C.-H. Köhne

5 Fluorouracil (5FU) is a rationally designed antineoplastic agent (1,2) with distinct antifolate and antipyrimidine properties. 5FU is usually given in combination with other agents for the treatment of various types of cancer (3–11) such as cancers of the gas-trointestinal tract, breast cancer, and head and neck cancer. For combinations of leucov-orin (LV) and 5FU objective response rates between 20 and 40% have been achieved in randomized trials in patients with colorectal cancer, which means that more than 60% of the tumors are still resistant and will thereafter develop resistance. This resistance can be multifactorial (Table 1), and related to either the antipyrimidine or the antifolate prop-erties of the drug. This also implies that many patients have an intrinsic resistance to 5FU, and since almost all patients will show a relapse, this means that in the remaining tumors acquired resistance will occur. Unfortunately the mechanism of modulation-re-sistance has hardly been addressed in most of these studies.

BACKGROUND: To evaluate the therapeutic activity of 24-hour continuously infused 5-fluorouracil (5-FU) modulated by high-dose folinic acid in patients with metastatic colorectal cancer who had recurred or progressed following mainly bolus 5-FU/folinic acid chemotherapy. PATIENTS AND METHODS: Forty-two patients with a median age of 59 years (45-76) were enrolled. Karnofsky status was 90% (80-100), previous chemotherapy regimen bolus 5-FU/folinic acid (n=33, 79%) or 24-hour continuous 5-FU+/-interferon alpha2 (n=9, 21 %). Chemotherapy was given as a weekly infusion of 500 mg/m2 folinic acid over 2 h followed by a 24-hour continuous infusion of 2,600 mg/m2 5-FU for 6 consecutive weeks followed by a 2-week rest period. RESULTS: No complete but 6 partial responses were observed (ORR: 14%, CI95%: 3.5-25.1%) with a median response duration of 7.3 months (range: 1.4-10.6). The median survival from the start of continuous infusion of 5-FU was 11.6 months (range: 2-27, CI95%: 9.4-13.8) and the 1-year survival rate was 46%. Disease stabilization and minor responses were achieved in another 25 patients (61%). WHO grade III/IV diarrhea occurred in 26% of patients, mucositis, nausea/vomiting and hand-foot syndrome in 5% each. Two cases of WHO grade III anemia and leukocytopenia were observed (5% each). Dose reductions had to be performed in 11 patients because of unacceptable diarrhea with subsequent stop of treatment in 2 patients. Progressive disease while receiving previous bolus 5-FU chemotherapy was associated with a lower response rate, shorter progression-free interval and overall survival compared to response and survival of patients who had achieved temporary disease stabilization during previous bolus 5-FU therapy. CONCLUSIONS: Continuous infusion of 5-FU/folinic acid displays activity in pretreated and refractory colorectal cancer with acceptable toxicity. Patients who had achieved disease stabilization or objective remission with previous 5-FU bolus therapy appear to be more likely to benefit from second-line treatment. Questions remaining to be addressed include the optimal starting dose of continuously infused 5-FU and whether the dose of folinic acid can be reduced or completely eliminated with respect to toxicity and health economics.