title: Assessing Cancer Progression and Stable Disease After Neoadjuvant Chemotherapy for Organ-confined Muscle-invasive Bladder Cancer.
abstract: To propose and validate a new approach to stratify clinically staged, organ-confined, muscle-invasive bladder cancer patients (cT2N0M0) who are pathologic non-responders to neoadjuvant chemotherapy (NAC) to better characterize NAC non-response.
  
  
  
  We retrospectively identified radical cystectomy patients with cT2N0M0 disease at our institution (2005-2014) and in the National Cancer Database (2004-2012) for external validation. Patients were stratified as stable (pT2N0M0) or progressors (>pT2 or pN+). The primary end points were cancer-specific survival (CSS), overall survival (OS), and recurrence-free survival (RFS).
  
  
  
  In the institutional cohort, NAC stable patients (n = 17) had better OS (P = .05) and RFS (P = .04) than NAC progressors (n = 50), and had comparable OS (P = .7) and CSS (P = .09) with non-NAC stable patients (n = 27). Multivariable Cox proportional hazard models showed that larger tumor size predicted worse OS (hazard ratio [HR] = 1.20 per centimeter, 95% confidence interval [CI: 1.07, 1.35]), CSS (HR = 1.27, 95% CI [1.11, 1.45]), and RFS (HR = 1.24, 95% CI [1.09, 1.42]). Similarly, in the National Cancer Database, NAC stable patients (n = 223) had improved OS (P < .0001) compared with NAC progressors (n = 232) and comparable (P = .4) OS with non-NAC stable patients (n = 950). Multivariable Cox proportional hazard model showed that larger tumor size (HR = 1.03 per centimeter, 95% CI [1.02, 1.03]) and progression (HR = 2.69, 95% CI [2.40, 3.01]) predicted worse OS.
  
  
  
  Distinct survival outcomes suggest that NAC non-responders should be further stratified into stable disease and progressors. Comparable survival between non-NAC and NAC stable disease patients suggests that NAC stable disease may represent a chemoresistant but more indolent phenotype on the disease spectrum. Moreover, tumor size is an important prognostic biomarker in NAC non-responders. Clinical predictors of disease progression on NAC were not identified, highlighting the need to explore molecular and genomic subtyping determinants of disease progression.
authors.affiliation: The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, MD. Electronic address: mchappi1@jhmi.edu.
authors.forename: Meera R
authors.initials: MR
authors.lastname: Chappidi
authors.affiliation: The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Max
authors.initials: M
authors.lastname: Kates
authors.affiliation: The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Aaron
authors.initials: A
authors.lastname: Brant
authors.affiliation: Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Baras
authors.affiliation: Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: George J
authors.initials: GJ
authors.lastname: Netto
authors.affiliation: The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Pierorazio
authors.affiliation: Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Noah M
authors.initials: NM
authors.lastname: Hahn
authors.affiliation: The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Trinity J
authors.initials: TJ
authors.lastname: Bivalacqua
mesh_terms: D000368:Aged; D017024:Chemotherapy, Adjuvant; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D009130:Muscle, Smooth / Q000473:pathology; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D012189:Retrospective Studies; D015996:Survival Rate; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*