Comparative pharmacokinetic analysis of 5-fluorouracil and its major metabolite 5-fluoro-5,6-dihydrouracil after conventional and reduced test dose in cancer patients.

The aim of this study was to investigate the clinical pharmacokinetics of 5-fluorouracil (5-FU) and its major metabolite 5-fluoro-5,6-dihydrouracil (5-FDHU) in 20 colorectal cancer patients given two dose levels of 5-FU, 250 and 370 mg/m2, administered by i.v. bolus. A reverse-phase high-performance liquid chromatographic method was used for the simultaneous assay of 5-FU and 5-FDHU in plasma samples obtained at baseline and at multiple time points from 5 min to 4 h after 5-FU bolus as well as to assess the activity of dihydropyrimidine dehydrogenase (DPD) in peripheral blood mononuclear cells (PBMCs) before 5-FU dosing. Plasma pharmacokinetic parameters of patients given 250 mg/m2 5-FU were significantly different from those receiving 370 mg/m2; main differences were observed in the trapezoidal areas under the plasma levels-versus-time curve from to to the last measurable concentration (area under the curve, 3.77+/-0.21 versus 13.61+/-2.3 h x microg/ml), peak plasma concentration (Cmax, 18.15+/-1.35 versus 48.41+/-7.69 microg/ml), and total body clearance (CL(TB), 54.64+/-3.54 versus 25.43+/-2.3 l/h/m2). Significant differences were also observed in the main pharmacokinetic parameters of 5-FDHU after 250 and 370 mg/m2 5-FU including the area under the curve from to to 4 h (5.39+/-0.32 versus 8.75+/-1.24 h x microg/ml), Cmax (3.60+/-0.16 versus 5.26+/-0.55 microg/ml) and time to Cmax (Tmax, 0.45+/-0.03 versus 0.69+/-0.06 h). The mean DPD activity in PBMCs in this group of patients was 205.7+/-36.4 pmol of 5-FDHU/min/mg of protein and was within the normal range; however, no significant correlations were found between 5-FU or 5-FDHU pharmacokinetic parameters at two dose levels and DPD activity of PBMCs. The results of the present study provide the first detailed comparison of the distribution of 5-FU and its major metabolite 5-FDHU at the therapeutic level as well as at reduced test dose levels to obtain pharmacokinetic data to be used as reference values for the identification of patients at risk of major 5-FU toxicity due to impaired metabolism to 5-FDHU.

FEC (5-fluorouracil, epidoxorubicin and cyclophosphamide) versus EM (epidoxorubicin and mitomycin-C) with or without lonidamine as first-line treatment for advanced breast cancer. A multicentric randomised study. Final results.

From May 1991 to December 1996, 326 patients with advanced metastatic breast cancer were enrolled in a multicentre, randomised, phase III clinical trial with four arms. Patients were randomised to receive chemotherapy according to the FEC regimen (5-fluorouracil (5-FU) 500 mg/m2, epidoxorubicin (EPI) 75 mg/m2 and cyclophosphamide (CFA) 500 mg/m2, intravenously (i.v.). every 3 weeks) or the EM regimen (EPI 75 mg/m2, i.v. every 3 weeks; mitomycin C (MMC) 10 mg/m2, i.v. every 6 weeks) or the same regimens with the addition of lonidamine (LND) until disease progression (orally, thrice daily, 150+150+300 mg); a maximum of eight chemotherapy cycles were planned. The aim of the trial was 2-fold: to compare the EM regimen with the commonly used FEC regimen and to evaluate the possible role of the addition of LND. Patients were eligible if they had histologically proven breast carcinoma, metastatic or locoregional relapse with measurable and/or evaluable disease and were aged between 18 and 70 years: 318 patients were considered eligible. Patients with previous anthracycline-based adjuvant chemotherapy or those who relapsed within 6 months after any adjuvant chemotherapy regimen were excluded. Chemotherapy-related toxicity of grade > or = 3 was manageable and there was no significant difference between the arms in terms of haematological side-effects. The impact on heart function was mild. No increased toxicity was observed in the LND arms (apart from myalgias in 27-30% of the cases). A significant increase in the complete response rate was observed for the FEC/EM + LND group (20.4%) versus the FEC/EM group (10.8%). The median survival time and the median time to progression for the overall series were 608 days and 273 days, respectively; EM+/-LND achieved significantly improved survival and time to progression versus FEC+/-LND (P=0.01). This result was confirmed also when the analysis was restricted to patients previously treated with adjuvant CMF schedules. On the basis of these results, we conclude that EM may represent a valuable alternative to FEC for patients requiring a first-line regimen for advanced/ metastatic breast carcinoma, especially in patients previously treated with CMF in an adjuvant setting. Furthermore, we conclude that, in spite of a better complete response rate in the LND arms, as there was no clear advantage in time to progression or survival resulting from the addition of LND to the FEC or EM regimens, the routine use of LND is not warranted outside a clinical trial.

Patients' opinions, feelings, and attitudes after a campaign to promote the Di Bella therapy.

BACKGROUND: An emotional campaign promoting the Di Bella cancer therapy was launched by the Italian media in 1997. Its effects on patients' hopes, feelings, and decision-making processes were largely unknown. We undertook an investigation of this issue. METHODS: Between Feb 25 and March 31, 1998, a ten-item questionnaire was distributed to 1300 unselected adult patients attending 13 cancer centres throughout Italy. Four expert psycho-oncologists reviewed the design and validity of the contents of the questionnaire. Sociodemographic information was also collected. FINDINGS: 1120 (86%) questionnaires were returned and analysed. The main sources of information were television/radio (62%) and newspapers (26%); only 5% cited doctors. The campaign induced optimism in the patients about the efficacy of the method (ineffective 1%, effective 42%, uncertain 57%), and 53% said their hope of cure was increased. However, 48% felt more confused. 24% do not discuss new treatments with their oncologists, and 20% would like to but cannot. When choosing a treatment, the advice of a trusted doctor was judged more important than scientific progress (53% vs 32%) and 63% would try even unproven treatments in the hope of a cure. Replies to many of the questions were influenced by patients' educational attainment and by the degree of communication with their oncologists. INTERPRETATION: Science cannot prevent the harm caused by such campaigns and their psychological consequences, particularly for less educated patients. When making decisions, patients are looking for hope from the treatment and trust in their doctor, both of which depend on effective doctor-patient communications that therefore need to be improved.