title: Novel fluorescence in situ hybridization-based definition of bacille Calmette-Guérin (BCG) failure for use in enhancing recruitment into clinical trials of intravesical therapies.
abstract: OBJECTIVE
  To present a molecular definition of bacille Calmette-Guérin (BCG) failure that incorporates fluorescence in situ hybridization (FISH) testing to predict BCG failure before it becomes clinically evident, which can be used to enhance trial designs for patients with non-muscle-invasive bladder cancer.
  
  
  METHODS
  We used data from 143 patients who were followed prospectively for 2 years during intravesical BCG therapy, during which time FISH assays were collected and correlated to clinical outcomes.
  
  
  RESULTS
  Of the 95 patients with no evidence of tumour at 3-month cystoscopy, 23 developed tumour recurrence and 17 developed disease progression by 2 years. Patients with a positive FISH test at both 6 weeks and 3 months were more likely to develop tumour recurrence (17/37 patients [46%] and 16/28 patients [57%], respectively) than patients with a negative FISH test (6/58 patients [10%] and 3/39 patients [8%], respectively; both P < 0.001). Using hazard ratios for recurrence with positive 6-week and 3-month FISH results, we constructed clinical trial scenarios whereby patients with a negative 3-month cystoscopy and positive FISH result could be considered to have 'molecular BCG failure' and could be enrolled in prospective, randomized clinical trials comparing BCG therapy (control) with an experimental intravesical therapy.
  
  
  CONCLUSIONS
  Patients with positive early FISH and negative 3-month cystoscopy results can be considered to have molecular BCG failure based on their high rates of recurrence and progression. This definition is intended for use in designing clinical trials, thus potentially allowing continued use of BCG as an ethical comparator arm.
authors.affiliation: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Kamat
authors.affiliation: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Willis
authors.affiliation: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Rian J
authors.initials: RJ
authors.lastname: Dickstein
authors.affiliation: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Rooselvelt
authors.initials: R
authors.lastname: Anderson
authors.affiliation: Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Graciela
authors.initials: G
authors.lastname: Nogueras-González
authors.affiliation: Department of Cytopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ruth L
authors.initials: RL
authors.lastname: Katz
authors.affiliation: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Barton Grossman
authors.affiliation: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Colin P
authors.initials: CP
authors.lastname: Dinney
mesh_terms: D000283:Administration, Intravesical; D000368:Aged; D001500:BCG Vaccine / Q000627:therapeutic use*; D002278:Carcinoma in Situ / Q000473:pathology / Q000628:therapy; D002986:Clinical Trials as Topic; D003558:Cystoscopy; D018450:Disease Progression; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis*; D009367:Neoplasm Staging; D011446:Prospective Studies; D017211:Treatment Failure; D001749:Urinary Bladder Neoplasms / Q000473:pathology / Q000628:therapy*
chemical_list: D001500:BCG Vaccine
keywords: bacille Calmette-Guérin; bacille Calmette-Guérin failure; bladder cancer; clinical trials; fluorescence in situ hybridization