Results of POUT: A phase III randomised trial of perioperative chemotherapy versus surveillance in upper tract urothelial cancer (UTUC)

Background: The role of post nephro-ureterectomy (NU) treatment for UTUC is unclear. POUT (CRUK/11/027; NCT01993979) addresses whether adjuvant chemotherapy improves disease free survival (DFS) for pts with histologically confirmed pT2-T4 N0-3 M0 UTUC. Methods: Pts (max n = 345) ≤90 days post NU were randomised (1:1) to 4 cycles of gemcitabine-cisplatin (gemcitabine-carboplatin if GFR 30-49ml/min) or surveillance with subsequent chemotherapy if required. Pts had 6 monthly cross sectional imaging and cystoscopy for the first 2 years, then annually to 5 years. Toxicity was assessed by CTCAE v4. Primary endpoint was DFS. The trial was powered to detect a hazard ratio (HR) of 0.65 (i.e. improvement in 3 year DFS from 40% to 55%; 2-sided alpha = 5%, 80% power) with Peto-Haybittle (p < 0.001) early stopping rules for efficacy & inefficacy. Secondary endpoints included metastasis-free survival (PFS), overall survival (OS), toxicity & quality of life. Results: Between May 2012 & Sept 2017, 248 pts were recruited (123 surveillance; 125 chemotherapy) at 57 UK centres. In Oct 2017, the independent trial oversight committees recommended POUT close to recruitment as data collected thus far (data snapshot 05/09/2017) 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. 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). PFS favoured chemotherapy: HR = 0.49 (95% CI: 0.30, 0.79, p = 0.003). Conclusions: Adjuvant chemotherapy improved PFS in UTUC. POUT is the largest randomised trial in this pt population; the trial was terminated early because of efficacy favouring the chemotherapy arm. Whilst follow up for OS continues, this should be considered a new standard of care in these patients. Clinical trial information: ISRCTN98387754.