A dose of 1000 mg/m(2) bd of capecitabine is recommended for use on an intermittent schedule in combination with these doses and schedule of epirubicin and cisplatin. This regimen is tolerable and active in oesophago-gastric adenocarcinoma. A randomised phase III comparison with ECF is justified.

Previous studies have demonstrated that there are circadian rhythms in susceptibility to a range of commonly used cytotoxic drugs. In this study we have compared the pharmacokinetics and myelotoxicity of carboplatin administered at 18.00 and 06.00 in random order in patients with advanced ovarian carcinoma. Carboplatin treatment at 06.00 is associated with significantly greater thrombocytopenia than at 18.00 (platelet nadir 95,000 versus 180,000, p less than 0.05). There was no pharmacokinetic difference in the patients' handling of ultrafilterable platinum therefore it is possible that there is an intrinsic rhythm of susceptibility of bone marrow to carboplatin.

Summary We describe melphalan pharmacokinetics in 26 patients treated by isolated limb perfusion (ILP). Group A (n = 11) were treated with a bolus of melphalan (1.5 mg kg-'), and in a phase I study the dose was increased to 1.75 mg kg-'. The higher dose was given as a bolus to Group B (n = 9), and by divided dose to Group C (n = 6).Using high performance liquid chromatography (HPLC) the concentrations of melphalan in the arterial and venous perfusate (during ILP) and in the systemic circulation (during and after ILP) were measured. Areas under the concentration time curves for perfusate (AUCa, AUCV) and systemic (AUCS) data were calculated. In all three groups the peak concentrations of melphalan were much higher in the perfusate than in the systemic circulation. The pharmacokinetic advantages of ILP can be quantified by the ratio of AUCa/AUCS, median value 37.8 (2.1-131).AUCG and AUC, were both significantly greater in Group B than in Group A (P values <0.01, Mann-Whitney). In Groups B and C acceptable 'toxic' reactions occurred but were not simply related to melphalan levels.Our phase I study has allowed us to increase the dose of melphalan to 1.75 mg kg-', but we found no pharmacokinetic advantage from divided dose administration.The rationale for isolated limb perfusion (ILP) in the management of cancer depends on the generation of high levels of effective anticancer agent confined to the tumourbearing limb, thereby avoiding unacceptable systemic toxicity.It is clearly important to establish whether the complex and expensive technique of ILP genuinely achieves its major aim i.e. maximum levels of melphalan in the tumour-bearing limb and minimum systemic exposure.ILP is effective in the management of locally advanced malignant melanoma, and may be an effective adjuvant to surgery for thick, high risk primary lesions. Having reviewed our early experience of patients treated by ILP, it was confirmed that, because of the absence of melphalan-induced toxicity, there was scope for a phase I (dose escalating) clinical study.The study of pharmacokinetics is concerned with the absorption, distribution, biotransformation and excretion of drugs (Goodman et al., 1985). For a given dose these factors govern the concentration of drug at the site of action and they determine how the concentration varies with time.We have studied melphalan pharmacokinetics in the context of a phase I study of ILP.The aims of our studies were:(1) to measure melphalan concentrations in perfusate during ILP, and compare these with the levels in the systemic circulation during and after perfusion, (2) to study the pharmacokinetics of melphalan in ILP, as the dose was increased in a phase I study, (3) to compare the pharmacokinetics of bolus dose with divided dose administration.Patients, materials and methods Patient groupsOnly patients having external iliac perfusion for malignant melanoma were included in the study. The starting dose of melphalan was 1.5 mg kg' body weight, which is the maximum dose recommended in the protocols on which our t...

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