Correlation between melphalan pharmacokinetics and hepatic toxicity following hyperthermic isolated liver perfusion for unresectable metastatic disease.

BACKGROUND: In the present work, we report on the results of our pilot study of hyperthermic isolated hepatic perfusion (IHP) with melphalan alone for patients with unresectable metastatic liver tumors refractory to conventional treatments, with particular regard to the correlation between pharmacokinetic findings and hepatic toxicity. PATIENTS AND METHODS: Inclusion criteria were unresectable liver metastases, hepatic parenchyma replacement

True versus mild hyperthermia during isolated hepatic perfusion: effects on melphalan pharmacokinetics and liver function.

Hyperthermic antiblastic isolated hepatic perfusion (IHP) with melphalan has been recently proposed as an alternative therapeutic option for patients with unresectable liver tumors. Although melphalan-heat antiblastic synergism is at a maximum at temperatures higher than 41 degrees C, IHP has so far been performed in humans at lower temperatures. In this experimental work, we compared IHP under mild versus true hyperthermic conditions in terms of drug pharmacokinetics and liver function. Ten pigs were submitted to IHP with melphalan 1.5 mg/kg at a mean temperature of 40 degrees C (group A, n = 5) or 42 degrees C (group B, n = 5). After a 60-minute perfusion, a 15-minute washout was performed. Perfusate-to-plasma leakage was monitored using scintigraphy. Throughout perfusion, samples from the systemic blood, perfusate, and liver parenchyma were obtained to measure melphalan concentrations. Liver function was assessed using standard blood tests and the indocyanine green-based test. No deaths related to the IHP procedure were recorded. All animals had transient liver function impairment, with all liver function test results returning to normal within the observation period. At histologic examination, liver damage was similar under both hyperthermic conditions. Melphalan levels in the perfusate were not significantly different in the two study groups (the mean perfusate/plasma area under the curve from 0 to 60 minutes ratios were 463 and 501, respectively). These results correlated well with those obtained using the scintigraphic method. Liver drug concentrations remained unchanged after true hyperthermia IHP. Under true hyperthermic conditions, neither an increase in liver parenchyma toxicity nor changes in melphalan pharmacokinetics were observed. These findings support the use of true hyperthermia in the clinical setting to exploit fully the antitumor synergism between melphalan and heat.

Hyperthermic intraperitoneal intraoperative chemotherapy for peritoneal carcinomatosis arising from gastric adenocarcinoma.

BACKGROUND: Patients with peritoneal carcinomatosis from gastric carcinoma have a dismal prognosis. Hyperthermic intraperitoneal intraoperative chemotherapy (HIIC) has been proposed to treat residual disease after cytoreductive surgery. PATIENTS AND METHODS: From January 1998 through July 2002, 13 patients with peritoneal carcinomatosis from gastric cancer underwent complete cytoreductive surgery followed by HIIC. Chemo-hyperthermia was performed using mitomicin C (3.3 mg/m2) and cisplatin (25 mg m2) for 90 minutes, at a mean intraperitoneal temperature of 41.7 degrees C. RESULTS: No postoperative death was observed. Moderate locoregional toxicity (ileus) was observed in eight cases (42%), while two patients (10%) experienced mild systemic toxicity (myelosuppression or fever). Postoperative complication rate was 26% (pleural effusion, n = 4; septicemia = 1). Median overall survival was 15 months, and the median local progression free survival was 10 months. CONCLUSIONS: Cytoreductive surgery followed by HIIC resulted a feasible procedure, the overall morbidity rate being acceptable. Although the study was conducted in a subset of patients with peritoneal carcinomatosis from gastric cancer (resectable disease), survival results are encouraging.