A pilot phase I trial of continuous hyperthermic peritoneal perfusion with high-dose carboplatin as primary treatment of patients with small- volume residual ovarian cancer

Michael A. Steller, Merrill J. Egorin, Edward Trimble, David L. Bartlett, Eleanor G. Zuhowski, H. Richard Alexander, Robert L. Dedrick

Research output: Contribution to journalArticle

Abstract

Purpose: Because intraperitoneal (i.p.) therapy may provide a therapeutic advantage and because hyperthermia enhances carboplatin (CBDCA) cytotoxicity, we evaluated the feasibility, toxicity, and pharmacokinetics of CBDCA given via continuous hyperthermic peritoneal perfusion (CHPP) in patients with small-volume residual ovarian cancer. Patients and Methods: Six patients underwent optimal cytoreductive procedures (residual disease ≤5 mm) as initial treatment of stages II and III epithelial ovarian adenocarcinoma. All patients received a 90-min CHPP at a CBDCA dose of 800-1200 mg/m2, with the perfusate being recirculated rapidly from a reservoir through a heat exchanger, resulting in i.p. temperatures of 41-43 °C. Plasma, perfusate, and urine samples were collected and platinum was quantified by flameless atomic absorption spectrophotometry. Results: At no time did any patient's core temperature exceed 40 °C. Peak perfusate platinum concentrations were 8- to 15-fold higher than peak ultrafilterable plasma concentrations. The permeability-area product was extremely high and variable (14-90 ml/min), resulting in a regional advantage of 1.9-5.3. The percentage of the dose absorbed ranged widely from 27% to 77%. Dose-limiting hematologic toxicity was observed at a dose of 1200 mg/m2 and this was associated with a CBDCA AUC in plasma of 1 mg min ml-1. Conclusions: CHPP with CBDCA was safely given to three patients at a dose of 800 mg/m2, and dose-limiting hematologic toxicities observed at 120 mg/m2, correlated with the plasma CBDCA exposure established when lower doses of CBDCA are given systemically. The pharmacokinetic data are consistent with the expected effect of vigorous mixing on the exposed peritoneal surface area. Variable drug absorption and clearance make the prediction of systemic exposure highly uncertain. These findings may have important implications for novel therapies given i.p.

Original languageEnglish (US)
Pages (from-to)106-114
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume43
Issue number2
DOIs
StatePublished - 1999
Externally publishedYes

Fingerprint

Carboplatin
Residual Neoplasm
Ovarian Neoplasms
Perfusion
Toxicity
Plasmas
Pharmacokinetics
Therapeutics
Platinum
Atomic Spectrophotometry
Temperature
Spectrophotometry
Cytotoxicity
Area Under Curve
Heat exchangers
Permeability
Adenocarcinoma
Fever
Hot Temperature
Urine

Keywords

  • Continuous hyperthermic peritoneal perfusion
  • Hepatic toxicity
  • High-dose CBDCA
  • Small- volume residual ovarian cancer
  • Systemic exposure

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

A pilot phase I trial of continuous hyperthermic peritoneal perfusion with high-dose carboplatin as primary treatment of patients with small- volume residual ovarian cancer. / Steller, Michael A.; Egorin, Merrill J.; Trimble, Edward; Bartlett, David L.; Zuhowski, Eleanor G.; Alexander, H. Richard; Dedrick, Robert L.

In: Cancer Chemotherapy and Pharmacology, Vol. 43, No. 2, 1999, p. 106-114.

Research output: Contribution to journalArticle

Steller, Michael A. ; Egorin, Merrill J. ; Trimble, Edward ; Bartlett, David L. ; Zuhowski, Eleanor G. ; Alexander, H. Richard ; Dedrick, Robert L. / A pilot phase I trial of continuous hyperthermic peritoneal perfusion with high-dose carboplatin as primary treatment of patients with small- volume residual ovarian cancer. In: Cancer Chemotherapy and Pharmacology. 1999 ; Vol. 43, No. 2. pp. 106-114.
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T1 - A pilot phase I trial of continuous hyperthermic peritoneal perfusion with high-dose carboplatin as primary treatment of patients with small- volume residual ovarian cancer

AU - Steller, Michael A.

AU - Egorin, Merrill J.

AU - Trimble, Edward

AU - Bartlett, David L.

AU - Zuhowski, Eleanor G.

AU - Alexander, H. Richard

AU - Dedrick, Robert L.

PY - 1999

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AB - Purpose: Because intraperitoneal (i.p.) therapy may provide a therapeutic advantage and because hyperthermia enhances carboplatin (CBDCA) cytotoxicity, we evaluated the feasibility, toxicity, and pharmacokinetics of CBDCA given via continuous hyperthermic peritoneal perfusion (CHPP) in patients with small-volume residual ovarian cancer. Patients and Methods: Six patients underwent optimal cytoreductive procedures (residual disease ≤5 mm) as initial treatment of stages II and III epithelial ovarian adenocarcinoma. All patients received a 90-min CHPP at a CBDCA dose of 800-1200 mg/m2, with the perfusate being recirculated rapidly from a reservoir through a heat exchanger, resulting in i.p. temperatures of 41-43 °C. Plasma, perfusate, and urine samples were collected and platinum was quantified by flameless atomic absorption spectrophotometry. Results: At no time did any patient's core temperature exceed 40 °C. Peak perfusate platinum concentrations were 8- to 15-fold higher than peak ultrafilterable plasma concentrations. The permeability-area product was extremely high and variable (14-90 ml/min), resulting in a regional advantage of 1.9-5.3. The percentage of the dose absorbed ranged widely from 27% to 77%. Dose-limiting hematologic toxicity was observed at a dose of 1200 mg/m2 and this was associated with a CBDCA AUC in plasma of 1 mg min ml-1. Conclusions: CHPP with CBDCA was safely given to three patients at a dose of 800 mg/m2, and dose-limiting hematologic toxicities observed at 120 mg/m2, correlated with the plasma CBDCA exposure established when lower doses of CBDCA are given systemically. The pharmacokinetic data are consistent with the expected effect of vigorous mixing on the exposed peritoneal surface area. Variable drug absorption and clearance make the prediction of systemic exposure highly uncertain. These findings may have important implications for novel therapies given i.p.

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KW - Hepatic toxicity

KW - High-dose CBDCA

KW - Small- volume residual ovarian cancer

KW - Systemic exposure

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