title: Intravesical gemcitabine: a phase 1 and pharmacokinetic study.
abstract: BACKGROUND
  Superficial bladder cancer can be treated by transurethral resection and additional intravesical therapy. Although agents like Mitomycin C, Epirubicin and BCG are routinely used, there is a need for more potent and/or less toxic agents. Gemcitabine is a deoxycytidine analogue, used systemically for several tumours, such as non-localised bladder cancer, where it is effective and well tolerated. We investigated the use of three dose levels of gemcitabine when given intravesically in humans for safety and pharmacokinetic research.
  
  
  METHODS
  Patients with superficial bladder cancer, except pT1G3 or CIS were included. Six weekly instillations of 1000, 1500 or 2000 mg gemcitabine were given in 50 ml saline for one hour. Dose modifications were defined in case of dose limiting toxicities. Blood samples were taken before, and 5, 30, 60 (= evacuation) and 120 minutes after instillations 1, 3 and 6. Samples were used for blood counts and pharmacokinetics. Side effects were noted.
  
  
  RESULTS
  3, 4 and 3 patients were treated with 1000, 1500, and 2000 mg gemcitabine respectively, of which 2, 3 and 1 patients had highly recurrent tumours before treatment. Seven patients experienced side effects: 2 with dysuria after the first instillation, 2 after instillations 3-6 and 4-6 and in 3 patients headache, fatigue and heavy legs were experienced once. All side effects were reversible, non-limiting and WHO 1. No macroscopic hematuria was seen. Haematology showed only one case of drop in white blood cell count (lowest dose level, after the first instillation). Gemcitabine plasma levels were immeasurable or low, with peak levels between 30 and 60 minutes, decreasing after more instillations. The metabolite difluorodeoxyuridine reached levels of at most 5 microM, indicating a very low passage of the drug to the systemic circulation.
  
  
  CONCLUSIONS
  Intravesical gemcitabine in the dose used has minimal and reversible side effects. Plasma evaluation indicates that its intravesical use is safe.
authors.affiliation: Department of Urology, University Medical Center St. Radboud, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. fwitjes@uro.umcn.nl
authors.forename: J A
authors.initials: JA
authors.lastname: Witjes
authors.forename: A G
authors.initials: AG
authors.lastname: van der Heijden
authors.forename: J L J
authors.initials: JL
authors.lastname: Vriesema
authors.forename: G J
authors.initials: GJ
authors.lastname: Peters
authors.forename: A
authors.initials: A
authors.lastname: Laan
authors.forename: J A
authors.initials: JA
authors.lastname: Schalken
mesh_terms: D000283:Administration, Intravesical; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006801:Humans; D013997:Time Factors; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine