Pharmacokinetics, Pharmacological Stability, Safety and Efficacy of MMC Administered with a New Hyperthermia Device

Introduction and Objective: Patients with BCG refractory NMIBC represent a widely argued therapeutic challenge. Many conservative treatments have been proposed so far. Bladder wall thermochemotherapy seems to be an interesting treatment option. UniThermia is a new device that provides bladder wall thermochemotherapy with uniform hyperthermia (44,5°C) all over the bladder by high flow of a heated MMC solution. Aim of our study was to evaluate drug stability, pharmacokinetics, tolerability and activity of the drug. Materials and Methods: Twenty-eight patients with BCG refractory NMIBC (intermediate and high risk) have been treated with a course of 6 instillations after TUR-BT (1 early single and 5 weekly instillations). Drug solution was completely replaced at the half of each instillation. After the treatment, patients underwent to cistoscopy every 3 months for one year, and every 6 months for another year. Results: We noticed that there is a significant loss of MMC in the first half of instillation, while in the second half most of the drug is retrieved. This observation suggests that there is a significant absorption of MMC in the first half of instillation, and minimal in the second half. Plasmatic Cmax resulted considerably lower than the reported threshold concentration for toxicity (400 ng/ml). Most of side effects not beyond grade II, showing a good safety profile. Data about activity are partial, follow-up at 1 year is available only for 16 patients. Among these patients, 6 are negative, 6 presented a progression and 4 a recourrence. Conclusions: The analysis of drug solutions retrieved at mid and end of instillation demonstrates that MMC stability was not affected by Unithermia administration. Plasmatic MMC levels remained negligible. Discontinuation rates were not related to severe toxicity. The enrollment and the endoscopic follow-up will be complete in order obtain final results.