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The addition of hyperthermia (HT) to regional isolated perfusion (RIP) with Melphalan theoretically has two advantages. Firstly, heat can selectively kill cells in poorly vascularised areas that are usually not reached by the drug. Secondly, in vitro data have revealed that the effect of Melphalan is enhanced at temperatures 39-45 degrees C. However, for the simultaneous application of Melphalan and HT, as it is given in most institutes, both normal and tumour tissues within the volume are treated with both modalities. It is unclear whether--for the same heat dose--the cytotoxicity of Melphalan is enhanced more in tumour tissue than in normal tissues. As the applied dose of Melphalan in RIP is selected on maximum acceptable toxicity, any enhancement of toxicity is undesired. Indeed, Melphalan application at temperatures > 41 degrees C has resulted in unacceptable toxicity. In most institutes, the hyperthermia dose is reduced in comparison to application as a single-modality treatment, to allow simultaneous combination without unacceptable toxicity. In this review, the rationale for two different approaches is summarised which may make it possible to improve the benefit from the theoretical advantage of the use of HT in RIP. It is meant to stimulate discussion as a possible first step in the design of new treatment protocols.

The relationship between duration of a period of vascular occlusion and magnitude of pH decrease in tumour and normal tissue was investigated in rats. To acidify tissue pH further, moderate dose glucose (2.4-3.0 g.kg(-1).hr(-1)) was administered intravenously through a catheter positioned in a tail vein, immediately after the clamp was released. This sequence of pH modifying modalities was chosen since it is employed in clinical regional isolation perfusion for recurrence of malignant melanoma of the limbs. Tumour pH in rat rhabdomyosarcoma BA1112 decreased more than normal tissue pH under 10, 20, 30 or 60 min of temporary vascular occlusion. Administration of glucose following any period of clamping always decreased tumour pH further. The largest pH decrease (0.29 pH units) was obtained after 30 min of clamping followed by 60 min glucose and 60 min saline infusion. In the clinic the combination of a maximum of 30 min of clamping followed by moderate dose glucose infusion, which can decrease tumour pH effectively, can be easily achieved in the setting of regional isolation perfusion. It can be used for treatment modalities that are known to be enhanced at lowered tissue pH, such as hyperthermia and certain chemotherapeutic drugs. These results form the basis for studying the therapeutic gain which can be obtained with this model.

Human tumour and normal tissue pH were investigated during hyperthermic and normothermic antiblastic regional isolation perfusion and the effects of vascular occlusion, artificially induced hypoxia, hyperglycaemia, haemoglobin level of the perfusate and hyperthermia on tumour and normal tissue pH were evaluated. A pilot study was performed on 10 patients, with locally inoperable recurrent and primary malignant melanoma of the leg. The treatment consisted of a regional isolation perfusion with hyperthermia (120 min at 42-43 degrees C), at femoral level, followed by a normothermic regional isolation perfusion with Melphalan (60 min at 37-38 degrees C), at iliacal level, 7-10 can be distinguished: (1) first ischaemic anoxia period; (2) extracorporeal circulation, during which the leg is heated to the desired temperature, after which either hyperthermia or Melphalan is applied; (3) second ischaemic anoxia period. During the anoxia periods the large vessels that supply the leg are temporarily clamped and the effects on tissue pH can be investigated. During extracorporeal circulation, high-dose glucose can be administered to the isolated leg, to acutely decrease tumour tissue pH. Such a decrease is expected to sensitize tumours to hyperthermia, when applied immediately prior to or during heating. At the beginning of the treatment the mean tumour pH was significantly lower than normal tissue pH (7.14, with a mean tumour volume of 39.2 cm3, and 7.38, respectively; p < 0.01). During the perfusions with hyperthermia and Melphalan, tissue pH decreased by -0.41 units and -0.20 for tumour, and -0.11 units for normal tissue, respectively (all statistically significant). The two anoxia periods accounted for approximately half of the net decrease. During these periods tumour pH appeared to decrease more selectively, although there was great variation. The other investigated modalities, such as hyperglycaemia and hyperthermia, also decreased tissue pH, but to a lesser extent. However, a combination of more than one modality caused a larger decrease than a single one, but no preference for tumour could be detected. Before the second perfusion mean tumour pH was significantly increased by 0.14 units, and was no longer significantly different from normal tissue pH in the course of the regional isolation perfusion. This could be the reflection of the reduced tumour volume (by 30%, n.s.). Similar pH changes occurred during this Melphalan perfusion, but they were less pronounced since the total treatment time was shorter. Summarizing, tumour pH can be decreased more than normal tissue pH in the course of the regional isolation perfusion. In particular, vascular occlusion appeared to be tumour pH selective.(ABSTRACT TRUNCATED AT 400 WORDS)

A patient with recurrent rectal cancer was treated with the combination of radiotherapy plus hyperthermia. Intratumoral thermometry probes were introduced within closed-tip catheters, inserted through the buttocks under computed tomography (CT) control. Catheters were fixed to the skin to stay in place during the whole treatment series. At the end of the radiotherapy series, tumour progression was apparent. Seven months following treatment, tumour growth was visible at the insertion site of one of the catheters. This finding indicates that catheters should not be placed outside the treatment volume involved in any locally curative treatment.

A potentially dangerous complication occurring during deep regional hyperthermia is described. A patient receiving epidural analgesics for pain caused by a large pelvic recurrent rectal tumour was treated by hyperthermia induced by electromagnetic radiation. The epidural infusion pump failed during heating and further analgesics were administered by bolus injections into the epidural space. Following the second bolus injection, a severe drop in arterial blood pressure was observed. The most likely multifactorial pathogenesis is discussed and measures to avoid such an event are recommended.

The influence of hyperthermia on tissue pH was investigated using a modified version of the fiber optic monitoring system. This newly developed system was tested for use in tissues and found to be suitable for pH measurement during microwave induced hyperthermia. The fiber optic pH probe (0.7 mm diameter) could be easily used in the electromagnetic fields produced by the microwave applicators, whereas only the display unit required some shielding. Tissue pH of experimental and clinical tumors was measured concurrently with local microwave hyperthermia treatment. The mean initial intratumor pH of a rat rhabdomyosarcoma was 7.03 (SD 0.13, n = 19) and the pH of human subcutis was 7.45 (SD 0.02, n = 8). In rat tumor a primary pH decrease was observed during heating which was fully reversed during cooling. The coefficient of temperature dependence was -0.016 pH unit/degree C (SD 0.004, n = 12). After approximately 1 hr of heating at 43 degrees C a further pH decrease of 0.1-0.3 unit occurred which was not reversed directly after treatment. Measurements during clinical local microwave hyperthermia treatments after radiotherapy revealed similar changes in pH values, primary as well as secondary. The estimated coefficient of temperature dependence for the reversible pH change, which occurred in subcutis as well as in tumor tissue, was -0.016 pH unit/degree C (SD 0.004, n = 12). The fiber optic pH measurement system is expected to be a valuable tool in the thorough investigation of temperature and time related pH changes in tumor during experimental as well as clinical hyperthermia treatment.