Results of POUT - A phase III randomised trial of peri-operative chemotherapy versus surveillance in upper tract urothelial cancer (UTUC)
The role of post nephro-ureterectomy (NU) treatment for UTUC is unclear. POUT (CRUK/11/027; NCT01993979) is a UK led trial that addresses whether adjuvant chemotherapy improves disease free survival (DFS) for patients (pts) with histologically confirmed pT2-T4 N0-3 M0 UTUC.
Pts (max n=345), WHO performance status 0-1, ≤90 days post NU were randomised (1:1) to 4 cycles gemcitabine-cisplatin (gemcitabine-carboplatin if GFR 30-49ml/min) or surveillance with chemotherapy at recurrence if required. Pts had 6 monthly cross sectional imaging & cystoscopy for 2 years, then annually to 5 years. The primary endpoint was DFS. The trial was powered to detect a hazard ratio (HR) of 0.65 (ie improvement in 3 year DFS from 40% to 55%; 2-sided alpha 5%, 80% power) with Peto-Haybittle early stopping rules for efficacy & inefficacy. Secondary endpoints included toxicity (CTCAE v4), pt reported quality of life (QL; EORTC QLQ-C30 & EQ5D assessed pre-randomisation, mid trt & at 3, 6, 12, 24 months), metastasis-free & overall survival.
Between 31st May 2012 and 5th Sept 2017, 248 pts were randomised (123 surveillance; 125 chemotherapy) at 57 centres. In Oct 2017, the independent trial oversight committees recommended POUT close to recruitment as data collected thus far (data snapshot 5th Sept 2017) met the early stopping rule for efficacy. At the time of interim analysis, median follow-up was 17.6 months (IQR 7.5-33.6). Pts had median age 69 years (range 36-88), 30% pT2, 65% pT3; 91% pN0. Grade ≥3 toxicities were reported in 60% chemotherapy pts & 24% surveillance pts. During the treatment period the most common grade ≥3 [≥4] toxicities in chemotherapy pts were neutropenia 29% [5%] (vs. 0% surveillance) & thrombocytopenia 7% [6%] (vs. 0%). [QL outcomes analysis planned early 2018]. 47/123 (surveillance) & 29/125 (chemotherapy) DFS events were reported; unadjusted HR = 0.47 (95% CI: 0.29, 0.74) in favour of chemotherapy (log-rank p= 0.0009). Two year DFS was 51% for surveillance (95% CI: 39, 61) and 70% for chemotherapy (95% CI: 58, 79). Metastasis-free survival also favoured chemotherapy: HR = 0.49 (95% CI: 0.30, 0.79, p=0.003).
Adjuvant chemotherapy is tolerable & improved metastasis-free survival in UTUC. Recruitment to the POUT trial was terminated early because of efficacy favouring the chemotherapy arm; follow up for overall survival continues. POUT is the largest randomised trial in UTUC; its results support the use of adjuvant chemotherapy as a new standard of care.