EAU 2021: Optimal Timing of Perioperative Systemic Therapy for High-Risk Upper Urinary Tract Cancer: Adjuvant

(UroToday.com) The Controversies in Onco-Urology session at the EAU 2021 annual meeting included a presentation by Dr. Nadine Houede who discussed the adjuvant approach to the optimal timing of perioperative systemic therapy for high-risk upper tract urothelial carcinoma. Dr. Houede notes that upper tract urothelial carcinoma makes up 5% of urothelial carcinomas, with 50-60% comprising the pyelocaliceal location, and 60% diagnosed at an invasive stage of the disease. Upper tract urothelial carcinoma shares the same risk factors as bladder urothelial carcinoma, but also has its own risk factors such as aristolochic acid (aka Chinese herbal nephropathy), and HNPCC/Lynch Syndrome. For pT3-4N0-X disease, the estimated 5-year relapse-free survival after radical nephroureterectomy is 54.9% and the 5-year overall survival after radical nephroureterectomy is 62.6%.


In the adjuvant setting for upper tract urothelial carcinoma, the POUT trial1 has changed the landscape of treatment for locally advanced disease. Eligible patients had received a radical nephroureterectomy for upper tract urothelial carcinoma, were postoperatively staged with either muscle-invasive (pT2–pT4, pNany) or lymph node-positive (pTany, pN1–3) M0 disease with predominantly transitional cell carcinoma histology, and were fit to receive adjuvant chemotherapy within 90 days of surgery. Patients were randomized 1:1 to receive either surveillance or adjuvant chemotherapy, with a primary endpoint of DFS defined as the time from randomization to either first recurrence in the tumor bed, first metastasis, or death from any cause. There were 261 patients included in the trial, including 129 patients randomized to surveillance and 132 to chemotherapy. There were 60 (47%) DFS events in the surveillance cohort and 35 (27%) in the chemotherapy cohort; as such, the unadjusted HR was 0.45 (95%CI 0.30-0.68) in favor of chemotherapy (log-rank p = 0.0001). The three-year DFS rate was 46% for surveillance (95%CI 36-56) and 71% for chemotherapy (95%CI 61-78):

 

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At the GU ASCO 2021 meeting, POUT lead PI Dr. Birtle provided updated analyses with a median follow-up of 48.1 months (IQR: 36.0-60.1). The unadjusted hazard ratios for disease-free survival was 0.51 (95% CI 0.35-0.76; p = 0.0006) and for metastasis-free survival was 0.52 (95% CI 0.36-0.77; p = 0.0007):

 

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There were 93/260 (35.8%) patients that died (52/129 [40.3%] surveillance and 41/131 [31.3%] chemotherapy) during follow-up. Chemotherapy conferred a non-statistically significant 30% reduction in relative risk of death (HR 0.70, 95% CI 0.46-1.06; p = 0.09):

 

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The 3-year overall survival rate for surveillance patients was 67% (95% CI 58-75%) and 79% for chemotherapy (95% CI 71%-86%). From the updated POUT analyses, Dr. Houede notes that there is a confirmed benefit on DFS and MFS after a median follow-up of more than four years, as well as an overall survival trend in favor of adjuvant chemotherapy (although not significant). Dr. Houede also emphasized that this is the first phase 3 trial questioning the value of perioperative chemotherapy for a rare tumor, designed to detect a 15% absolute improvement in 3-year DFS and not powered to detect an OS benefit. Importantly, there were more T2 tumors in the chemotherapy arm versus more T4 in the surveillance arm, and no standardization of lymph node dissection. To conclude, she highlighted an important phase II trial ongoing, the iNDUCT CCAFU/GETUG clinical trial of neoadjuvant durvalumab in combination with neoadjuvant chemotherapy in patients with operable high-risk, localized, urothelial carcinoma of the upper tract.

 

Presented by: Nadine Houede, PhD, Professor at the Universities of Montpellier-Nimes - Head of the medical oncology department, CHU Nîmes, University Hospital, Bordeaux, France

 

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.

References:

  1. Birtle A, Johnson M, Chester J, et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): A phase 3, open-label, randomized controlled trial. Lancet 2020 Apr 18;395(10232):1268-1277.

 

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