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Few predictors are known for determining the response to neoadjuvant chemotherapy (NAC) for bladder cancer. We investigated the clinicopathologic predictors of extravesical disease in cohorts receiving NAC and upfront cystectomy. The present study demonstrated an inferior response to alternative NAC regimens, implicating cardiovascular comorbidities and nutritional status in the tolerability and response to NAC.Radical cystectomy (RC) is delayed in a subset of patients who respond poorly to neoadjuvant chemotherapy (NAC). The present study investigated the clinicopathologic characteristics predicting extravesical disease at RC and the factors associated with NAC tolerability to improve patient selection and the sequence of definitive therapy.Patients with cT2 urothelial carcinoma of the bladder who underwent NAC were stratified by the final pathologic stage: complete (ypT0N0), partial (≤ pT2), and nonresponse (> pT2 and/or N+). Patients treated with upfront cystectomy were divided into those with organ-confined (≤ pT2) and those with extravesical disease (> pT2 and/or N+).Of 145 patients, 89 received NAC and 56 underwent upfront RC. The univariate predictors of extravesical disease in the patients treated with upfront RC included increased age (P = .021), higher Eastern Cooperative Oncology Group performance status (P < .001), hydronephrosis (P = .021), and cardiovascular risk factors. The complete, partial, and nonresponse rates to NAC were 25.8%, 39.3%, and 34.8%, respectively. The multivariate predictors of pathologic progression on NAC included low serum albumin (P = .005), hydronephrosis (P = .040), incomplete NAC (P = .014), and alternative NAC (non-gemcitabine/cisplatin or MVAC, P = .022). Significant multivariate predictors of incomplete NAC included increased age, coronary artery disease (P = .027), and Eastern Cooperative Oncology Group performance status.Redundant clinicopathologic features predicted adverse cystectomy pathology in patients treated with both NAC and upfront RC. The results of the present study demonstrated an inferior pathologic response to alternative NAC regimens in clinically organ-confined disease and implicated cardiovascular comorbidities and nutritional status in the tolerability and response to NAC. Our findings predicate the importance of using patient-specific factors to guide the sequence of definitive treatment toward timely, centralized care to improve clinical outcomes.