Impact of Neoadjuvant Chemotherapy on Pathologic Response in Patients With Upper Tract Urothelial Carcinoma Undergoing Extirpative Surgery - Beyond the Abstract

High grade upper tract urothelial carcinoma (UTUC) is an aggressive malignancy with poor outcomes among patients with locally advanced disease. Radical nephroureterectomy (RNU) is the gold-standard treatment with curative intent, with cisplatin-based neoadjuvant chemotherapy (NAC) being increasingly utilized extrapolating from level I evidence demonstrating an overall survival benefit in muscle-invasive bladder cancer. Studies examining the impact of NAC on pathologic outcomes have been largely limited to retrospective single institutional studies, with results from the phase II ECOG-ACRIN 8141 trial recently reported (Hoffman-Censits, et al. AUA 2018).

Acknowledging these limitations in the existing literature, we sought to examine the impact of NAC on pathologic outcomes in patients with UTUC undergoing RNU or segmental ureterectomy on a national level. Using data from the National Cancer Database, which captures approximately 70% of newly diagnosed cancers in the United States, we identified a cohort of 6174 patients with non-metastatic UTUC who underwent RNU or segmental ureterectomy from 2006 – 2014.

Two-hundred sixty patients (4.2% of the cohort) received NAC, with increasing NAC utilization observed over the study period from 1.9% in 2006 to 7.1% in 2014. Patients receiving NAC were younger (median age 67.5 vs. 73 years) and had a higher frequency of clinical T2-4 stage (47% vs. 29%), reflecting the biases inherent to selecting patients for NAC before extirpative surgery. Defining pathologic response as a pathologic stage less than the clinical stage, we observed a higher incidence of pathologic response among patients receiving NAC (25.2% vs. 1.8%), including complete pathologic response (pT0) in 6% of patients receiving NAC. On multivariable logistic regression analysis, NAC was independently associated with pathologic response (odds ratio 19.8, 95% confidence interval 11.8 – 33.5).

The results of this analysis of national registry data reflecting ‘real world’ practice provide further evidence supporting the benefit of NAC in pathologic down-staging in patients with high-grade UTUC undergoing extirpative surgery. The decision to administer neoadjuvant versus adjuvant chemotherapy is especially important in UTUC, given that renal functional decline after RNU can render up to 61% of patients cisplatin-ineligible, based on prior studies. Although the recent phase III POUT trial demonstrated significantly improved disease-free survival with adjuvant platinum-based chemotherapy in locally advanced UTUC (pT2-T4 N0-3), 38% of patients in that trial were cisplatin-ineligible after RNU (Birtle, et al. GU ASCO Symposium 2018). These inherent limitations to adjuvant chemotherapy make NAC an appealing alternative for UTUC. While the recently-reported single arm phase II trial (ECOG-ACRIN 8141) provided additional data suggesting a pathologic response in a proportion of patients with NAC, additional prospective (ideally randomized) trials are needed to better define the impact of NAC on clinical outcomes in UTUC.

Written by: Nima Almassi, MD1, and Petros Grivas, MD, PhD2
Author Affiliation:
1Glickman Urological and Kidney Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
2University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA

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