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.