Marked variability of melphalan plasma drug levels during regional hyperthermic isolated limb perfusion

Background: Hyperthermic isolated limb perfusion (HILP) with melphalan as treatment for locally recurrent or in-transit malignant melanoma is frequently performed but the principle for calculating drug dosage remains poorly understood. Methods: This study examined the pharmacokinetic profile of 14 consecutive patients to determine what variables were associated with toxicity and tumor responses. Results: Marked fourfold variability was noted in patient plasma melphalan concentrations. We defined a factor - the ratio of estimated limb volume (Vesti) to melphalan volume of distribution (Vss), Vesti/Vss - that was much more strongly correlated with acute regional toxicity than either area under concentration-time curve or peak plasma concentration. In addition, we found that AUX2 was the best correlate of tumor response. Conclusions: Pharmacokinetic evaluation of prospective HILP trials is critical to not only understand response and toxicity outcomes but also to potentially improve the therapeutic index of regional perfusion.