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

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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%).