Controlled Phase III Clinical Study of 4-Epi-Doxorubicin + 5-Fluorouracil versus 5-Fluorouracil Alone in Metastatic Gastric and Rectosigmoid Cancer

Abstract

The combination of 4-epi doxorubicin (4-epi-DX) and 5-fluorouracil (5-FU) versus 5-FU alone was studied in previously untreated patients with metastatic gastric and rectosigmoid cancer. 5-FU alone was administered at the dose of 12mg/kg/day i.v. on days 1, 2, 3, 4 and 5 every 3–4 weeks. The combination regimen included 4-epi-DX 40 mg/m²/day i.v., on days 1 and 2 (80 mg/m²/cycle) and 5-FU administered as in the single-agent schedule, but at a somewhat lower dose (10 mg/m²/day i.v. on days 1, 2, 3, 4 and 5). Sixty-two patients with gastric cancer were evaluable, 30 in the 5-FU group and 32 in 4-epi-DX + 5-FU group. The results showed 6 partial remissions out of 30 patients treated with 5-FU alone (response rate 20%) with a median remission duration of 4 months. With 4-epi-DX + 5FU the response rate was 41% (13/32) with 1 complete and 12 partial remissions. The median remission duration was 8 months. The difference in treatment results was statistically significant (p <0.05). In rectosigmoid cancer the group on 5-FU included 26 patients who showed a response rate of 19% (5/26). 4-epi-DX + 5-FU resulted in 6 responses (2 complete remissions, 4 partial remissions) out of 27 patients treated (22%). Median remission duration in the 5-FU group was 3 months whereas it was 6 months in the 4-epi-DX + 5-FU group. Toxicity was mild and well tolerated in both treatment modalities. The results of the study in gastric cancer showed a clear-cut superiority of 4-epi-DX + 5-FU over 5-FU alone, while no difference in response rate was observed between the two approaches in rectosigmoid cancer. Nevertheless, rectal localization of primary tumors showed a slightly better response to 4-epi-DX + 5-FU (33 vs. 16%).

Current Status of Epirubicin (Farmorubicin) in the Treatment of Solid Tumours

“…A randomized study comparing single agent 5-fluorouracil and 5-fluorouracil in combination with epirubicin in colorectal cancer has been carried out at haematologic equitoxicity (205). Similar response rates were observed with single agent and combination chemotherapy ( 19 and 22%).…”

“…One randomized study has compared the effect of single agent 5-fluorouracil with the combination of 5-fluorouracil and epirubicin (205). The haematologic toxicity was mild in both regimens.…”

Epirubicin in Advanced Gastrointestinal (GI) Cancer

“…In rectosigmoid cancer epirubicin combined with 5-FU has been compared in a randomized way with 5-FU alone in a total of 53 patients. Response rates were 22% and 19%, respectively, and for patients with rectal localization 33% and 16% [14],…”

“…In this study that included 62 evaluable patients epi rubicin was given in a dose of 40 mg/m2, day 1 and 2. The median duration of remission was 8 months in the combination group [14]-Used in combination with 5-FU and mitomycin-C, epi rubicin was given in two different schedules. In the first sched ule the dose was 50 mg/m2, day 2, every 3 weeks (FEM-2), and in the second 40mg/m2, day 1, every 4 weeks (FEM-5).…”

Dose Escalation and Split Course of 4-Epidoxorubicin in Combination Chemotherapy (FEM II) of Advanced Gastric Carcinoma

“…In several phase II studies of 4-epidoxorubicin at single doses of 40-75 mg/m2, given every 3 weeks, response rates of 27% [1], 16% [2], 17% [3], 13% [4] and 22% [5] were reported for gastric carcinoma. This com pound was first introduced into combination chemotherapy of gastric carcinoma by Kolaric et al [6], who compared the combination of 4-epidoxorubicin + 5-fluorouracil with 5-fluorouracil alone, suggesting a response rate of 41% vs. 20% in favor of the combination. In our previous study published in this journal [7] we sub stituted within the classical FAM schedule adriamycin with 4-epidoxorubicin using a dose of 45 mg/m2 at day 1 and 29 instead of adriamycin at 30 mg/m2 (FEM).…”