Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high-dose folinic acid.

Abstract

We report the results of an expanded trial of 5-fluorouracil (5-FU) combined with high-dose folinic acid for treatment of patients with advanced colorectal or advanced gastric adenocarcinoma. In each treatment course, the patients received both 5-FU (340 to 400 mg/m2/d by intravenous (IV) infusion for a period of 15 minutes) and folinic acid (200 mg/m2/d by IV bolus) for 5 consecutive days, with a 21-day interval between courses. Eighty-six patients with colorectal carcinoma were evaluated. The combined complete and partial response rates were 39% for 54 patients who did not receive prior chemotherapy and 22% for 32 patients who had previously received chemotherapy. Four patients who were previously resistant to 5-FU attained objective responses. The median time to disease progression for the 28 responders was 10 months. The median survival time of responders was 19.5 months, and the probability of their being alive at 2 years was 40%. Of 27 patients with gastric adenocarcinoma, 13 (48%) responded to therapy. Their median time to disease progression was 5.5 months. The median survival time of responders was 11 months, and their probability of being alive at 15 months was 30%. Toxicity was within acceptable limits. Toxic effects included stomatitis, diarrhea, conjunctivitis, skin rash, and mild myeloid hypoplasia. In a separate study, plasma concentrations of L-folates greater than 10(-5) mol/L were achieved after a rapid single IV injection of 200 mg/m2 of folinic acid. Comparisons of our results with those reported in previous studies on 5-FU administered as a single agent suggest that, in advanced colorectal and gastric adenocarcinoma, folinic acid administered in high doses enhances the effectiveness of 5-FU administered concomitantly. Furthermore, some colorectal tumors that were previously resistant to 5-FU become sensitive to this drug. The survival of the patients who responded to therapy was markedly improved over that observed in reported series of untreated patients with advanced colorectal and gastric adenocarcinomas.

The establishment of a large collaborative trial programme in the adjuvant treatment of colon cancer

“…No clear trends were apparent in patients with Dukes' B2 disease. These results were confirmed in a later report after a median follow-up period of 6.5 years (Moertel et al, 1995 (Machover et al, 1986)] for 5 days every 28 days for six cycles. Of the 1493 evaluable patients, 736 were in the adjuvant treatment group and 757 were in the control (surgery only) group.…”

Adjuvant and neoadjuvant therapy for gastric cancer using epirubicin/cisplatin/5-fluorouracil (ECF) and alternative regimens before and after chemoradiation

“…This regimen was first reported in 1991, with the three drugs being selected on the basis of their single agent activity in upper GIT tumours (Beer et al, 1983;Cersosimo and Hong, 1986;Machover et al, 1986), and on the synergy demonstrated between 5-FU and cisplatin in preclinical models (Etienne et al, 1991). ECF is associated with response rates of approximately 45% in patients with metastatic gastric cancer, although higher response rates are seen when used for locally advanced disease (Findlay et al, 1994;Waters et al, 1999).…”

Mature results from three large controlled studies with raltitrexed ('Tomudex')

“…Although the optimal treatment regimen for these two drugs has not been unequivocally defined, the Mayo regimen of 5-FU and low-dose LV is widely regarded as an acceptable treatment and is the only regimen to have demonstrated a significant survival advantage over unmodulated 5-FU (Poon et al, 1989). However, other combination regimens, such as the Machover (5-FU with high-dose LV) regimen (Machover et al, 1986), or continuously infused 5-FU (Seifert et al, 1975;Lokich et al, 1989;de Gramont et al, 1995) are also used.…”