A first pharmacokinetic study of mitomycin C intravesical thermo-chemotherapy for the treatment of superficial transitional cell carcinoma, "Beyond the Abstract," by Paola Milla, et al

BERKELEY, CA (UroToday.com) - The standard of treatment for patients with superficial TCC is surgical transurethral resection (TUR) of tumors. Further treatment after TUR depends on the degree of the risk of recurrence and progression of the tumor: low-risk TCC is characterized by a low risk of recurrence and progression and can be managed with standard endovesical chemotherapy protocols, whereas high-risk TCC presents a high risk of recurrence and progression and should be treated with endovesical instillation of the immuno-modulating agent bacillus Calmette–Guérin (BCG). At the appearance of tumor recurrence or progression after BCG treatment, the only remaining option is radical cystectomy. However, more than 50% of Ta or T1 superficial TCC can be defined as intermediate-risk TCC which presents a low risk of progression, but a high risk of recurrence. The management of patients affected by intermediate-risk TCC represents a still unsolved problem for the urologic oncology community because the only remaining therapeutic option for patients who relapse after BCG is the resection of tumors by repeated TURs, as intravesical instillation of conventional cytostatic drugs proves to be less effective than BCG in reducing the risk of tumor recurrence, and radical cystectomy represents over treatment.

A number of different strategies have been clinically tested in order to enhance the efficacy of intravesical chemotherapy: one of the most promising is the intravesical instillation of mitomycin C (MCC) by thermo-chemotherapy which is able to improve recurrence-free survival, both in short- and long-term follow-up, without a without an increase in local or systemic side effects, compared to intravesical chemotherapy alone. Unitl now, in all published studies, intravesical thermo-chemotherapy was performed by means of Synergo® (Medical Enterprises), that delivers hyperthermia to the bladder lumen by direct irradiation with an intravesical microwave applicator. Local hyperthermia, obtained with Synergo®, enhances the systemic absorption of MMC, in comparison with intravesical chemotherapy alone, but the MMC plasma concentrations remain, at all times, well below the threshold concentration for myelo-suppression. The routine clinical use of the Synergo® system, however, is limited by the high costs of the proper catheters needed and the high degree of skill required to assure a correct positioning of the catheter. More recently, Elmedical has developed UniThermia®, a new system for the delivery of intravesical thermo-chemotherapy based on conductive heat, that require less expensive catheters and allows a better control of the temperature, thus reducing the risk of burns.

The aim of our study was to evaluate, for the first time, the MMC pharmacokinetics during hyperthermia treatment performed with UniThermia®, and the stability and recovery of the drug from the residual bladder contents at the end of the instillation period.

Eleven patients, affected by intermediate risk TCC -- and having relapsed after TUR and BCG treatment -- were enrolled and treated with intravesical MMC (40 mg/50 ml) in local hyperthermia (45°C) with Unithermia® system. After 22 minutes of treatment, the bladder was emptied and reinstilled with fresh MMC solution at the same dosage and temperature for a second 23-minute period. The same treatment was repeated weekly for a total of 6 cycles.

In order to determine the stability and the absorption of drug during the treatment, MMC recovery at the end of the 2 instillation periods was evaluated for all 11 patients in all the instillation cycles, and the systemic exposure of the patients to the drug was assessed by evaluating, in 7 patients, the MMC plasmatic pharmacokinetics during the third cycle.

UniThermia® proved to be a safe and easy-to-use system, as no technical miscarriage nor serious side effects were reported. Nine patients completed all the 6 planned cycles, whereas 2 patients missed the last cycle because of an allergic reaction, with a rate comparable to the rate reported in the literature for the use of intravesical MMC alone (about 3%). No other systemic toxicities were observed; the local toxicities were in any case mild.

MMC showed good intravesical stability with a median recovery, in residual bladder content, of 66.2% (range 38.6-92.3) for the 0-22 minute instillation period, and 99.6% (range 68.6-136) for the 22-45 minute instillation period. Results demonstrated that the absorption of MMC occurs mainly during the first minutes of instillation. The plasmatic MMC concentration -- evaluated during the instillation and at 30 and 60 min after the voiding of bladder -- always resulted in a considerably rate lower than the reported threshold concentration for toxicity (400 ng/ml), even when the permeability of the bladder wall was increased, as occurred in one patient (Cmax = 142 ng/ml). This finding was well confirmed by the total lack of hematological toxicity evidenced by the patients during the study.

The results obtained in our study demonstrate that MMC stability and systemic absorption during the hyperthermia treatment performed with UniThermia® are comparable with the results already described in literature with the Synergo® system. In order to evaluate the efficacy of the treatment performed with UniThermia® in reducing 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.

Written by:
Paola Milla, Chiara Fiorito,* Francesco Soria,* Silvia Arpicco, Luigi Cattel, and Paolo Gontero* as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Dipartimento di Scienza e Tecnologia del Farmaco, University of Turin, and *Urologia 1, University of Turin Italy

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

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