The pharmacokinetic advantages of isolated limb perfusion with melphalan for malignant melanoma

Abstract

Summary We describe melphalan pharmacokinetics in 26 patients treated by isolated limb perfusion (ILP). Group A (n = 11) were treated with a bolus of melphalan (1.5 mg kg-'), and in a phase I study the dose was increased to 1.75 mg kg-'. The higher dose was given as a bolus to Group B (n = 9), and by divided dose to Group C (n = 6).Using high performance liquid chromatography (HPLC) the concentrations of melphalan in the arterial and venous perfusate (during ILP) and in the systemic circulation (during and after ILP) were measured. Areas under the concentration time curves for perfusate (AUCa, AUCV) and systemic (AUCS) data were calculated. In all three groups the peak concentrations of melphalan were much higher in the perfusate than in the systemic circulation. The pharmacokinetic advantages of ILP can be quantified by the ratio of AUCa/AUCS, median value 37.8 (2.1-131).AUCG and AUC, were both significantly greater in Group B than in Group A (P values <0.01, Mann-Whitney). In Groups B and C acceptable 'toxic' reactions occurred but were not simply related to melphalan levels.Our phase I study has allowed us to increase the dose of melphalan to 1.75 mg kg-', but we found no pharmacokinetic advantage from divided dose administration.The rationale for isolated limb perfusion (ILP) in the management of cancer depends on the generation of high levels of effective anticancer agent confined to the tumourbearing limb, thereby avoiding unacceptable systemic toxicity.It is clearly important to establish whether the complex and expensive technique of ILP genuinely achieves its major aim i.e. maximum levels of melphalan in the tumour-bearing limb and minimum systemic exposure.ILP is effective in the management of locally advanced malignant melanoma, and may be an effective adjuvant to surgery for thick, high risk primary lesions. Having reviewed our early experience of patients treated by ILP, it was confirmed that, because of the absence of melphalan-induced toxicity, there was scope for a phase I (dose escalating) clinical study.The study of pharmacokinetics is concerned with the absorption, distribution, biotransformation and excretion of drugs (Goodman et al., 1985). For a given dose these factors govern the concentration of drug at the site of action and they determine how the concentration varies with time.We have studied melphalan pharmacokinetics in the context of a phase I study of ILP.The aims of our studies were:(1) to measure melphalan concentrations in perfusate during ILP, and compare these with the levels in the systemic circulation during and after perfusion, (2) to study the pharmacokinetics of melphalan in ILP, as the dose was increased in a phase I study, (3) to compare the pharmacokinetics of bolus dose with divided dose administration.Patients, materials and methods Patient groupsOnly patients having external iliac perfusion for malignant melanoma were included in the study. The starting dose of melphalan was 1.5 mg kg' body weight, which is the maximum dose recommended in the protocols on which our t...

Prerequisites for effective isolated limb perfusion using tumour necrosis factor alpha and melphalan in rats

“…Traditionally a perfusion time of 1 h has been adopted for ILPs in patients with melphalan based on pharmacokinetic patterns that request a duration of at least 30 min. The pharmacokinetic profile of melphalan in the perfusate in our model showed a similar rapid decrease in melphalan concentrations as was previously demonstrated by others (Benckhuijsen et al, 1988;Scott et al, 1992). We therefore did not study perfusions longer than 30 min and were more interested if identical results could be obtained after shorter perfusions.…”

The effects of perfusion conditions on melphalan distribution in the isolated perfused rat hindlimb bearing a human melanoma xenograft

“…Flow and melphalan concentration It has been stated that it is desirable to know the proportions of administered melphalan taken up by the tissues and the tumours in a leg during ILP (Scott et al, 1992b). We found that the perfusion flow rate increased proportionally more (1.5-fold) in the skin, fat and muscle than in the tumour (1.2-fold) of the melanoma-bearing rat hindlimb, when the perfusion rate is doubled from 4 to 8 ml min-'.…”

TNF dose reduction and shortening of duration of isolated limb perfusion for locally advanced soft tissue sarcoma of the extremities is safe and effective in terms of long‐term patient outcome

“…In the clinical setting, after a 90 min ILP more leakage and other perfusion related problems were seen which was uncomfortable for patient and surgeon. Whereas TNF concentrations remain stable during perfusions, from pharmacokinetic studies of Melphalan it can be derived that there is rapid uptake by the tissues of the limb and almost all uptake of the drug occurs during the first 30 min, so the shortest duration for an effective isolated limb perfusion should be 30 min [33]. With shorter perfusions lesser efficacy was observed, probably due to the fact that exposure times over 20 min are needed to get the vascular occlusive and destructive effects of TNF, needed for adequate tumor responses [13,14].…”