5-fluorouracil modulated by leucovorin, methotrexate and mitomycin: highlyeffective, low cost chemotherapy for advanced colorectal cancer

We have reported that an alternating regimen of bolus and continuous infusi on 5-fluorouracil (FU) was superior to bolus FU in terms of response rate a nd progression-free survival in advanced colorectal cancer. Biochemical mod ulation was an essential part of this regimen and it was selective for the schedule of FU administration: bolus FU was in fact modulated by methotrexa te (MTX) while continuous infusion FU was potentiated by 6-s-leucovorin (LV ). Considering the low cost and the favourable report on the activity of mi tomycin C (mito) added to CI FU, we have incorporated this agent in the inf usional part of our treatment programme. 105 patients with untreated, advan ced, measurable colorectal cancer were accrued from 13 Italian centres and treated with the following regimen. 2 biweekly cycles of FU bolus (600 mg/m (2)), modulated by MTX (24 h earlier, 200 mg/m(2)) were alternated with a 3 -week continuous infusion of FU (200 mg/m(2) daily), modulated by LV (20 mg /m(2) weekly bolus). Mito, 7 mg/m(2), was given on the first day of the inf usional period. After a 1 week rest, the whole cycle (8 weeks) was repeated , if indicated. 5 complete and 34 partial responses were obtained (response rate, 37% on the intention to treat basis; 95% confidence limits, 28-46%). After a median follow-up time of 26 months, 37 patients are still alive. T he median progression-free survival is 7.7 months with an overall survival of 18.8 months and a 2-year survival rate of 30%. The regimen was very well tolerated with fewer than 13% of patients experiencing WHO grade III-IV to xicity. These results are consistent with those obtained by our group in 3 previous trials of schedule specific biochemical modulation of FU. They als o indicate a highly active, little toxic, inexpensive regimen of old drugs to be used (a) as an alternative to the more expensive combinations includi ng CPT-11 or oxaliplatin or (b) as the basis for combination programmes wit h these agents. (C) 2001 Cancer Research Campaign.