Adjuvant Chemotherapy in Upper Tract Urothelial Carcinoma: Results of the POUT Trial - Expert Commentary

Upper tract urothelial (UTUC) is an uncommon malignancy. Defining the impact of adjuvant chemotherapy on long term outcomes in UTUC patients is a critical clinical question. Recently, Birtle et al. reported in The Lancet the results of a landmark Phase III, open-label, randomized controlled POUT trial to evaluate the use of adjuvant platinum-based chemotherapy after radical nephroureterectomy in UTUC patients1.
Between June 19, 2012, and November 8, 2017, 261 UTUC patients staged as either pT2–T4 pN0–N3 M0 or pT any N1–3 M0 were randomly assigned 1:1 to either surveillance (n = 129) or four 21-day cycles of chemotherapy (n = 132). One participant withdrew consent and is not included in any analyses. Of note, the chemotherapy used in this trial was either cisplatin (70 mg/m2) or carboplatin (area under the curve [AUC] 4·5 or 5, for glomerular filtration rate <50 mL/min only) administered intravenously on day one and gemcitabine (1000 mg/m2) administered intravenously on days one and eight. The study required initiating adjuvant chemotherapy within 90 days of surgery. The primary endpoint was disease-free survival.

The study showed that adjuvant chemotherapy was significantly improved disease-free survival (hazard ratio 0·45, 95% confidence interval [CI] 0·30–0·68; p=0·0001). A preplanned interim analysis met the efficacy criterion for early termination. The 3-year disease-free survival rate was 71% (95% CI 61–78) in the chemotherapy group compared to 46% (36–56) in the surveillance group. Grade 3 or worse acute treatment-related adverse events in 44% (55/126) of participants who started chemotherapy vs. 4% (5/129) in the surveillance group (p<0·0001). No treatment-related deaths were reported.

The POUT trial is the largest reported adjuvant trial in UTUC patients. These results establish adjuvant chemotherapy as a standard of care for these patients. Our understanding of the molecular profile of UTUC is rapidly improving. Recent studies showed enrichment of FGFR3 alterations in UTUC patients. An ongoing Phase III trial (NCT04197986) is investigating the use of adjuvant FGFR3 inhibition in these patients2.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York

References:

  1. Birtle, Alison, Mark Johnson, John Chester, Robert Jones, David Dolling, Richard T. Bryan, Christopher Harris et al. "Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial." The Lancet (2020).
  2. Robinson, Brian D., Panagiotis J. Vlachostergios, Bhavneet Bhinder, Weisi Liu, Kailyn Li, Tyler J. Moss, Rohan Bareja et al. "Upper tract urothelial carcinoma has a luminal-papillary T-cell depleted contexture and activated FGFR3 signaling." Nature communications 10, no. 1 (2019): 1-11.

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