A comparative study of isolated liver perfusion versus hepatic artery infusion with mitomycin C in rats

Abstract

Summary Systemic toxicity is usually the dose-limiting factor in cancer chemotherapy. Regional chemotherapy is therefore an attractive strategy in the treatment of liver metastasis. Two ways of regional chemotherapy, hepatic artery infusion (HAI) and isolated liver perfusion (ILP), were compared investigating the difference in toxicity with tissue and biofluid concentrations of mitomycin C (MMC). In wistar derived WAG rats the maximally tolerated dose of mitomycin C via HAI was 1.2 mg kg-'. Body weight measurements after HAI with doses higher than 1.2 mg kg-' suggest both an acute and delayed toxic effect of mitomycin C since the time weight curves were triphasic: a rapid weight loss, a steady state and a second fall in weight phase. These rats died due to systemic toxicity. ILP with 4.8 mg kg-' was associated with no signs of systemic toxicity and only transient mild hepatotoxicity. ILP with 6.0 mg kg-' was fatal mainly due to hepatic toxicity. The four times higher maximally tolerated dose in ILP resulted in a 4-5 times higher peak concentration of mitomycin C in liver tissue, while the plasma concentration remained significantly lower than in the HAI treated rats. In the tumour tissue a 500% higher concentration of mitomycin C was measured in the ILP with 4.8 mg kg-' than in HAI with 1.2 mg kg-' treated rats. We demonstrated that when mitomycin C was administered by ILP a 400% higher dose could be safely administered and resulted in a five times higher tumour tissue concentration. In view of the steep dose-response curve of this alkylating agent this opens new perspectives for the treatment of liver metastasis.The liver is a major site of metastatic spread of primary colorectal cancer; in as many as 30% of the patients it is also the sole site of initial tumour recurrence . At the time of operation for the primary tumour approximately 5% of patients with colorectal cancer have resectable liver metastases (Foster & Lundy, 1981). Another 5% will develop resectable metastases confined to the liver after resection of the primary tumour (Foster & Berman, 1977;Adson, 1983). These patients can be cured by surgery and a 5-year survival rate of about 35% can be achieved (Foster & Lundy, 1981;Adson et al., 1984;August et al., 1985;Iwatsuki et al., 1986).Unfortunately, in the majority (75%) of the patients with colorectal cancer metastases confined to the liver, the tumour is not resectable. These patients are eligible for locoregional therapies. The rationale of regional administration of chemotherapy is based on the concept of achieving a high local concentration, while minimising systemic drug levels and, accordingly, reducing dose limiting systemic side-effects (Collins, 1984). For most chemotherapeutic agents steep dose-response curves can be demonstrated. Therefore, high drug concentrations are important for both sensitive and resistant tumour cells. For resistant cells extremely high exposure is required for adequate cell kill (Slee et al., 1987;Kuppen et al., 1988).Exploiting high extraction ratios of the fluoro...

Increasing the effective concentration of melphalan in experimental rat liver tumours: comparison of isolated liver perfusion and hepatic artery infusion

“…The differences in the results of this study with melphalan and a previously published study with MMC (Marinelli et al, 1990a) will be discussed.…”

“…Only with MMC complete remissions and a significantly prolonged survival has been reported (Marinelli et al, 1991). In rats, hepatotoxic side effects of MMC was dose limiting (Marinelli et al, 1990a). In six out of seven evaluable patients treated with 30 mg m-2 of MMC in ILP an objective response was seen (> 50% tumour volume reduction on CT).…”

“…(1) Isolated liver perfusion with two inflow limbs This technique has been previously described in detail (de Brauw et al, 1988;Marinelli et al, 1990a). In short, after performing a midline abdominal incision cannulas were inserted into the gastroduodenal artery and the pyloric vein with their tips in the hepatic artery and portal vein respectively.…”

Effectiveness of isolated liver perfusion with mitomycin C in the treatment of liver tumours of rat colorectal cancer

“…Isolated liver perfusion and hepatic artery infusion are described elsewhere (Marinelli et al, 1990). Briefly: in the isolated liver perfusion two inflow limbs of the isolated circuit were established by cannulation of the pyloric branch of the portal vein and the gastroduodenal branch of the common hepatic artery.…”

“…In this study, we evaluated the effect of mitomycin C, which has a steep dose-response relationship (Mitra & Maillova, 1986;Wallner & Li, 1987;de Bruijn et al, 1988) and has been reported to be a promising drug for colorectal cancer (Doll et al, 1985;Schneider et al, 1989). In a previous study (Marinelli et al, 1990), it was determined that in isolated liver perfusion a four times higher dose of mitomycin C could be administered than via hepatic artery infusion, resulting in a five times higher concentration in tumour tissue. In the present study, we investigated whether this higher tissue concentration is also more effective in the actual elimination of tumour cells.…”