The role of vascularity as a prognostic factor was investigated in 35 patients undergoing arterial chemotherapy for liver tumours. Compared with parenchyma, tumour vascularity was classified as hot (18 cases), cold (12 cases), and mixed (12 cases) using 99mTc-macroaggregated albumin (MAA) hepatic arterial scans. The proportion of patients showing complete and partial responses to treatment was higher in the hot group (56 per cent) than in the combined cold and mixed group (12 per cent). In 15 cases (six hot, six cold and three mixed lesions), additional MAA scans were performed immediately after arterial embolization with degradable starch microspheres (DSMs). Either complete or partial reversal of tumour vascularity was observed after DSM-embolization in five and seven cases respectively, two and two of them respectively showing native cold lesions. As tumour vascularity appears to be a prominent prognostic factor, DSM-embolization should improve the efficacy of treatment by improving liver extraction of drugs and causing flow redistribution towards hypovascular areas.

Arterial chemoembolization of liver tumors should improve regional treatment by reducing native blood flow of the whole organ and redistributing residual flow toward hypovascular masses. Plasma cisplatin pharmacokinetics and its tissue uptake and relative tumor and liver vascularity were studied during surgical placement of arterial catheters in four patients and in four patients with colorectal metastases given intraoperative arterial cisplatin (DDP, 25 mg/m2), with and without coadministration of 600 mg degradable starch microspheres (DSM). Mean (± standard deviation) filterable plasma platinum levels peaked later (2 minutes) and were significantly lower after DDP with DSM (1.23 ± 0.69 μg/ml) than after DDP alone (2.13 ± 0.43 μg/ml, P less than 0.05), with the area under the curve (AUC10–30 min) values of 15.8 ± 5.5 and 25.1 ± 3.8 μg × min/ml (P less than 0.05), respectively. No differences in urine excretion, total body clearance, or plasma protein binding of platinum were observed. Tissue biopsies were started 15 minutes after DDP administration and completed in all cases within 5 minutes. Tumor platinum concentrations were significantly higher after DDP with DSM (3.03 ± 1.60 μg/g) than after DDP alone (0.67 ± 0.49 μg/ml, P less than 0.05). Liver concentrations and tumor‐liver ratios of platinum also were higher, although not significantly, after DDP with DSM. Preoperative vascularization, studied with arterial perfusion scan, influenced individual tissue drug uptake in cases given DDP alone, with the lowest tumor levels in cold masses. Very high and almost superimposable liver and tumor concentrations were measured in those receiving DDP and DSM. The latter phenomenon was irrespective of native vascularization, indicating that DSM administration induced both an increased whole‐liver extraction of the drug and a redistribution of blood flow and flow‐dependent tissue uptake of platinum.

Performances of totally implantable infusion systems were analyzed in patients with colorectal liver metastases undergoing intra-arterial treatment. It consisted of 14-day continuous infusion of 5-fluor-2′deoxyuridine with pumps (pump14, 44 patients) or ports fed by external pumps (port14, 34 patients), or bolus infusion of cisplatin (port21, 57 patients) or epirubicin (port7, 22 patients) every 3rd week and weekly, respectively. Toxicity and disease progression were the most common causes of treatment interruption. System failure occurred in 2 pump14, 9 port14, 6 port21 and 2 port7 cases. Pocket problems were most frequent in the pump14 group (30%), whereas catheter- and infusion-related problems were mostly observed in the port14 group (109%). The devices were still functional after 12 months in 92% of pump14, 24% of port14, 65% of port21 and in 78% of port7 patients. Although implantable ports allow adequate infusion periods, in most cases they appear especially suitable for bolus infusions.

Several phase III clinical trials demonstrated that hepatic arterial chemotherapy for unresectable colorectal liver metastases is able to provide significantly higher response rates than those obtained by systemic route: in more than 500 patients collected from 6 randomized trials, the median values of objective response rates were 55% after fluoxuridine (FUdR) continuous hepatic arterial infusion (HAI) vs. 18.5% after FUdR or 5‐fluorouracil (5‐FU) intravenous (i.v.) chemotherapy. Furthermore, the majority of those studies reported that median survival increased in the patient subgroups treated with intrahepatic chemotherapy, even if not always statistically significant [1‐6]. Certainly, FUdR can be recognized as the first drug, among those regionally given, able to modify the natural history of colorectal liver metastases: it results from both the highest rates of objective responses ever reported in literature and the almost constant notice of unusual sites of extrahepatic metastases [7‐10].

A pharmacokinetic study was carried out in patients with unresectable colorectal liver metastases who had primarily been included in a phase II trial of intra-arterial cisplatin (DDP) plus intravenous fluorouracil. Ten patients of those accrued for the clinical study underwent the pharmacokinetic investigation upon liver progression of the disease. Four patients were treated with DDP (24 mg/m(2)) through short intra-arterial infusion (baseline study) and 4 patients received intra-arterial hyaluronidase (HY, 100 000IU) 2 minutes before DDP infusion. Two additional patients were treated with both DDP alone and DDP + HY. Plasma concentrations of total and free platinum (Pt) were consistently lower than baseline in the presence of HY. HY administration resulted in a longer terminal half-life (2.1 ± 0.7 vs 1.0 ± 0.2 days, p < 0.05), a reduced area under the plasma concentration-time curve from 0 to 2 hours (AUC0-2h) [0.08 ± 0.009 vs 0.12 ± 0.017 g/L•min, p < 0.01], and an increased volume of distribution, both initially (11.7 ± 3.4 vs 6.6 ± 2.1L, p < 0.05) and at steady-state (43.0 ± 10.8 vs 22.1 ± 8.8L, p < 0.05), for total Pt. However, significant HY-related effects on the overall plasma exposure (AUC0-∞) to total Pt or on the total body clearance were not observed. HY treatment was also associated with a lower plasma concentration at time zero (C0) [p < 0.01 ] and AUC0-2h (p < 0.02), and a higher plasma clearance (p < 0.02) and apparent volume of distribution (p < 0.05), for free Pt. Renal clearance (CLR) and cumulative urinary excretion of Pt were significantly increased (p < 0.01) by HY, while fluid output was not significantly affected. The increase in both CLR and the extent of Pt distribution was not due to a protein binding drug interaction nor to a reaction between DDP and HY in the plasma. Combined treatment with HY yielded a clinically acceptable toxicity.