AUA 2018: Results of POUT - Phase III Randomized Trial of Peri-Operative Chemotherapy vs. Surveillance in Upper Tract Urothelial Cancer

San Francisco, CA (UroToday.com) The role of post-radical nephroureterectomy (RNU) treatment for upper tract urothelial carcinoma (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 with histologically confirmed pT2-T4 N0-3 M0 UTUC.  A total of 345 patients, with a WHO performance status 0-1, 90 days post-RNU were randomized (1:1) to 4 cycles of 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 a duration of 2 years, then annually for 5 years. 

The primary endpoint was disease-free survival (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). Secondary endpoints included toxicity (CTCAE v4), pt reported quality of life (QL; EORTC QLQ-C30 & EQ5D assessed pre-randomization, mid-treatment & at 3, 6, 12, 24 months), metastasis-free & overall survival. Between 31st May 2012 and 5th Sept 2017, 261 pts were randomized (129 surveillance; 131 chemotherapy) at 57 centers. 

In Nov 2017, the independent trial oversight committees recommended POUT close to recruitment as data collected up to that point 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 toxicities in chemotherapy pts were neutropenia 29% [5%] (vs. 0% surveillance) & thrombocytopenia 7% [6%] (vs. 0%). A total of 29/125 (chemotherapy) DFS events were reported; unadjusted HR = 0.47 (95% CI: 0.29, 0.74) in favor of chemotherapy (log-rank p¼ 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 favored chemotherapy: HR = 0.49 (95% CI: 0.30, 0.79, p=0.003). 

In conclusion, Adjuvant chemotherapy is tolerable & it appears that it provides improved metastasis-free survival and cancer-specific survival in UTUC. The results of POUT, the largest randomized trial in UTUC, support the use of adjuvant chemotherapy as a new standard of care. 

Presented By: James Catto, Sheffield, UK 

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre Twitter: @GoldbergHanan at the 2018 AUA Annual Meeting - May 18 - 21, 2018 – San Francisco, CA USA
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