Adjuvant Chemotherapy Versus Observation Following Radical Cystectomy for Locally Advanced Urothelial Carcinoma of the Bladder - Beyond the Abstract

The role of adjuvant chemotherapy (AC) in patients with locally advanced urothelial carcinoma of the bladder after radical cystectomy (RC) remains uncertain, with existing literature yielding conflicting results. While adjuvant immunotherapy is a promising emerging paradigm, consideration of AC remains critical for patients with locally advanced bladder cancer. In this study, we examine the comparative effectiveness of AC after RC on survival in patients with locally advanced bladder cancer using the National Cancer Data Base (NCDB).


We conducted observational analyses designed to emulate a completed target trial (EORTC 30994) of AC versus delayed chemotherapy for patients with locally advanced bladder cancer after RC using the emulation framework described by Hernan and Robins.1,2 Based on EORTC 30994 eligibility criteria, we identified adult bladder cancer patients in the NCDB aged 35 to 75 who did not receive neoadjuvant chemotherapy who underwent RC with pathology demonstrating pT3/pT4 or pN1-3 bladder cancer. We defined the intervention arm as patients who received multi-agent adjuvant chemotherapy within 3 months of RC and the observation arm as patients who did not receive any chemotherapy within 3 months of RC (“Observation” arm). A propensity score for receipt of AC within 3 months of RC was estimated, and the associations of AC with overall survival were evaluated after adjusting for differences in baseline characteristics between the groups using standardized inverse probability of treatment weights.

Of the 2,416 patients, approximately 39% received adjuvant chemotherapy. We found that the 5-years overall survival was 43% for patients treated with AC versus 36% for those managed with observation. Similarly, the 10-year overall survival was 34% for patients treated with AC versus 24% for those managed with observation. In adjusted models, AC was associated with improved all-cause mortality (HR 0.71; 95% CI 0.63-0.81; p<0.01). Treatment effect estimates were consistent in analyses that examined heterogeneity of treatment effects.

The present study provides further evidence for the efficacy of adjuvant chemotherapy in patients with locally advanced bladder cancer, with a 29% reduction in the hazard of death with AC. Notably, this effect estimate is consistent with that reported in the EORTC 30994 trial, but statistically significant due to the larger sample size. Moreover, the emulation framework employed herein provides a number of advantages to improve the accuracy of causal inferences that derive from explicit specification of the target trial to be emulated, as described elsewhere. Future studies will be required to examine the role of adjuvant chemotherapy in relation to adjuvant immunotherapy in patients with locally advanced bladder cancer.

Written by: Maheetha Bharadwaj,1 & Boris Gershman, MD2
 
  1. MD Candidate, Harvard Medical School, Boston, MA
  2. Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, MA

References:

  1. Sternberg, C.N., Skoneczna, I., Kerst, J.M., Albers, P., Fossa, S.D., Agerbaek, M., Dumez, H., de Santis, M., Théodore, C., Leahy, M.G. and Chester, J.D., 2015. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3–pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. The lancet oncology16(1), pp.76-86.
  2. Hernán MA, Robins JM. Using Big Data to Emulate a Target Trial When a Randomized Trial Is Not Available. Am J Epidemiol. 2016;183(8):758-64.

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