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Heated intraoperative intraperitoneal mitomycin C and early postoperative intraperitoneal 5-fluorouracil:
P Jacquet1, A Averbach, A D Stephens
1The Washington Cancer Institute, Washington Hospital Center, Washington, DC 20010, USA.
Purpose:
The purpose of this study was to report the pharmacokinetics of heated intraoperative intraperitoneal mitomycin C (MMC) and to analyze the impact of heat, extent of peritoneal resections, and effect of intraoperative hyperthermic chemotherapy on the pharmacological properties of the peritoneal plasma barrier.
Methods:
Sixty patients with peritoneal carcinomatosis were included in a phase I/II study combining cytoreductive surgery with 2 h of heated intraperitoneal mitomycin C in an intraoperative lavage technique and one cycle of early postoperative 5-fluorouracil (5-FU) given on postoperative days 1-5. Three pharmacokinetic analyses were performed: (1) pharmacokinetics of heated intraoperative intraperitoneal MMC was determined for 18 patients by sampling peritoneal fluid, plasma, and urine during the 2-h procedure; (2) impact of peritoneal resections on MMC pharmacokinetics was assessed by comparing a group of patients who underwent < or = 1 peritonectomy procedure (minimal surgery) to a group of patients who underwent > or = 2 peritonectomy procedures (extensive surgery), and (3) effects of heated intraoperative intraperitoneal chemotherapy on the pharmacokinetics of early postoperative intraperitoneal 5-FU by comparing a group of patients treated with heated intraoperative intraperitoneal MMC to a control group who did not receive heated intraoperative intraperitoneal chemotherapy.
Results:
The mean dose of heated intraoperative intraperitoneal MMC per patient was 22.5+/-7.1 mg (12.9+/-3.8 mg/m2). Drug absorption from perfusate was 14.3+/-2.7 mg. The mean aeras under the curve (AUC) for perfusate and plasma were, respectively, 340+/-138 and 15+/-4 microg/ml x min. The mean AUC peritoneal fluid/plasma ratio was 23.5+/-5.8. Patients who underwent extensive peritoneal resections exhibited a significantly (p = 0.037; Wilcoxon rank test) increased peak plasma concentration of MMC, a significantly (p = 0.029) increased AUC of plasma concentrations and a significantly (p = 0.034) decreased peritoneal fluid/plasma AUC ratio. Pharmacokinetic studies of early postoperative intraperitoneal 5-FU showed no significant difference in plasma AUC, perfusate AUC and AUC ratio between patients who received and those who did not receive heated intraoperative intraperitoneal MMC.
Conclusions:
Heated intraoperative intraperitoneal chemotherapy achieves high peritoneal concentrations of MMC with limited systemic absorption. Systemic drug absorption during heated intraoperative intraperitoneal chemotherapy is increased when extensive peritoneal resections are performed, but such slight increases are unlikely to change the risk of systemic drug toxicities. Heated intraoperative intraperitoneal chemotherapy does not alter the pharmacokinetics of early postoperative intraperitoneal 5-FU.
Insights
Heated intraoperative intraperitoneal chemotherapy with mitomycin C (MMC) achieves high peritoneal drug levels with limited systemic absorption. Extensive surgery increases MMC absorption but is unlikely to raise toxicity risks.
Area of Science:
- Oncology
- Pharmacokinetics
- Surgical Oncology
Background:
- Peritoneal carcinomatosis presents a significant challenge in cancer treatment.
- Intraoperative hyperthermic chemotherapy is an evolving therapeutic strategy.
- Understanding drug pharmacokinetics is crucial for optimizing treatment efficacy and safety.
Purpose of the Study:
- To determine the pharmacokinetics of heated intraoperative intraperitoneal mitomycin C (MMC).
- To analyze how heat, extent of peritoneal resections, and hyperthermic chemotherapy affect the peritoneal plasma barrier.
- To evaluate the impact on early postoperative intraperitoneal 5-fluorouracil (5-FU) pharmacokinetics.
Main Methods:
- A phase I/II study involving 60 patients with peritoneal carcinomatosis.
- Cytoreductive surgery combined with 2-hour heated intraperitoneal MMC lavage.
- Pharmacokinetic analyses of MMC and 5-FU in peritoneal fluid, plasma, and urine.
- Comparison of patients based on the extent of peritoneal resections (minimal vs. extensive).
Main Results:
- Heated intraoperative intraperitoneal MMC achieved high peritoneal concentrations with limited systemic absorption (mean AUC ratio 23.5).
- Extensive peritoneal resections significantly increased peak plasma MMC concentrations and AUC (p=0.037, p=0.029).
- Heated intraoperative intraperitoneal chemotherapy did not significantly alter the pharmacokinetics of early postoperative intraperitoneal 5-FU.
Conclusions:
- Heated intraoperative intraperitoneal chemotherapy effectively delivers MMC to the peritoneum with minimal systemic exposure.
- While extensive surgery increases systemic MMC absorption, it is unlikely to elevate toxicity.
- This approach does not negatively impact the pharmacokinetics of subsequent 5-FU treatment.