Gemcitabine, Cisplatin, and sunitinib for metastatic urothelial carcinoma and as preoperative therapy for muscle-invasive bladder cancer

Clin Genitourin Cancer. 2013 Jun;11(2):175-81. doi: 10.1016/j.clgc.2012.10.001. Epub 2012 Dec 8.

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.

Patients and 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.

Trial registration: ClinicalTrials.gov NCT00821327 NCT00859339.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Angiogenesis Inhibitors / adverse effects
  • Angiogenesis Inhibitors / therapeutic use
  • Antimetabolites, Antineoplastic / adverse effects
  • Antimetabolites, Antineoplastic / therapeutic use
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Transitional Cell / drug therapy*
  • Carcinoma, Transitional Cell / pathology
  • Carcinoma, Transitional Cell / secondary*
  • Carcinoma, Transitional Cell / surgery
  • Cisplatin / adverse effects
  • Cisplatin / therapeutic use*
  • Deoxycytidine / adverse effects
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / therapeutic use
  • Female
  • Humans
  • Indoles / adverse effects
  • Indoles / therapeutic use*
  • Male
  • Middle Aged
  • Neoadjuvant Therapy
  • Neoplasm Invasiveness
  • Pyrroles / adverse effects
  • Pyrroles / therapeutic use*
  • Sunitinib
  • Survival Rate
  • Urinary Bladder Neoplasms / drug therapy*
  • Urinary Bladder Neoplasms / mortality
  • Urinary Bladder Neoplasms / pathology
  • Urinary Bladder Neoplasms / surgery
  • Urothelium / pathology

Substances

  • Angiogenesis Inhibitors
  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents
  • Indoles
  • Pyrroles
  • Deoxycytidine
  • gemcitabine
  • Cisplatin
  • Sunitinib

Associated data

  • ClinicalTrials.gov/NCT00821327
  • ClinicalTrials.gov/NCT00859339