Intravesical thermo-chemotherapy based on conductive heat: a first pharmacokinetic study with Mitomycin C in superficial transitional cell carcinoma patients

Abstract

3ABSTRACT Purpose To evaluate, for the first time, the mitomycin C (MMC) pharmacokinetics during intravesical hyperthermia treatment based on conductive heat and the stability and recovery of the drug at the end of the instillation period. MethodsEleven patients with recurrent intermediate risk superficial transitional cell carcinoma of the bladder were treated weekly for 6 cycles with intravesical MMC (40 mg MMC in 50 ml) in local hyperthermia (45°C) with Unithermia ® system. Each instillation lasted 45 min, with the solution being replaced after the first 22 min. The MMC recovery at the end of the two instillation period and the plasmatic pharmacokinetics of MMC were evaluated by high-pressure liquid chromatography (HPLC). ResultsNine patients completed all the 6 planned cycles, whereas 2 patients missed the last cycle because of allergic reactions No other systemic toxicity was observed, the local toxicities were mild. Median MMC concentration in the instillation residual solution decrease from the initial 0.8 mg/ml to 0.22 mg/ml for the 0-22 min instillation period and to 0.38 mg/ml for the 22-45 min instillation period; the median % of MMC recovered after instillation was 66.2 and 99.6, respectively. In all patients MMC plasmatic C max resulted considerably lower than the toxic threshold (400 ng/ml). ConclusionsThe MMC is stable during the instillation and its absorption occurs mainly during the first minutes of the treatment. The plasmatic MMC concentration is always well below the threshold level for myelosuppression, as confirmed by the total lack of hematological toxicity evidenced by the patients. In order to evaluate the efficacy of the treatment performed with UniThermia ® in reducing the disease recurrence rate in short-and long-term follow-up, we are currently carrying out a clinical multicentric study involving a larger number of patients.

Intravesical bacillus Calmette-Guérin versus chemohyperthermia for high-risk non-muscle-invasive bladder cancer

“…Although MMC stability and systemic absorption were comparable between conductive and microwave-induced heating, there are no studies evaluating the effectiveness of UniThermia. 7 The efficacy of the different heating methods may not be identical in tumour recurrence. Additionally, there are no studies comparing C-HT and BCG in NMIBC patients.…”

“…6 To enhance the efficacy of MMC, two different methods for intravesical C-HT delivering have been introduced: microwave-induced heating (Synergo, Medical Enterprises, Amsterdam, Netherlands) and conductive heat (UniThermia, Elmedical, Hod-Hasharon, Israel). 7 Although studies have promising results of C-HT in high-risk NMIBC, to our knowledge, there are no comparative studies on the effectiveness of BCG and C-HT. In this retrospective study, we evaluated recurrence-free interval between BCG and C-HT, using propensity score-matched analysis.…”

Bladder intracavitary hyperthermic perfusion chemotherapy for the prevention of recurrence of non-muscle invasive bladder cancer after transurethral resection

“…Mitomycin C (MMC) as an alkylating cytostatic agent is commonly used to treat NMIBC. Local administration to the bladder can be effective without causing high concentrations in the serum, and thus, causing only mild side-effects (8,12,14,16,17). Numerous clinical trials have shown that combining MMC administration with hypothermia can improve tumor ablation and prevent recurrence post-TUR.…”

Intravesical Chemotherapy and Chemohyperthermia in Non-Muscle-Invasive Bladder Cancer; An Overview on Drug Administration Technologies and Pharmacokinetics

“…An experiment with heated MMC [63] showed that in at least half the subjects, the amount of MMC retrieved at the end of the experiment (after two 22 minute-cycles of instillations were administered) was higher than the amount placed in the bladder after the first cycle, with a median of 99.6% of the drug recovered. One plausible explanation of this phenomenon is the aforementioned barrier of drug created on the urothelium, only to be retrieved at the end of the treatment (substantiated elsewhere [58]).…”

“…Upon experimentation of the use of heated drug (MMC), researchers concluded that the "suboptimal heating profiles" may be different than with RF [64], the absorption rate was negligible [63] and these are part of the reasons for the different clinical results. Another clinical paper [65] comparing the use of a heated MMC solution to the use of BCG, concluded that the Recurrence Free Survival (RFS) was significantly improved with the administration of BCG.…”