Modification of human tumour and normal tissue pH during hyperthermic and normothermic antiblastic regional isolation perfusion for malignant melanoma: a pilot study

Abstract

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°C), at femoral level, followed by a normothermic regional isolation perfusion with Melphalan (60 min at 37–38°C), at iliacal level, 7–10 days later. In general, several phases during a regional isolation perfusion 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 snorter. 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. The observed tumour regression between the first, hyperthermic, and the second perfusion strengthens the hypothesis that acutely lowered tumour pH sensitizes tumour to hyperthermia.

Key Words:

• Tissue pH
• melanoma
• hyperthermic perfusion
• Melphalan perfusion
• hyperglycaemia
• vascular occlusion