European Urology European Urology 45 (2004) 182–186 Intravesical Gemcitabine: APhase1and PharmacokineticStudy J.A. Witjes * , A.G. van der Heijden, J.L.J. Vriesema, G.J. Peters, A. Laan, J.A. Schalken Department of Urology, University Medical Center St. Radboud, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands Accepted 17 September 2003 Published online 10 October 2003 Abstract Introduction: 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. Material and 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 (¼ 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 mM, indicating a very low passage of the drug to the systemic circulation. Conclusion: Intravesical gemcitabine in the dose used has minimal and reversible side effects. Plasma evaluation indicates that its intravesical use is safe. # 2003 Elsevier B.V. All rights reserved. Keywords: Intravesical chemotherapy; Gemcitabine; Phase 1; Pharmacokinetics 1. Introduction For intravesical instillation after transurethral resec- tion (TUR) of superficial transitional cell carcinoma (TCC) of the bladder the choice is between intravesical chemotherapy and intravesical immunotherapy. Intravesical chemotherapy is a well-established form of therapy. The side effects are limited, except for potential systemic problems after thiotepa, due to its low molecular weight. The efficacy of intravesical chemotherapy in low and intermediate risk patients is also well documented. In low risk patients one immedi- ate instillation after TUR is able to lower the relative recurrence rate in the next one to two years with up to 50% [1,2]. With longer follow-up and in optimal con- ditions a course of intravesical chemotherapy after complete TUR is able to improve recurrence rates with 15 to 25% for one to three years [3]. Others have suggested greater reductions in the 1- to 3-year recur- rence rates, which in part might be explained by the study design of the studies included in this meta-analysis * Corresponding author. Tel. þ31-24-3616712; Fax: þ31-24-3541031. E-mail address: fwitjes@uro.umcn.nl (J.A. Witjes). 0302-2838/$ – see front matter # 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2003.09.014