A phase I trial of continuous hyperthermic peritoneal perfusion with tumor necrosis factor and cisplatin in the treatment of peritoneal carcinomatosis

David L. Bartlett, Joseph F. Buell, Steven K. Libutti, Eddie Reed, Kang Bo Lee, William D. Figg, David J. Venzon, H. Richard Alexander

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

BACKGROUND. Tumor necrosis factor (TNF), hyperthermia, and cisplatin have synergistic cytotoxicity against cancer cells in vitro. This combination may be well suited to the regional treatment of peritoneal tumor spread in patients. Continuous hyperthermic peritoneal perfusion (CHPP) is a technique that allows uniform delivery of cytotoxic agents and heat to the peritoneal surface. A Phase I trial of CHPP with TNF and cisplatin was conducted to define the maximum tolerated dose (MTD) for TNF and cisplatin under moderate hyperthermia in the treatment of peritoneal carcinomatosis. METHODS. Twenty- seven patients with peritoneal carcinomatosis underwent exploratory laparotomy and tumor debulking followed by a 90-minute CHPP with cisplatin (100-350 mg/m2) and TNF (0-0.3 mg/L). Perfusion parameters included a perfusate volume of 3-9 L a peritoneal temperature of 42-43°C, and a flow rate of 1.5 L/minute. Sodium thiosulfate was administered systemically during and after the perfusion as a cisplatin binding agent. RESULTS. There was no operative or treatment-related mortality in this study. CHPP resulted in a 14-fold higher area under the concentration versus time curve (AUC) for cisplatin in the perfusate compared with plasma, and a 4854-fold higher AUC for TNF. The MTD was defined as 250 mg/m2 cisplatin plus 0.1 mg/L TNF. The dose-limiting toxicity was renal insufficiency. No other systemic toxicity was identified, and no significant regional toxicity was identified. The median time to toleration of a regular diet was 8 days (range, 5-20 days). CONCLUSIONS. The favorable regional pharmacologic profile of the combination of cisplatin and TNF suggests that these agents administered via CHPP warrant further evaluation as prophylaxis against or treatment for peritoneal carcinomatosis.

Original languageEnglish (US)
Pages (from-to)1251-1261
Number of pages11
JournalCancer
Volume83
Issue number6
DOIs
StatePublished - Sep 15 1998
Externally publishedYes

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Cisplatin
Tumor Necrosis Factor-alpha
Perfusion
Carcinoma
Maximum Tolerated Dose
Therapeutics
Area Under Curve
Fever
Neoplasms
Cytotoxins
Laparotomy
Renal Insufficiency
Hot Temperature
Diet
Temperature
Mortality

Keywords

  • Cisplatin
  • Hyperthermia
  • Mesothelioma
  • Peritoneal carcinomatosis
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

A phase I trial of continuous hyperthermic peritoneal perfusion with tumor necrosis factor and cisplatin in the treatment of peritoneal carcinomatosis. / Bartlett, David L.; Buell, Joseph F.; Libutti, Steven K.; Reed, Eddie; Lee, Kang Bo; Figg, William D.; Venzon, David J.; Alexander, H. Richard.

In: Cancer, Vol. 83, No. 6, 15.09.1998, p. 1251-1261.

Research output: Contribution to journalArticle

Bartlett, David L. ; Buell, Joseph F. ; Libutti, Steven K. ; Reed, Eddie ; Lee, Kang Bo ; Figg, William D. ; Venzon, David J. ; Alexander, H. Richard. / A phase I trial of continuous hyperthermic peritoneal perfusion with tumor necrosis factor and cisplatin in the treatment of peritoneal carcinomatosis. In: Cancer. 1998 ; Vol. 83, No. 6. pp. 1251-1261.
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T1 - A phase I trial of continuous hyperthermic peritoneal perfusion with tumor necrosis factor and cisplatin in the treatment of peritoneal carcinomatosis

AU - Bartlett, David L.

AU - Buell, Joseph F.

AU - Libutti, Steven K.

AU - Reed, Eddie

AU - Lee, Kang Bo

AU - Figg, William D.

AU - Venzon, David J.

AU - Alexander, H. Richard

PY - 1998/9/15

Y1 - 1998/9/15

N2 - BACKGROUND. Tumor necrosis factor (TNF), hyperthermia, and cisplatin have synergistic cytotoxicity against cancer cells in vitro. This combination may be well suited to the regional treatment of peritoneal tumor spread in patients. Continuous hyperthermic peritoneal perfusion (CHPP) is a technique that allows uniform delivery of cytotoxic agents and heat to the peritoneal surface. A Phase I trial of CHPP with TNF and cisplatin was conducted to define the maximum tolerated dose (MTD) for TNF and cisplatin under moderate hyperthermia in the treatment of peritoneal carcinomatosis. METHODS. Twenty- seven patients with peritoneal carcinomatosis underwent exploratory laparotomy and tumor debulking followed by a 90-minute CHPP with cisplatin (100-350 mg/m2) and TNF (0-0.3 mg/L). Perfusion parameters included a perfusate volume of 3-9 L a peritoneal temperature of 42-43°C, and a flow rate of 1.5 L/minute. Sodium thiosulfate was administered systemically during and after the perfusion as a cisplatin binding agent. RESULTS. There was no operative or treatment-related mortality in this study. CHPP resulted in a 14-fold higher area under the concentration versus time curve (AUC) for cisplatin in the perfusate compared with plasma, and a 4854-fold higher AUC for TNF. The MTD was defined as 250 mg/m2 cisplatin plus 0.1 mg/L TNF. The dose-limiting toxicity was renal insufficiency. No other systemic toxicity was identified, and no significant regional toxicity was identified. The median time to toleration of a regular diet was 8 days (range, 5-20 days). CONCLUSIONS. The favorable regional pharmacologic profile of the combination of cisplatin and TNF suggests that these agents administered via CHPP warrant further evaluation as prophylaxis against or treatment for peritoneal carcinomatosis.

AB - BACKGROUND. Tumor necrosis factor (TNF), hyperthermia, and cisplatin have synergistic cytotoxicity against cancer cells in vitro. This combination may be well suited to the regional treatment of peritoneal tumor spread in patients. Continuous hyperthermic peritoneal perfusion (CHPP) is a technique that allows uniform delivery of cytotoxic agents and heat to the peritoneal surface. A Phase I trial of CHPP with TNF and cisplatin was conducted to define the maximum tolerated dose (MTD) for TNF and cisplatin under moderate hyperthermia in the treatment of peritoneal carcinomatosis. METHODS. Twenty- seven patients with peritoneal carcinomatosis underwent exploratory laparotomy and tumor debulking followed by a 90-minute CHPP with cisplatin (100-350 mg/m2) and TNF (0-0.3 mg/L). Perfusion parameters included a perfusate volume of 3-9 L a peritoneal temperature of 42-43°C, and a flow rate of 1.5 L/minute. Sodium thiosulfate was administered systemically during and after the perfusion as a cisplatin binding agent. RESULTS. There was no operative or treatment-related mortality in this study. CHPP resulted in a 14-fold higher area under the concentration versus time curve (AUC) for cisplatin in the perfusate compared with plasma, and a 4854-fold higher AUC for TNF. The MTD was defined as 250 mg/m2 cisplatin plus 0.1 mg/L TNF. The dose-limiting toxicity was renal insufficiency. No other systemic toxicity was identified, and no significant regional toxicity was identified. The median time to toleration of a regular diet was 8 days (range, 5-20 days). CONCLUSIONS. The favorable regional pharmacologic profile of the combination of cisplatin and TNF suggests that these agents administered via CHPP warrant further evaluation as prophylaxis against or treatment for peritoneal carcinomatosis.

KW - Cisplatin

KW - Hyperthermia

KW - Mesothelioma

KW - Peritoneal carcinomatosis

KW - Tumor necrosis factor

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