Rationale for different approaches to combined melphalan and hyperthermia in regional isolated perfusion.

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.

Physiological implications of hyperbaric oxygen tensions in isolated limb perfusion using melphalan: a pilot study.

Controversy exists concerning the optimal pO2 of the perfusate during isolated limb perfusion (ILP) with melphalan. Therefore we studied the implications of hyperbaric oxygen tensions in the perfusate. In 12 consecutive patients, subcutaneous pO2 (Continucath 1000), tissue and tumor pH, and blood gas values were monitored throughout the ILP procedure. ILP started with an oxygen flow through the bubble oxygenator which was set routinely at one half of the flow of the perfusate; 30 min before the end of ILP, the oxygen flow was tripled. Mean arterial pO2 before and during ILP (before and after increasing the oxygen supply) was 19.4, 25.5 and 49.4 kPa, respectively. Mean subcutaneous pO2 values before, during (before and after increasing the oxygen supply), and post-ILP, were 7.4, 10.1, 16.3, and 9.1 kPa, respectively. Tissue pH values in the subcutis and muscle decreased during routine oxygen supply (p = 0.001); muscle pH moved towards starting values after increase of the oxygen supply (p = 0.011). In 4 patients, tumor pH was recorded showing a rise after increasing the oxygen supply (from 7.10 to 7.22; p = 0.11). In conclusion, high pO2 in the perfusate improves muscle pH during ILP. However, a concomitant rise in tumor pH may unfavorably influence the therapeutic effect of ILP, as it has been shown that low pH increases the cytotoxicity of melphalan.

Temporary vascular occlusion and glucose: effects on tumour and normal tissue pH in animal experiments.

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.

Comparison between the use of whole blood versus a diluted perfusate in regional isolated perfusion by continuous monitoring of transcutaneous oxygen tension: a pilot study.

In 12 successive women (median age, 58 [39-89] years) who were treated with regional isolated perfusion for melanoma of the lower extremities, peroperative continuous monitoring of the transcutaneous oxygen tension (PtcO2) was performed as an indicator for tissue oxygenation and (sub)cutaneous perfusion. Regional perfusion started using whole blood as perfusate with a hematocrit of 40.7 +/- 4.9. After 40 min of drug circulation the perfusate was diluted to a hematocrit of 25.3 +/- 4.9, a value usually applied in perfusion. Flow rates (mean 51.2 +/- 14.4 mL/min/L perfused tissue) were kept at a level that caused no systemic leakage and no more than 10-cm increase above starting venous pressure. Oxygen supply was set at one half of the flow of the perfusate (in mL/min). The mean PtcO2 during the first part of perfusion, in which seven patients could achieve preperfusion levels for at least some of the time, was significantly higher than during the last part, in which no patient reached the preperfusion level (30.8 mm Hg vs 23.5 mm Hg; p = .0019). The mean maximal decrease in PtcO2 after dilution was 21.3 +/- 11.6 mm Hg. Venous blood gases of the perfusate also deteriorated after dilution. Two patients encountered a grade III and two a grade IV toxicity reaction after perfusion. We conclude that increasing the hematocrit of the perfusate to physiologic levels by using whole blood can guarantee a physiologic tissue oxygenation at relatively low flow rates. However, physiologic tissue oxygenation on its own is not enough to prevent toxicity after perfusion.

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

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)

Risk of acute hypotension following epidural analgesia during deep regional hyperthermia: a case report.

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.

Risk of tumour growth along thermometry catheter trace: a case report.

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.

Measurement of tumor pH during microwave induced experimental and clinical hyperthermia with a fiber optic pH measurement system.

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.