Combination chemotherapy with tauromustine (TCNU), 5-fluorouracil and leucovorin in advanced colorectal carcinoma: a...

In preparation for a phase II trial we performed a dose-finding study involving tauromustine (TCNU), fluorouracil (5-FU) and leucovorin (LV), applied in patients with colon cancer. To prevent TCNU/5-FU antagonism, a phenomenon recently demonstrated in vitro, special attention was paid to the sequencing of these agents.

In 25 patients with advanced colorectal carcinoma (13 M, 12 F, median age 51 yrs), four dose levels of TCNU (25, 30, 35 or 40 mg/m2) were investigated. The agent was administered orally once per week in weeks 1 through 4, in combination with fixed i.v. doses of 400 mg/m2 5-FU and 80 mg/m2 LV, once a week, weeks 1 through 8. Unless progression occurred, two 8-week cycles were applied. TCNU was administered at least 24 hours prior to 5-FU, because recent in vitro studies suggested that such an interval is required to obtain additive cytotoxicity.

All 25 patients were evaluable for toxicity; 23 patients received at least one full 8-week course, and 13 were eligible for second cycles. Significant haematologic toxicity, predominantly thrombocytopenia WHO grade 3 or 4, was mainly encountered at the 35 and 40 mg/m2 dose levels. Although occasionally severe, myelosuppression did not result in toxic deaths; spontaneous haemorrhage was never observed, and platelet transfusions were not required. Additional toxicity, also related to the two higher dose levels, consisted of diarrhea (WHO grade 3) and the 'hand and foot syndrome', both occurring in a single patient; two patients developed fever of undetermined origin, but only one of them required hospitalization and antibiotic treatment. The overall response rate was 20% (7 partial responses in 25 evaluable patients).

For phase II studies, we recommend a weekly oral dose of 40 mg/m2 TCNU, weeks 1 through 4, in combination with 400 mg/m2 5-FU and 80 mg/m2 LV (IV), once a week, weeks 1 through 8.