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

Abstract

Background: We analyzed prospectively collected data on 145cis-platin hyperthermic isolation limb perfusion (HILPs) for melanoma and soft-tissue sarcoma to determine the pharmacokinetics and maximum tolerable dose ofcis-platin. There were 70 melanoma and 75 sarcoma patients. Dosages ranged from 26 to 265 mg/m². Perfusate and systemiccis-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 ofcis-platin were equivalent to those of routine intravenous administration, while perfusate levels were 33 times higher. Tissue levels ofcis-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 ofcis-platin for lower-extremity HILPs. Neoadjuvantcis-platin HILP may improve local control rates for sarcomas. However, no tolerable dose ofcis-platin provides control of nodal metastases from melanoma.