Vijay V
        • et al.
        High response rates to neoadjuvant chemotherapy in high-grade upper tract urothelial carcinoma.
        Urology. 2019; 129: 146-152
        • Hosogoe S
        • Hatakeyama S
        • Kusaka A
        • et al.
        Platinum-based neoadjuvant chemotherapy improves oncological outcomes in patients with locally advanced upper tract urothelial carcinoma.
        Eur Urol Focus. 2018; 4: 946-953
        • Necchi A
        • Martini A
        • Raggi D
        • et al.
        A feasibility study of preoperative pembrolizumab before radical nephroureterectomy in patients with high-risk, upper tract urothelial carcinoma: PURE-02.
        Urol Oncol Semin Orig Investig. 2022; 40: 10.e1-10.e6
        • Hahn AW
        • Giri S
        • Pathak R
        • Bhatt VR
        • Martin MG.
        Effect of adjuvant radiotherapy on survival in patients with locoregional urothelial malignancies of the upper urinary tract.
        Anticancer Res. 2016; 36: 4051-4055
        • Fang D
        • Li XS
        • Xiong GY
        • Yao L
        • He ZS
        • Zhou LQ.
        Prophylactic intravesical chemotherapy to prevent bladder tumors after nephroureterectomy for primary upper urinary tract urothelial carcinomas: a systematic review and meta-analysis.
        Urol Int. 2013; 91: 291-296