Methods: We did a phase 3, open-label, randomized controlled trial at 71 hospitals in the UK. We recruited patients with UTUC after nephroureterectomy staged as either pT2–T4 pN0–N3 M0 or pTany N1–3 M0. We randomly allocated participants centrally (1:1) to either surveillance or four 21-day cycles of chemotherapy, using a minimization algorithm with a random element. Chemotherapy was either cisplatin (70 mg/m2) or carboplatin (area under the curve [AUC]4·5/AUC5, for glomerular filtration rate <50 mL/min only) administered intravenously on day 1 and gemcitabine (1000 mg/m2) administered intravenously on days 1 and 8; chemotherapy was initiated within 90 days of surgery. Follow-up included standard cystoscopic, radiological, and clinical assessments. The primary endpoint was disease-free survival analyzed by intention to treat with a Peto-Haybittle stopping rule for (in)efficacy. The trial is registered with ClinicalTrials.gov, NCT01993979. A preplanned interim analysis met the efficacy criterion for early closure after recruitment of 261 participants.
Findings: Between June 19, 2012, and Nov 8, 2017, we enrolled 261 participants from 57 of 71 open study sites. 132 patients were assigned chemotherapy and 129 surveillance. One participant allocated chemotherapy withdrew consent for data use after randomization and was excluded from analyses. Adjuvant chemotherapy significantly improved disease-free survival (hazard ratio 0·45, 95% CI 0·30–0·68; p=0·0001) at a median follow-up of 30·3 months (IQR 18·0–47·5). 3-year event-free estimates were 71% (95% CI 61–78) and 46% (36–56) for chemotherapy and surveillance, respectively. 55 (44%) of 126 participants who started chemotherapy had acute grade 3 or worse treatment-emergent adverse events, which accorded with frequently reported events for the chemotherapy regimen. Five (4%) of 129 patients managed by surveillance had acute grade 3 or worse emergent adverse events. No treatment-related deaths were reported.
Interpretation: Gemcitabine–platinum combination chemotherapy initiated within 90 days after nephroureterectomy significantly improved disease-free survival in patients with locally advanced UTUC. Adjuvant platinum-based chemotherapy should be considered a new standard of care after nephroureterectomy for this patient population.
Funding: Cancer Research UK.
Authors: Alison Birtle, MD, Mark Johnson, MD, Prof John Chester, Ph.D., Prof Robert Jones, Ph.D., David Dolling, Ph.D., Richard T Bryan, Ph.D., Christopher Harris, Andrew Winterbottom, Anthony Blacker, MBChB, Prof James WF Catto, Ph.D., Prabir Chakraborti, MD, Prof Jenny L Donovan, Ph.D., Paul Anthony Elliott, Ph.D., Ann French, MSc, Satinder Jagdev, MDRB, Benjamin Jenkins, MSc, Francis Xavier Keeley Jr, MD, Roger Kockelbergh, MBChB, Prof Thomas Powles, Ph.D., Prof John Wagstaff, MD, Caroline Wilson, Ph.D., Rachel Todd, MSc, Rebecca Lewis, BSc, Prof Emma Hall, PhD
Source: A Birtle et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. The Lancet. March 05, 2020. DOI: https://doi.org/10.1016/S0140-6736(20)30415-3.
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