Microdialysis and response during regional chemotherapy by isolated limb infusion of melphalan for limb malignancies

This study sought to use a microdialysis technique to relate clinical and b iochemical responses to the time course of melphalan concentrations in the subcutaneous interstitial space and in tumour tissue (melanoma, malignant f ibrous histiocytoma, Merkel cell tumour and osteosarcoma) in patients under going regional chemotherapy by Isolated Limb Infusion (ILI). 19 patients un dergoing 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 melph alan were significantly higher in plasma than in subcutaneous or tumour mic rodialysate. There was no significant difference between drug peak and mean concentrations in interstitial and tumour tissue, indicating that there wa s no preferential uptake of melphalan into the tumours. The time course of melphalan in the microdialysate could be described by a pharmacokinetic mod el which assumed melphalan distributed from the plasma into the interstitia l space. The model also accounted for the vascular dispersion of melphalan in the limb. Tumour response in the whole group to treatment was partial re sponse: 53.8% (n = 7); complete response: 33.3% (n = 5); no responses 6.7% (n = 1). There was a significant association between tumour response and me lphalan 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 pea k melphalan microdialysate or plasma concentrations. It is concluded that m icrodialysis is a technique well suited for measuring concentrations of cyt otoxic drug during ILI. The possibility of predicting actual concentrations of cytotoxic drug in the limb during ILI using our model opens an opportun ity for improved drug dose calculation. The combination of predicting tissu e concentrations and monitoring in microdialysate of subcutaneous tissue co uld help optimise ILI with regard to post-operative limb morbidity and tumo ur response. (C) 2001 Cancer Research Campaign http:,//www.bjcancer.com.