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

William S. Fletcher, Rodney Pommier, Eugene A. Woltering, Charles R. Mueller, K. Owen Ash, Karen A. Small

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    Abstract

    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 2. 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.

    Original languageEnglish (US)
    Pages (from-to)236-243
    Number of pages8
    JournalAnnals of Surgical Oncology
    Volume1
    Issue number3
    DOIs
    StatePublished - May 1994

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    Extremities
    Pharmacokinetics
    Perfusion
    Sarcoma
    Melanoma
    Lower Extremity
    Myoglobinuria
    Recurrence
    Rhabdomyolysis
    Hyponatremia
    Intravenous Administration
    Neoplasm Metastasis

    Keywords

    • Cis-platin
    • Hyperthermic isolation limb perfusion
    • Melanoma
    • Sarcoma

    ASJC Scopus subject areas

    • Surgery
    • Oncology

    Cite this

    Pharmacokinetics and results of dose escalation in Cis-platin hyperthermic isolation limb perfusion. / Fletcher, William S.; Pommier, Rodney; Woltering, Eugene A.; Mueller, Charles R.; Owen Ash, K.; Small, Karen A.

    In: Annals of Surgical Oncology, Vol. 1, No. 3, 05.1994, p. 236-243.

    Research output: Contribution to journalArticle

    Fletcher, William S. ; Pommier, Rodney ; Woltering, Eugene A. ; Mueller, Charles R. ; Owen Ash, K. ; Small, Karen A. / Pharmacokinetics and results of dose escalation in Cis-platin hyperthermic isolation limb perfusion. In: Annals of Surgical Oncology. 1994 ; Vol. 1, No. 3. pp. 236-243.
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    abstract = "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 2. 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.",
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    AU - Pommier, Rodney

    AU - Woltering, Eugene A.

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    AU - Owen Ash, K.

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    N2 - 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 2. 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.

    AB - 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 2. 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.

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