You are here

The Effect of Conductive Hyperthermia on Mitomycin C Absorption During Intravesical Chemotherapy

Hyperthermia (heating to 43°C) activates the innate immune system and improves bladder cancer (BC) chemosensitivity. In this study, we evaluated the impact of convective hyperthermia on intravesical mitomycin C (MMC) pharmacokinetics in live porcine bladder models.

Methods

Forty 60 kg female swine were anesthetized and catheterized with a 3-way, 16-F catheter. The Combat BRS device was used to heat the porcine bladders to a target temperature of 43°C with recirculating intravesical MMC (2 mg/mL) at doses of 40mg, 80mg and 120mg. Dwell-heat time ranged from 30 to 120 min, after which rapid necropsy with immediate flash freezing of tissues (bladder, lymph nodes, liver, kidney, spleen, heart and lung) occurred. Blood and urine were collected longitudinally. Serum and tissue MMC concentrations were measured by liquid chromatography tandem-mass spectrometry (Agilent 1200 – Applied Biosciences/SCIEX API 5500 QTrap). Data acquisition and quantification was performed by Analyst 1.6.2 software.

Results

Figure 1: Medican concentration of mitomycin C at body temperature and 43 degree C in the bladder and various organ.As shown in the Table, 3 factors increased MMC absorption into the bladder: dwell time, drug concentration, and the presence of heat. Bladder MMC concentrations were, in general, significantly higher in pigs that underwent convective hyperthermia than in those that did not (it is uncertain why this relationship was not present at the 120 mg dose with 1-hour dwell time). The relationship between bladder penetration of drug and heating showed a weak linear relationship with dose (Kendall’s tau = 0.35). In the hyperthermia arm, drug penetration saturated at 80 mg dose, suggesting that with heating, drug absorption may saturate and not require higher doses to achieve the maximal biological effect. Importantly, convective hyperthermia did not increase the MMC concentration in the liver, heart, kidney, spleen, lung, and lymph node tissue and is therefore not expected to result in excess toxicity in humans, even at the 120 mg dose.

 

Table 1: Concentration of Mitomycin C in the bladder based on drug concentration, dwell time and presence of hyperthermia.

Figure 2: Jitterplot on concentration of Mitomycin C in various organs at body temperature and 43 degree celcius

Video

Contact

For more information on this presentation, please contact:

Wei Phin Tan, MD
Twitter: @DrTanWP
Email: weiphin.tan@duke.edu
Phone: 919.384.5057