FOIU 2018: Adjuvant Therapy for Locally Advanced and Node-positive Upper Tract UC

Tel-Aviv, Israel ( Marc Wygoda, MD gave a talk on the role of adjuvant therapy for locally advanced upper tract urothelial carcinoma (UTUC). UTUC is a rare tumor, accounting for 5% of all urothelial carcinomas. The common and standard treatment is radical nephroureterectomy (RNU). Approximately 60% of these tumors are muscle invasive with a high rate of recurrence and metastatic disease. These result in poorer survival, stage for stage, when compared to bladder cancer.

Previous adjuvant chemotherapy studies have been hampered by low patient numbers (<50 patients) and have produced inconsistent results. Data from studies in the neoadjuvant and palliative treatment for muscle-invasive bladder cancer (MIBC) demonstrate that urothelial malignancies are chemo-sensitive. Neoadjuvant chemotherapy (NAC) improves survival in MIBC, however, no real data exists on the usage of NAC in UTUC.

The greatest benefit of adjuvant chemotherapy is the fact that there is definitive histology before receipt of chemotherapy, minimizing the risk of over-treatment. Thus, although there are strong data in favor of NAC in MIBC, its routine use in potentially resectable UTUC is less logical. The POUT (Perioperative chemotherapy versus surveillance in upper tract urothelial cancer) trial was discussed later by Dr. Wygoda. In this trial, it was assessed whether adjuvant chemotherapy improves disease-free survival (DFS) for patients with histologically confirmed pT2-T4 N0-3 M0 UTUC. For this trial, patients with a WHO performance status 0-1, and less than 90 days post nephroureterectomy were randomized (1:1) to 4 cycles of gemcitabine-cisplatin or surveillance with chemotherapy given on recurrence, if required. The primary endpoint was DFS, and patients had cross-sectional imaging and cystoscopy every 6 months for the first 2 years, then annually up to 5 years. Toxicity was assessed as well. 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%, and 80% power). Secondary endpoints included metastasis-free survival, overall survival, toxicity and patient-reported quality of life.

There were 248 patients included in the trial, with 123 patients randomized to surveillance and 125 to chemotherapy at 57 UK centers. In October 2017, the independent trial oversight committee recommended POUT close to recruitment as the data collected thus far 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). Patients were a median 69 years of age (range 36-88), 30% had pT2 disease, 65% pT3, and 91% pN0. Grade ≥3 toxicities were reported in 60% of chemotherapy patients and 24% of surveillance patients. Overall, there were 47 (38.2%) DFS events in the surveillance group and 29 (23.2%) in the chemotherapy group; the HR was 0.49 (95%CI 0.31-0.76, p=0.01) in favor of chemotherapy. Two-year DFS was 51% for surveillance (95% C.I. 39-61) and 70% for chemotherapy (95% C.I. 58-79). Metastasis-free survival also favored chemotherapy, with an HR of 0.49 (95% C.I. 0.30-0.79, p=0.002).

According to Dr. Wygoda, Dr. Birtle and her colleagues, leading this trial, concluded that adjuvant chemotherapy is tolerable and improved metastasis-free survival in UTUC. Recruitment to the POUT trial was terminated early because of efficacy favoring the chemotherapy arm, however, follow-up for overall survival continues. POUT is the largest randomized trial in UTUC, and its results support the use of adjuvant chemotherapy as a new standard of care.

Presented by: Marc Wygoda, MD, Hadassah Medical Center - Hadassah University Hospital, Ein Kerem, Jerusalem,  Israel

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the 2018 FOIU 4th Friends of Israel Urological Symposium, July 3-5. 2018, Tel-Aviv, Israel