Pathologic downstaging is a surrogate marker for efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy for muscle-invasive urothelial bladder cancer

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Abstract

Background: Characterising responders to neoadjuvant chemotherapy (NAC) is important to minimise overtreatment and the unnecessary delay of definitive treatment of urothelial urinary bladder cancer. Objective: To assess the effect of NAC on tumour downstaging and overall survival. Design, setting, and participants: A total of 449 patients from the randomised prospective Nordic Cystectomy Trials 1 and 2 were analysed retrospectively. Eligible patients were defined as T2-T4aNXM0 preoperatively and pT0-pT4aN0-N + M0 postoperatively. The median follow-up time was 5 yr. Intervention: The experimental arm consisted of cisplatin-based NAC; the control arm consisted of cystectomy only. Measurements: The primary outcome was tumour downstaging defined as pathologic TNM less than clinical TNM. Different downstaging thresholds were applied: complete downstaging (CD) (pT0N0), noninvasive downstaging (NID) (pT0/pTis/pTaN0), and organ confinement (OC) (≤pT3aN0). Downstaging rates and nodal status were compared between the study arms using the chi-square test. Secondary outcome was overall survival (OS) stratified by treatment arm, downstaging categories, and clinical stages, analysed by the Kaplan-Meier method. The following covariates were tested as prognostic factors in univariate and multivariate analyses using the Cox regression method: age, sex, clinical stage, pN status, NAC, CD, NID, and OC. Results and limitations: Downstaging rates increased significantly in the NAC arm independent of the downstaging threshold. The impact was more prominent in clinical T3 tumours, with a near threefold increase in CD tumours. The combination of CD and NAC showed an absolute risk reduction of 31.1% in OS at 5 yr compared with CD controls. The combination of NAC and CD revealed a hazard ratio of 0.32 compared with 1.0 for the combination of no NAC and no CD. Limitations were the retrospective approach and uncertain clinical TNM staging. Conclusions: Survival benefits of NAC are reflected in downstaging of the primary tumour. Chemo-induced downstaging might be a potential surrogate marker for OS. © 2011 European Association of Urology.

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Rosenblatt, R., Sherif, A., Rintala, E., Wahlqvist, R., Ullén, A., Nilsson, S., & Malmström, P. U. (2012). Pathologic downstaging is a surrogate marker for efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy for muscle-invasive urothelial bladder cancer. European Urology, 61(6), 1229–1238. https://doi.org/10.1016/j.eururo.2011.12.010

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