The POUT trial, a multicenter collaboration from the UK, enrolled 260 patients with locally advanced or node-positive UTUC (pT2-T4 N0-3 M0) from May of 2012 to September of 2017. The patients were then randomized (1:1) to 4 cycles of gemcitabine-cisplatin (gem-cis)/gem-carboplatin (GFR 30-49 ml/min) or surveillance 90-days following a nephroureterectomy. Patients with a GFR < 30, and those with an incomplete resected macroscopic disease where excluded from the trial. Patients were followed closely with cross-sectional imaging and cystoscopy every 6 months for the first two years and transitioned to annual follow-up for a total of 5 years. The primary end-point for the trial was disease-free survival (DFS), with recurrence-free survival (RFS), overall survival (OS), toxicity and quality of life (QoL) as secondary end-points.
The trial was expected to recruit 338 patients in order to detect a 15% improvement in 3-year DFS; however, the trial was stopped early by the safety monitoring committee due to significant improvement in observed DFS. The intent to treat analysis included 260 patients with 131 patients undergoing chemotherapy treatment and 131 followed by a surveillance protocol. Baseline characteristics were balanced between the groups, with the majority of patients being male (67.7%) and older (median age of 69). The majority of patients enrolled had pT3 disease (30% pT2, 65% pT3) and were node negative following node dissection (91%). Of patients undergoing chemotherapy, 66% were treated with Gem-Cis, and 68% successfully completed the 4 planned chemotherapy cycles. Toxicities observed were consistent with those known with the provided chemotherapy agents. Approximately 50% of patients undergoing chemotherapy developed a grade 3 or greater adverse event with only one patient suffering a death related to an upper GI bleed.
A significant difference in DFS (HR 0.49 [CI 0.31-0.76], p=0.001) was observed at a median follow-up of 17.3 months. Following adjustment for nodal involvement, the difference was more pronounced with an HR 0.47 [CI 0.30-0.74), p=0.001). On univariate analysis, positive margins and receipt of gem-carboplatin had a non-significant improved DFS following chemotherapy, which may be related to the early follow-up and low numbers in these groups. On secondary end-points, adjuvant chemotherapy was also associated with an improvement in recurrence-free survival (RFS) (HR 0.49 (0.30-0.78), p=0.02). A separation in the OS curves was seen, but the difference remains non-significant likely related to the early analysis.
In summary, the POUT trial provides exciting and convincing high-level evidence on the added value of adjuvant chemotherapy in patients with locally advanced or node-positive UTUC. The benefit of adjuvant chemotherapy appears to be inferior in those treated with carboplatin and or those with positive resection margins. While data remains too immature to make hard conclusions on these observations they may provide future quality standards for the care of these patients.
Presented by: Alison J. Birtle, MRCP, FRCR, MD, Lancashire Teaching Hospitals NHS Foundation Trust, Lancashire, UK
Written by: Andres F. Correa, MD, Fox Chase Cancer Center, Philadelphia, PA at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA