Combined intravesical hyperthermia and mitomycin chemotherapy: a preliminary in vivo study

Abstract

Previous clinical studies of the combination of local intravesical hyperthermia with cytostatic drugs for the treatment of Superficial Transitional Cell Carcinoma of the urinary bladder (STCCB) showed encouraging results both in reducing recurrence rate to 20-30% within 2 years and in ablative success rate of 79%. Our objectives were to evaluate bladder tissue and adjacent organs during and following hyperthermia treatment. An intravesical catheter equipped with a radio-frequency antenna (Synergo SB-TS 101.1 System) was used for hyperthermia and intravesical chemotherapy (mitomycin C) was instilled in vivo for 60 min in two anaesthetized sheep. Thirteen to fifteen thermocouples were sewn surgically on the internal and external surfaces of the bladder wall and on adjacent organs to monitor the temperature during the treatment. We expected the intravesical temperature to be under 46 degrees C and the external layers below 45 degrees C. The bladder was filled with 50 mL of chemotherapeutic solution (400 micro g/mL of mitomycin C in distilled water). The sheep were sacrificed at the end of the treatment. Three other sheep, which underwent thoracic surgery, served as control group. Histological changes in both groups showed foci of oedema and haemorrhage with inflammation in the lamina propria and serosa. Foci of desquamation of the epithelium were noticed in the treated sheep. Histological analysis of the treated group showed no significant differences from the control group. The control group showed similar changes, some less pronounced. The combined treatment of hyperthermia with mitomycin C did not cause major damage to the urinary bladder or adjacent organs. All changes were superficial and reversible, and the control group showed similar changes, some less pronounced. Although this is an experimental model based on one single session treatment, rather than repeated treatments, it suggests that the approach may be useful in future studies both in models and man.

Figure 1a

In sheep no. 2, the internal bladder temperature range was 42°C−46°C depending on the thermocouple's location. The refreshing of the intravesical solution and RF discontinuation after 30 min of treatment corresponds to the dip in temperature distribution. During the second part of the experiment, a temperature above 46°C was intentionally employed for limited periods of time, and the maximal internal bladder temperature was then increased to 46°C. Rates of temperature rise were, as expected, higher in the right ventral (4), dome right (6) and left ventral (3) areas of the bladder compared to the posterior wall region, because of the closeness of these areas to the RF antenna. (b). In sheep no. 1 the internal bladder temperature range was 41°C−44.5°C, depending on the thermocouple's location. The refreshing of the intravesical solution and RF discontinuation after 44 min of treatment corresponds to the dip in temperature distribution. The difference in the temperature homogeneity in comparison to sheep no. 2 (Figure 1a) was caused by fluid leakage from the sheep's bladder during the study. As a result, the RF energy had to be altered often (due to variable bladder volume). (c). External bladder temperatures varied in a safety range of 39°C−43°C, even though a temperature above 46°C was intentionally employed for limited periods of time in the bladder. (d). Adjacent organ temperatures were mildly elevated to a maximal temperature value of 40°C even though a temperature above 46°C was intentionally employed for limited periods of time in the bladder. The maximum temperature reached in the adjacent organ is close to the average external bladder wall surface temperature. The rise in temperature in adipose tissue may be explained by the proximity (or even physical contact) of the dorsal adipose tissue with the external bladder wall. In contrast, the more distant (ventral) adipose tissue temperature evolved independently from the bladder wall temperature. (e). External bladder temperatures were raised up to 40°C for a limited period. During most of the study, external bladder temperature remained within a safety limit of 38°C. (f). Adjacent organ temperatures were mildly elevated to a maximal temperature value of 38.4°C. During most of the treatment temperature remained in a safety range of 37–38°C, being mainly influenced by body temperature variations that are assumed to be related to rich vascularization.

Figure 2

Urinary bladder mucosa of treated sheep no. 2. There is focal sloughing of the epithelium, and mild inflammatory infiltrate in the lamina propria with a focus of lymphocytic aggregation. H&E ×100.

Figure 3

Urinary bladder mucosa of control sheep no. 1. The surface epithelium is intact. A mild inflammatory infiltrate is seen in the lamina propria. H&E ×100.