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Locoregional chemotherapy has the dual aim of increasing the exposure of tumor-bearing areas to drugs while partially reducing the cytotoxic effects on the patient's healthy tissues (Ansfield et al., 1971;Ensminger et al., (1978). The recent interest shown in this therapeutic approach can be explained by better knowledge about pharmacokinetics, allowing more objective and rational use of drugs (Balis et al., 1983;Schabel et al., 1983) and by biotechnological progress in the field of implantable pumps (Blackshear et al., 1972) permitting chemotherapy infusions on an ambulatory basis.
Fluoropyrimidines represent the predominant class of drugs used for locoregional chemotherapy of colorectal cancer (Davis, 1982). Long clinical experience has been gained with chemotherapy protocols administered by an intra-arterial hepatic (i.a.h.) route (Ansfield et al., 1971;Stagg et al., 1984;Ensminer et al., 1978). Use of the portal vein appears advisable for small liver metastases (Ackerman et al., 1969). Immediate post-surgery infusion of 5-flourouracil (5-FU) in the portal vein has recently been shown to significantly reduce the rate of disease recurrence at two years for Dukes' C lesions (Taylor et al., 1979). Ensminger et al. (1978) have published detailed pharmacokinetic data concerning the i.a.h. administration of 5-FU, but Correspondence: G. Milano. Received 19 November 1984;and in revised form 5 March 1985. for short infusions (40 to 60 min) at dose rates 10-100 times higher than those usually used. Their conclusions are thus difficult to extrapolate to continuous 5-day infusions which are the most commonly used regimens today (Petrek et al., 1979;Stagg et al., 1984). Only indirect pharmacokinetic data are available for intra-portal (i.p.v.) 5-FU infusion. However, Speyer et al. (1981) and Gyves et al. (1984), on the basis of i.p. 5-FU administration, suggested that considerable hepatic 5-FU extraction might occur through portal vein circulation. No pharmacokinetic evaluations have been published to date concerning intra-arterial pelvic (i.a.p.) 5-FU treatment aimed at better control of locoregional recurrences of colorectal cancer.
This study present pharmacokinetic data collected for 18 patients with liver metastasis or locoregional recurrence of colorectal cancer treated by continuous 5-day regional infusion of 5-FU. (i.a.h.), i.p.v. and i.a.p. routes were compared at increasing drug doses.

Materials and methods
Patients All 18 patients (13 male, 5 female) had histologically confirmed colorectal cancer. Mean patients age was 65 years (range 57-78). Three of the patients had only locoregional disease recurrence; the other 15 had liver metastasis but no pelvic recurrence. Twelve patients were treated by the i.a.h. route, 3 by the i.p.v. route, and 3 by the i.a.p. route. Criteria for inclusion in the study were: estimated survival of >3 months, performance status .2 (ECOG), no ascites neutrophilic polynuclear cells >2500mm-, platelets > 100,000 mm-3, and total bilirubin < 1.5 mg dl 1 Catheter insertion Catheters were inserted using an axillary or femoral artery route under local anesthesia. The tip of the catheter was placed in the hypogastric artery for patients with pelvic recurrences and in the hepatic artery for patients with liver metastasis. Three patients underwent surgery for insertion of a catheter in the portal vein, via the ombilical vein. Angiographic controls were performed systematically, during each cycle, prior to the start of 5-FU infusion.
Chemotherapy protocols 5-FU (Roche, France) was given by continuous 5day infusion at doses varying from 500 to 1650mgm-224h -. The daily dose of 5-FU was diluted in 21 of 5% dextrose in water (D5W) using an external delivery pump (Fresenius, France). No other concurrent treatments were administered. Antiemetics were not used. The interval between the start of two successive cycles was 4 weeks. A total of 87 cycles was analyzed, 17 of which concerned 5-FU administered by a peripheral venous route (i.v.). In an attempt to simplify data presentation, 5-FU doses were classed in two groups: conventional doses: 500-900 mg m-224 hand high doses: 900-1650mg m -224 h -1.

Pharmacokinetics
Blood samples were obtained every day of each cycle at 8am and 5pm, i.e. at Oh, 9h, 24h, 33h, 48h, 57h, 72h, 81h, 96h and 105h. Samples (5ml on EDTA tubes) were rapidly transferred to the laboratory. After centrifugation (10min, 4°C, 2500rpm), the supernatant was frozen at -200C until analysis. Plasma 5-FU measurement was performed by HPLC (Christophidis et al., 1979); the limit of sensitivity was 5ngml-1. The day-today variation coefficient evaluated for 14 different analyses of a plasma spiked with 100ngml-l was 4% (sd/mean x 100). The trapezoidal rule was used to compute the area under the curve (AUC) for the entire cycle, i.e. AUC010osh5 Based on the theoretical considerations described by Chen & Gross (1980), the local extraction parameter was defined as follows: This parameter was only evaluated for patients who received 5-FU i.v. infusions in cycles just before locoregional treatment. Table I gives the respective values of the areas under the plasma concentration x time curve (AUC>losh) for the different sites of locoregional 5-FU treatment. Data collected for i.v. infusions of 6 patients in the study have been shown as control values, corresponding to systemic circulating 5-FU levels when the drug is administered directly into the general circulation. Intra-hepatic (i.a.h. and i.p.v.) administration of 5-FU appears to significantly reduce the circulating levels of the drug as compared to the values observed following i.v. infusion. By contrast, no significant change was noted in AUC-losh between i.a.p. and i.v. infusions.

Results
Increasing the 5-FU dose led to different modifications in pharmacokinetics, depending on the route of drug administration. Thus, for i.v. and i.a.p., the mean 5-FU circulating levels rose proportionately with the dose increase. By contrast, the AUCo105h values for i.a.h. and i.p.v. increased out of proportion to dose increases, and significant differences were noted between conventional and high 5-FU doses. Figure 1 details the changes observed in the i.a.h. and i.p.v. groups for both intra-and inter-cycle drug levels. Circulating 5-FU blood levels were 2.6 times higher during the second half of the cycle than during the first half (P<0.001); Figure l(a) presents the typical profile for 5 patients. A saturation mechanism is also perceptible when the evolution of AUClO05h is considered as a function of the dose (Figure 1(b)): 5-FU AUColosh is linked to the dose by an exponential function (r=0.75, P<0.O01). A dose of lOOOmgm-2 day-' appears to be the critical threshold value above which wide inter-patient variations become patent.

Discussion
Existence of a dose/response relationship is one of the criteria for selection of anticancer agents for locoregional treatment . Experimentally, 5-FU appears to fulfil this condition (Schabel et al., 1983). On this basis, increasing local drug exposure can reasonably be expected to have a high probability of causing more quantitative regression than an equivalent dose administered by a venous route.   conventional doses (500-900 mg m 2 24 h-1 x 5 days), direct 5-FU infusion into the liver resulted in elevated local extraction (over 0.90), with lower AUC values for both the intra-arterial and portal routes than with systemic venous administration. These observations have several implications. They confirm the general absence of systemic toxicity after intra-arterial chemotherapy for metastasis of colorectal cancer to the liver (Stagg et al., 1984). The elevated hepatic extraction values we observed do not fully agree with those reported by Ensminger et al. (1978), which varied from 0.22 to 0.45. This difference is probably due to the shorter infusion times (40 to 60min) and the higher drug delivery rates used by these last authors, which caused the hepatic capacities for drug uptake and metabolism to be exceeded. Our high extraction rates are comparable to those obtained with 5-FUDR, the fluoropyrimidine recommended for intrahepatic treatment . We thus feel that continuous i.a.h. 5-FU infusions may offer therapeutic advantages over rapid i.a.h. administration. The very low circulating 5-FU levels observed after portal infusion indicate high pre-systemic extraction with this route. This feature was previously suggested by Speyer et al. (1981) and Gyves et al. (1984) following i.p. 5.-FU administration. This observation provides a possible explanation for the clinical trial results of Taylor et al. (1979), who reported a marked benefit for the prevention of recurrences with adjuvant treatment by i.p.v. 5-FU.
By contrast with liver administration, the i.a.p. route for 5-FU gave the same circulating drug levels as i.v. infusion (Tables I and II). On these bases, locoregional pelvic 5-FU treatment appears to have little advantage, if any, over classical systemic administration of the drug. However, because of the small number of patients in this group, these results have only an indicative value.
With regional chemotherapy, attention must be paid to the possibility of acute systemic drug exposure once local drug extraction capacities have been exceeded when drug doses are increased. Increasing the 5-FU dose from conventional to high levels clearly modified pharmacokinetic data, although to different degrees depending on the route of administration.
The AUC,O,105h values for both i.v. and i.a.p. rose proportionally to the dose. By contrast, highly significant differences were observed for i.a.h. and i.p.v. infusions between conventional and high doses. In agreement with this, individual values for local hepatic extraction were exceeded when doses were increased (Table II). These data may be considered new arguments in the characterization of the non-linear kinetics of 5-FU (Myers, 1981 , 1981). Figure 1 provides details on the saturable 5-FU hepatic uptake observed for our patients. During infusion, intra-cycle circulating 5-FU levels were significantly higher during the second half of the cycle. This observation corroborates similar recent data published by . Regression analysis revealed an exponential relationship between AUCO105h and the 5-FU dose (r = 0.75, P <0.001; Figure 1(b)). High interindividual variations were perceptible in AUClo05h as a function of the dose above a threshold value of lOOOmgm-2day-1. While this threshold is only an indication, it may prove of clinical importance for other investigations during which intrahepatic 5-FU doses are increased during patient treatment. However, the limited capacity for hepatic biotransformation, resulting in an important non-linear elevation in systemic drug concentrations when 5-FU doses are increased, should not be considered a drawback. Since the central problem raised by locoregional chemotherapy is extra-regional tumour growth (Aronsen et al., 1979;Stagg et al., 1984), appreciable diffusion of 5-FU only when local hepatic capacities have been exceeded could potentially control extra-hepatic disease evolution. Individual evaluations of pharmacokinetic parameters such as AUC might thus be very useful for adjustment of the 5-FU dose administered locally to the liver; this would permit both increased locoregional drug exposure and systemic protection due to cytotoxic circulating 5-FU concentrations. This is the basis of an ongoing pharmaco-clinical trial at our institution concerning i.a.h. 5-FU treatment.