Prognostic significance of pathologic response to neoadjuvant chemotherapy in muscle-invasive urothelial carcinoma of the bladder with histologic subtype.

INTRODUCTION

Patients with histologic subtypes (HS) of urothelial cancers are often excluded from neoadjuvant chemotherapy (NAC) trials for muscle-invasive bladder cancer (MIBC). Additionally, there exist conflicting data regarding the inherent chemotherapeutic sensitivity of individual HS. Herein, we assess the prognostic significance of pathologic response to NAC, a common surrogate endpoint of success in NAC trials, in patients with HS versus pure urothelial carcinoma (PUC).

METHODS

The National Cancer Database (NCDB) was queried for patients with cT2-4N0M0 MIBC who received NAC and radical cystectomy (RC) between 2004 and 2020. Pathologic response to NAC was defined as complete (ypT0N0), partial (<ypT2N0), and no response (≥ypT2 or ypN+). Kaplan-Meier analysis and log-rank tests were performed for overall survival (OS) and Cox proportional hazard regressions were performed to test relationships between NAC response and the presence of a HS in predicting OS.

RESULTS

5,372 patients were included, with 345 (6.4%) having HS. Nonresponse rates to NAC in HS patients were significantly higher than those with PUC (65.2% vs. 55.8%, P = 0.003). Patients with squamous and glandular differentiation exhibited the highest rates of nonresponse (79% and 72.2%, respectively). In unstratified analysis, patients with HS exhibited shorter OS (P < 0.0001). Patients with HS had uniformly worse OS even after controlling for pathologic response (P = 0.013), with the most notable discrepancy in partial responders (HR = 4.88, 95% CI 2.29-10.38, P < 0.001; 3-year OS 91% vs. 66% for partial response in PUC vs. HS, respectively).

CONCLUSIONS

Patients with HS MIBC exhibit poor survival when treated with NAC followed by RC compared with PUC, even when controlling for pathologic response. These data suggest that pathologic response is a less accurate surrogate endpoint in patients with HS relative to PUC, and may suggest a role for therapeutic intensification in the adjuvant setting for patients with HS.