为了评估系统铂类化疗对UTUC患者的疗效，2012年6月19日至2017年11月8日，研究组在英国的71家医院进行了一项临床3期、开放标签、随机对照试验。招募了261例在肾结直肠切除术后分期为pT2-T4 pN0-N3 M0或pTany N1-3 M0的UTUC患者，将其按1：1随机分组，其中132例在术后90天接受吉西他滨-铂类联合化疗，129例接受监测。
Title: Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial
Author: Alison Birtle, Mark Johnson, John Chester, Robert Jones, David Dolling, Richard T Bryan, Christopher Harris, Andrew Winterbottom, Anthony Blacker, James W F Catto, Prabir Chakraborti, Jenny L Donovan, Paul Anthony Elliott, Ann French, Satinder Jagdev, Benjamin Jenkins, Francis Xavier Keeley, Roger Kockelbergh, Thomas Powles, John Wagstaff, Caroline Wilson, Rachel Todd, Rebecca Lewis, Emma Hall
Abstract: BackgroundUrothelial carcinomas of the upper urinary tract (UTUCs) are rare, with poorer stage-for-stage prognosis than urothelial carcinomas of the urinary bladder. No international consensus exists on the benefit of adjuvant chemotherapy for patients with UTUCs after nephroureterectomy with curative intent. The POUT (Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer) trial aimed to assess the efficacy of systemic platinum-based chemotherapy in patients with UTUCs.MethodsWe did a phase 3, open-label, randomised 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 minimisation 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 analysed 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.FindingsBetween 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 randomisation 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.InterpretationGemcitabine–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.