title: Sequential intravesical mitomycin plus Bacillus Calmette-Guérin for non-muscle-invasive urothelial bladder carcinoma: translational and phase I clinical trial.
abstract: OBJECTIVE
  To determine the safety and toxicities of sequential MMC (mitomycin C) + BCG (bacillus Calmette-Guérin) in patients with non-muscle-invasive bladder cancer (NMIBC) and explore evidence for potentiation of BCG activity by MMC.
  
  
  METHODS
  A 3 + 3 phase I dose-escalation trial of six weekly treatments was conducted in patients with NMIBC. MMC (10, 20, or 40 mg) was instilled intravesically for 30 minutes, followed by a 10-minute washout with gentle saline irrigation and then instillation of BCG (half or full strength) for 2 hours. Urine cytokines were monitored and compared with levels in a control cohort receiving BCG only. Murine experiments were carried out as described previously.
  
  
  RESULTS
  Twelve patients completed therapy, including 3 patients receiving full doses. The regimen was well tolerated with no treatment-related dose-limiting toxicities. Urinary frequency and urgency, and fatigue were common. Eleven (91.7%) patients were free of disease at a mean (range) follow-up of 21.4 (8.4-27.0) months. Median posttreatment urine concentrations of IL2, IL8, IL10, and TNFα increased over the 6-week treatment period. A greater increase in posttreatment urinary IL8 during the 6-week period was observed in patients receiving MMC + BCG compared with patients receiving BCG monotherapy. In mice, intravesical MMC + BCG skewed tumor-associated macrophages (TAM) toward a beneficial M1 phenotype.
  
  
  CONCLUSIONS
  Instillation of sequential MMC + BCG is safe tolerable up to 40-mg MMC plus full-strength BCG. This approach could provide improved antitumor activity over BCG monotherapy by augmenting beneficial M1 TAMs.
authors.affiliation: The Cancer Therapy and Research Center/Adult Cancer Program, The University of Texas Health Science Center San Antonio, San Antonio, Texas. Department of Urology, The University of Texas Health Science Center San Antonio, San Antonio, Texas. svatek@uthscsa.edu.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Svatek
authors.affiliation: The Cancer Therapy and Research Center/Adult Cancer Program, The University of Texas Health Science Center San Antonio, San Antonio, Texas. Department of Urology, The University of Texas Health Science Center San Antonio, San Antonio, Texas.
authors.forename: Xiang Ru
authors.initials: XR
authors.lastname: Zhao
authors.affiliation: Department of Urology, The University of Texas Health Science Center San Antonio, San Antonio, Texas.
authors.forename: Edwin E
authors.initials: EE
authors.lastname: Morales
authors.affiliation: Department of Urology, The University of Texas Health Science Center San Antonio, San Antonio, Texas.
authors.forename: Mithilesh K
authors.initials: MK
authors.lastname: Jha
authors.affiliation: Department of Urology, The University of Texas Health Science Center San Antonio, San Antonio, Texas.
authors.forename: Timothy Y
authors.initials: TY
authors.lastname: Tseng
authors.affiliation: Department of Urology, The University of Texas Health Science Center San Antonio, San Antonio, Texas.
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hugen
authors.affiliation: Department of Medical Oncology, The University of Texas Health Science Center San Antonio, San Antonio, Texas.
authors.forename: Vincent
authors.initials: V
authors.lastname: Hurez
authors.affiliation: Department of Urology, The University of Texas Health Science Center San Antonio, San Antonio, Texas.
authors.forename: Javier
authors.initials: J
authors.lastname: Hernandez
authors.affiliation: The Cancer Therapy and Research Center/Adult Cancer Program, The University of Texas Health Science Center San Antonio, San Antonio, Texas. Department of Medical Oncology, The University of Texas Health Science Center San Antonio, San Antonio, Texas.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Curiel
mesh_terms: D000283:Administration, Intravesical; D000368:Aged; D000818:Animals; D002295:Carcinoma, Transitional Cell / Q000628:therapy* / Q000652:urine; D003131:Combined Modality Therapy; D016207:Cytokines / Q000652:urine; D005260:Female; D006801:Humans; D007114:Immunization; D008264:Macrophages / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage*; D009163:Mycobacterium bovis / Q000276:immunology; D009368:Neoplasm Transplantation; D057170:Translational Research, Biomedical; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000628:therapy* / Q000652:urine
chemical_list: D016207:Cytokines; D016685:Mitomycin