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 < or = 200 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.
Department of Surgery, Oregon Health Sciences University, Portland 97201-3098.
W S
WS
Fletcher
R F
RF
Pommier
E A
EA
Woltering
C R
CR
Mueller
K O
KO
Ash
K A
KA
Small
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D010478:Chemotherapy, Cancer, Regional Perfusion; D002648:Child; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005121:Extremities; D005260:Female; D006358:Hot Temperature; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality; D008875:Middle Aged; D011446:Prospective Studies; D012509:Sarcoma / Q000188:drug therapy* / Q000401:mortality; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000401:mortality; D015996:Survival Rate
D002945:Cisplatin