title: Pathologic downstaging is a surrogate marker for efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy for muscle-invasive urothelial bladder cancer.
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.
  
  
  METHODS
  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.
  
  
  METHODS
  The experimental arm consisted of cisplatin-based NAC; the control arm consisted of cystectomy only.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, Kullbergska County Hospital, Katrineholm, Sweden.
authors.forename: Robert
authors.initials: R
authors.lastname: Rosenblatt
authors.forename: Amir
authors.initials: A
authors.lastname: Sherif
authors.forename: Erkki
authors.initials: E
authors.lastname: Rintala
authors.forename: Rolf
authors.initials: R
authors.lastname: Wahlqvist
authors.forename: Anders
authors.initials: A
authors.lastname: Ullén
authors.forename: Sten
authors.initials: S
authors.lastname: Nilsson
authors.forename: Per-Uno
authors.initials: PU
authors.lastname: Malmström
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D016009:Chi-Square Distribution; D002945:Cisplatin / Q000008:administration & dosage; D015653:Cystectomy / Q000009:adverse effects / Q000401:mortality; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D015999:Multivariate Analysis; D009130:Muscle, Smooth / Q000473:pathology / Q000601:surgery; D020360:Neoadjuvant Therapy / Q000009:adverse effects / Q000401:mortality; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012537:Scandinavian and Nordic Countries; D013997:Time Factors; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D019459:Urothelium / Q000473:pathology / Q000601:surgery
chemical_list: D004317:Doxorubicin; D002945:Cisplatin; D008727:Methotrexate