title: A randomized phase 2 trial of gemcitabine/cisplatin with or without cetuximab in patients with advanced urothelial carcinoma.
abstract: BACKGROUND
  Epidermal growth factor receptor overexpression is associated with poor outcomes in urothelial carcinoma (UC). Cetuximab (CTX) exhibited an antitumor effect in in vivo UC models. The efficacy of gemcitabine/cisplatin (GC) with or without CTX in patients with advanced UC was evaluated.
  
  
  METHODS
  Patients with advanced UC, measurable disease, and adequate organ function were randomized 1:2 to cisplatin (70 mg/m(2) ) on day 1 plus gemcitabine (1000 mg/m(2) ) on days 1, 8, and 15 (arm A) or GC plus CTX (500 mg/m(2) ) on days 1 and 15 (arm B). The primary endpoint was the overall response rate. The secondary endpoints were the response duration, safety, progression-free survival, overall survival, determination of whether or not CTX sensitized nonresponders to GC, and exploratory biomarker analysis. The accrual targets were 27 and 54 patients for the 2 arms, respectively. The overall response rate was reported by arm with binomial confidence intervals (CIs). Kaplan-Meier methods were used for time-to-event endpoints.
  
  
  RESULTS
  Eighty-eight eligible patients were randomized; 87 were toxicity-evaluable, and 85 were response-evaluable. The overall response rates were 57.1% for arm A (95% CI = 37%-76%) and 61.4% for arm B (95% CI = 48%-74%). The median progression-free survival times were 8.5 months for arm A (95% CI = 5.7-10.4 months) and 7.6 months for arm B (95% CI = 6.1-8.7 months). The median overall survival times were 17.4 months for arm A (95% CI = 12.8 months to unreached) and 14.3 months for arm B (95% CI = 11.6-22.2 months). The most common grade 3/grade 4 adverse events in both arms were myelosuppression and nausea. Thromboembolism, acneiform rash, fatigue, pain, hypersensitivity reactions, elevated transaminases, hyponatremia, and hypomagnesemia were more common in arm B; 3 grade 5 adverse events occurred in arm B. The presence of primary disease significantly correlated with thromboembolism. An increased soluble E-cadherin level after cycle 2 correlated with a higher risk of death.
  
  
  CONCLUSIONS
  GC plus CTX was feasible but was associated with more adverse events and no improvements in outcomes.
authors.affiliation: University of Michigan, Ann Arbor, Michigan.
authors.forename: Maha
authors.initials: M
authors.lastname: Hussain
authors.forename: Stephanie
authors.initials: S
authors.lastname: Daignault
authors.forename: Neeraj
authors.initials: N
authors.lastname: Agarwal
authors.forename: Petros D
authors.initials: PD
authors.lastname: Grivas
authors.forename: Arlene O
authors.initials: AO
authors.lastname: Siefker-Radtke
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.forename: Gary R
authors.initials: GR
authors.lastname: MacVicar
authors.forename: Ellis Glenn
authors.initials: EG
authors.lastname: Levine
authors.forename: Sandy
authors.initials: S
authors.lastname: Srinivas
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Twardowski
authors.forename: Mario A
authors.initials: MA
authors.lastname: Eisenberger
authors.forename: David I
authors.initials: DI
authors.lastname: Quinn
authors.forename: Ulka N
authors.initials: UN
authors.lastname: Vaishampayan
authors.forename: Evan Y
authors.initials: EY
authors.lastname: Yu
authors.forename: Scott
authors.initials: S
authors.lastname: Dawsey
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Day
authors.forename: Mark L
authors.initials: ML
authors.lastname: Day
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Al-Hawary
authors.forename: David C
authors.initials: DC
authors.lastname: Smith
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D015703:Antigens, CD; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D015820:Cadherins / Q000097:blood; D002295:Carcinoma, Transitional Cell / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D000068818:Cetuximab; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000093542:Gemcitabine
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; D015820:Cadherins; D003841:Deoxycytidine; D000068818:Cetuximab; D002945:Cisplatin; D000093542:Gemcitabine
keywords: cetuximab; chemotherapy; cisplatin; gemcitabine; urothelial carcinoma