A randomised study of tailored toxicity-based dosage of fluorouracil-epirubicin-cyclophosphamide chemotherapy for early breast cancer (SBG 2000-1).

STUDY AIM: Retrospective studies have demonstrated a worse outcome in breast cancer patients not developing leukopenia during adjuvant chemotherapy. The SBG 2000-1 is the first randomised trial designed to compare individually dosed chemotherapy without G-CSF support based on grade of toxicity to standard-dosed chemotherapy based on body surface area (BSA). METHODS: Patients with early breast cancer were included and received the first cycle of standard FEC (fluorouracil 600 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2). Patients with nadir leukopenia grade 0-2 after first cycle were randomised between either 6 additional courses of tailored FEC with increased doses (E 75-90 mg/m2, C 900-1200 mg/m2) or fixed treatment with 6 standard FEC. Patients with grade 3-4 leukopenia were registered and treated with 6 standard FEC. Primary end-point was distant disease-free survival (DDFS). RESULTS: The study enrolled 1535 patients, of which 1052 patients were randomised to tailored FEC (N = 524) or standard FEC (N = 528), whereas 401 patients with leukopenia grade 3-4 continued standard FEC and formed the registered cohort. Dose escalation did not statistically significantly improve 10-year DDFS (79% and 77%, HR 0.87, CI 0.67-1.14, P = 0.32) or OS (82% and 78%, respectively, HR 0.89, CI 0.57-1.16, P = 0.38). Corresponding estimates for the registered group of patients were DDFS 79% and OS 82%, respectively. CONCLUSIONS: The SBG 2000-1 study failed to show a statistically significant improvement of escalated and tailored-dosed chemotherapy compared with standard BSA-based chemotherapy in patients with low haematological toxicity, although all efficacy parameters showed a numerical advantage for tailored treatment.

Cardiovascular and renal effects of the combination of felodipine and metoprolol during a high-salt and a moderate-salt diet in spontaneously hypertensive rats.

In the present study the influence of dietary salt on the cardiovascular and renal effects of the calcium channel blocker felodipine (1.2 mg/kg sc) and the beta 1-adrenoceptor blocking drug metoprolol (250 mg/kg po), alone and in combination, was examined in the spontaneously hypertensive rats (SHRs) in a 4-week study. In addition, the influence of different diet and drug regimens on vascular functions was assessed by measuring the vascular relaxation and contractile responses of mesenteric arterial rings in vitro at the end of the experimental period. In SHRs, a high-salt diet caused a marked rise in blood pressure, impaired the endothelium-dependent vascular relaxation responses to acetylcholine and induced left ventricular hypertrophy (LVH) and renal hypertrophy. Metoprolol had little if any effect on salt-induced changes in blood pressure, endothelium-dependent vascular relaxation or renal hypertrophy, but it partially prevented the development of salt-induced LVH. Felodipine during the high-salt diet lowered blood pressure to normotensive level and completely prevented salt-induced left ventricular and renal hypertrophy as well as endothelial dysfunction. Felodipine produced tachycardia, especially at the beginning of drug treatment. The combination of felodipine and metoprolol abolished the effects of the individual drugs on heart rate. The drug combination also completely prevented the detrimental cardiovascular and renal effects induced by a high salt intake. Although salt restriction did not further enhance the profound antihypertensive effect of the combination of metoprolol and felodipine, it enhanced the effects of the drug combination on LVH and renal hypertrophy. Our findings indicate that felodipine treatment, alone and in combination with metoprolol, normalizes blood pressure and prevents the development of salt-induced LVH and renal hypertrophy. During the high-salt diet the beneficial vascular effects of felodipine as well as those of the combination of felodipine and metoprolol are mediated, at least in part, by prevention of salt-induced endothelial dysfunction. The only apparent benefit from the use of metoprolol in combination with a relatively high dose of felodipine was the prevention of tachycardia.