Pharmacokinetics and results of dose escalation in Cis-platin hyperthermic isolation limb perfusion

Background: We analyzed prospectively collected data on 145 cis-platin hyperthermic isolation limb perfusion (HILPs) for melanoma and soft-tissue sarcoma to determine the pharmacokinetics and maximum tolerable dose of cis-platin. There were 70 melanoma and 75 sarcoma patients. Dosages ranged from 26 to 265 mg/m². Perfusate and systemic cis-platin levels were measured in patients perfused at doses of 190-200 mg/m². Tissue levels were measured in patients perfused at 123-209 mg/m². Methods:Cis-platin HILP was well tolerated up to doses of 250 mg/m² for lower extremities. Higher doses produced toxicities of rhabdomyolysis, myoglobinuria, hyponatremia, and neuropathy. Systemic levels of cis-platin were equivalent to those of routine intravenous administration, while perfusate levels were 33 times higher. Tissue levels of cis-platin were five to six times higher than effective intravenous levels. Results: Six melanoma patients have developed local recurrences. All were perfused at doses <120 mg/m². However, regional nodal recurrences have occurred in six other patients perfused at doses ≤2000 mg/m². Four sarcomas have recurred locally, but three of them were present at the time of perfusion. Conclusions: We conclude that 250 mg/m² is the maximum tolerable dose of cis-platin for lower-extremity HILPs. Neoadjuvant cis-platin HILP may improve local control rates for sarcomas. However, no tolerable dose of cis-platin provides control of nodal metastases from melanoma.