Long-term Outcomes from a Phase 2 Study of Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer (SWOG S1314; NCT02177695)

Abstract

Background: The COXEN gene expression model was evaluated for prediction of response to neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC).

Objective: To conduct a secondary analysis of the association of each COXEN score with event-free survival (EFS) and overall survival (OS) and by treatment arm.

Design, setting, and participants: This was a randomized phase 2 trial of neoadjuvant gemcitabine-cisplatin (GC) or dose-dense methotrexate-vinblastine-adriamycin-cisplatin (ddMVAC) in MIBC.

Intervention: Patients were randomized to ddMVAC (every 14 d) or GC (every 21 d), both for four cycles.

Outcome measurements and statistical analysis: EFS events were defined as progression or death before scheduled surgery, a decision to not undergo surgery, recurrence, or death due to any cause after surgery. Cox regression was used to evaluate the COXEN score or treatment arm association with EFS and OS.

Results and limitations: A total of 167 evaluable patients were included in the COXEN analysis. The COXEN scores were not significantly prognostic for OS or EFS in the respective arms, but the GC COXEN score had a hazard ratio (HR) of 0.45 (95% confidence interval [CI] 0.20-0.99; p = 0.047) when the arms were pooled. In the intent-to-treat analysis (n = 227), there was no significant difference between ddMVAC and GC for OS (HR 0.87, 95% CI 0.54-1.40; p = 0.57) or EFS (HR 0.86, 95% CI 0.59-1.26; p = 0.45). Among the 192 patients who underwent surgery, pathologic response (pT0 vs downstaging vs no response) was strongly correlated with superior postsurgical survival (5-yr OS 90%, 89% and 52%, respectively).

Conclusions: The COXEN GC score has prognostic value for patients receiving cisplatin-based neoadjuvant treatment. The randomized, prospective design provides estimates of OS and EFS for GC and ddMVAC in this population. Pathologic response (<pT2) performed well as an intermediate endpoint in this modern cohort. For expediency in evaluating new regimens, pathologic response should continue to be used in phase 2 trials.

Patient summary: In this study, we evaluated a biomarker to predict the response to chemotherapy. The results did not meet the preset study parameters, but our study provides information on clinical outcomes with the use of chemotherapy before surgery for bladder cancer.

Trial registration: ClinicalTrials.gov NCT02177695.

Keywords: Biomarkers; Cystectomy; Neoadjuvant chemotherapy; Urinary bladder cancer.