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This non-randomized study reports pharmaco-clinical data on 5-FU administered by the widely used 5-day continuous infusion schedule to 42 patients with metastatic colorectal cancer; 5-FU was given by hepatic intra-arterial route (h.i.a.) at doses ranging from 800 to 1,450 mg/m2, and by a systemic intravenous route (i.v.) at doses ranging from 650 to 1,300 mg/m2. 5-FU blood levels were available for a total of 179 cycles. Toxicity was dose-dependent during h.i.a. cycles but not during i.v. cycles. For h.i.a. cycles, 1,000 mg/m2/day represented the threshold dose for tolerance. The individual total cycle drug concentration-time product might predict toxicity for both i.v. and h.i.a. cycle when the threshold is set at 30,000 ng/ml.hr. These data may be of practical value for improving the therapeutic index of 5-day continuous treatment by 5-FU given by i.v. or h.i.a. routes.

SummaryThe long-term prognostic value of tumoural MDR1 and MRP, along with p53 and other classical parameters, was analysed on 85 node-positive breast cancer patients receiving anthracycline-based adjuvant therapy. All patients underwent tumour resection plus irradiation and adjuvant chemotherapy (the majority receiving fluorouracil-epirubicin-cyclophosphamide). Median follow-up for the 54 alive patients was 7.8 years. Mean age was 53.7 years (range 28-79) and 54 patients were post-menopausal. MDR1 and MRP expression were quantified according to an original reverse transcription polymerase chain reaction multiplex assay with colourimetric enzyme-linked immunosorbent assay detection (β2-microglobulin as control). P53 protein was analysed using an immunoluminometric assay (Sangtec). MDR1 expression varied within an 11-fold range (mean 94, median 83), MRP within a 45-fold range (mean 315, median 242) and p53 protein from the limit of detection (0.002 ng mg ). P53 protein was significantly higher in oestrogen receptor (ER)-negative than in ER-positive tumours (P = 0.039). The higher the p53, the lower the MDR1 expression (P = 0.015, r = -0.27). P53 was not linked to progesterone receptor (PR) status, S phase fraction, or MRP. Significantly greater MDR1 expression was observed in grade I tumours (P = 0.029). No relationship was observed between MDR1 and MRP. Neither MDR1 nor MRP was linked to ER or PR status. Unlike MDR1, MRP was correlated with the S phase: the greater the MRP, the lower the S phase (P = 0.006, r = -0.42). Univariate Cox analyses revealed that MDR1, MRP, p53 and S phase had no significant influence on progression-free or specific survival. A tendency suggested that the greater the p53, the shorter the progression-free survival (P = 0.076 as continuous and 0.069 as dichotomous).

Our trial demonstrates pemetrexed to be active in breast cancer, with manageable toxicity. Activity of pemetrexed did not appear to be adversely affected by prior taxane, 5-fluorouracil or endocrine treatments.