Is continuous 24-hour infusion of 5-fluorouracil plus high-dose folinic acid effective in patients with progressive or recurrent colorectal cancer? A phase II study.

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.