This study sought to use a microdialysis technique to relate clinical and biochemical responses to the time course of
melphalan concentrations in the subcutaneous interstitial space and in tumour tissue (
melanoma, malignant fibrous histiocytoma, Merkel cell tumour and
osteosarcoma) in patients undergoing regional
chemotherapy by Isolated Limb Infusion (ILI). 19 patients undergoing ILI for treatment of various limb
malignancies were monitored for intra-operative
melphalan concentrations in plasma and, using microdialysis, in subcutaneous and tumour tissues. Peak and mean concentrations of
melphalan were significantly higher in plasma than in subcutaneous or tumour microdialysate. There was no significant difference between
drug peak and mean concentrations in interstitial and tumour tissue, indicating that there was no preferential uptake of
melphalan into the tumours. The time course of
melphalan in the microdialysate could be described by a pharmacokinetic model which assumed
melphalan distributed from the plasma into the interstitial space. The model also accounted for the vascular dispersion of
melphalan in the limb. Tumour response in the whole group to treatment was partial response: 53.8% (n = 7); complete response: 33.3% (n = 5); no response: 6.7% (n = 1). There was a significant association between tumour response and
melphalan concentrations measured over time in subcutaneous microdialysate (P< 0.01). No significant relationship existed between the severity of toxic reactions in the limb or peak plasma
creatine phosphokinase levels and peak
melphalan microdialysate or plasma concentrations. It is concluded that microdialysis is a technique well suited for measuring concentrations of cytotoxic
drug during ILI. The possibility of predicting actual concentrations of cytotoxic
drug in the limb during ILI using our model opens an opportunity for improved
drug dose calculation. The combination of predicting tissue concentrations and monitoring in microdialysate of subcutaneous tissue could help optimise ILI with regard to post-operative limb morbidity and tumour response.