title: Gemcitabine, Cisplatin, and sunitinib for metastatic urothelial carcinoma and as preoperative therapy for muscle-invasive bladder cancer.
abstract: BACKGROUND
  Data support chemotherapy combined with antiangiogenic therapy in metastatic urothelial cancer (mUC) and muscle-invasive bladder cancer (MIBC). We investigated the efficacy and safety of gemcitabine, cisplatin, and sunitinib (GCS) in mUC and MIBC in parallel phase II trials.
  
  
  METHODS
  Trial 1 enrolled 36 patients with mUC who were chemotherapy naive; trial 2 enrolled 9 patients with MIBC. The primary endpoints for trials 1 and 2 were response rate and pathologic complete response, respectively. GCS was given as first-line treatment for patients with mUC and as neoadjuvant therapy for patients with MIBC. The Simon minimax 2-stage design was used for an objective response rate in trial 1 and for the pathologic complete response rate in trial 2.
  
  
  RESULTS
  The initial trial 1 GCS dose was gemcitabine 1000 mg/m(2) intravenously, days 1 and 8; cisplatin 70 mg/m(2) intravenously, day 1; and sunitinib 37.5 mg orally daily, days 1 to 14 of a 21-day cycle. These doses proved intolerable. The doses of gemcitabine and cisplatin were subsequently reduced to 800 and 60 mg/m(2), respectively, without an improvement in drug delivery, and the trial was closed. This lower-dose regimen was applied in trial 2, which was stopped early due to excess toxicity. Grade 3 to 4 hematologic toxicities occurred in 70% (23/33) of patients in trial 1 and 22% (2/9) of patients in trial 2. In trial 1, the response rate was 49% (95% CI, 31%-67%); in trial 2, the pathologic complete response was 22% (2/9). Due to early closure secondary to toxicity, the sample sizes of both trials were small.
  
  
  CONCLUSIONS
  Delivery of GCS was hampered by excessive toxicity in both advanced and neoadjuvant settings.
authors.affiliation: US Oncology Research, McKesson Specialty Health, The Woodlands, TX, USA. matthew.galsky@mssm.edu
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Galsky
authors.forename: Noah M
authors.initials: NM
authors.lastname: Hahn
authors.forename: Thomas
authors.initials: T
authors.lastname: Powles
authors.forename: Beth A
authors.initials: BA
authors.lastname: Hellerstedt
authors.forename: Seth P
authors.initials: SP
authors.lastname: Lerner
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Gardner
authors.forename: Menggang
authors.initials: M
authors.lastname: Yu
authors.forename: Mark
authors.initials: M
authors.lastname: O'Rourke
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Vogelzang
authors.forename: Darren
authors.initials: D
authors.lastname: Kocs
authors.forename: Scott A
authors.initials: SA
authors.lastname: McKenney
authors.forename: Anton M
authors.initials: AM
authors.lastname: Melnyk
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hutson
authors.forename: Mary
authors.initials: M
authors.lastname: Rauch
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Wang
authors.forename: Lina
authors.initials: L
authors.lastname: Asmar
authors.forename: Guru
authors.initials: G
authors.lastname: Sonpavde
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary* / Q000601:surgery; D002945:Cisplatin / Q000009:adverse effects / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use*; D000077210:Sunitinib; D015996:Survival Rate; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D019459:Urothelium / Q000473:pathology; D000093542:Gemcitabine
chemical_list: D020533:Angiogenesis Inhibitors; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D003841:Deoxycytidine; D002945:Cisplatin; D000077210:Sunitinib; D000093542:Gemcitabine