Irinotecan combined with fluorouracil and leucovorin compared with fluorouracil, leucovorin as first-line treatment for unreaectable, locally advanced and metastatic colorectal cancer

ABSTRACT

CPT-11 is a topoisomerase I inhibitor that prolongs survival in patients with CRC refractory to 5-FU and LV. This demonstrated activity of CPT-1 1 as effective second-line therapy for CRC led to evaluation of combination CPT-11/5-FU/Ly as first-line therapy for patients with locally advanced and metastatic disease. To evaluate the efficacy of CPT-11/5-FU/LV combination compared to 5-FU/Ly alone in the management of locally advanced and metastatic colorectal cancer. Patients were assigned to receive CPT-11 180 mg/rn2 as 60-minute IVI on day 1 followed by LV 200 mg/m2/day as a 2 hour IVI followed by 5-FU as an IV bolus at 400 mg/m2/day and then as 22 hour CI at 600 mg/m2/day, repeated on 2 consecutive days [30 patients] every 2 weeks, or 5-FU and LV at the same doses and administration as in the CPT-l I arm [32 patients]. End points included RR, PFS and Os. As compared with treatment with 5-FU/Ly, treatment with CPT-l 1/5-FU/Ly resulted in significantly a higher rate of response [43.4% vs 18.8%, P=0.03], longer PFS [median 8 vs 4.3 months; p0.02] and longer OS [median 17 vs 12 months, p=0.04]. Grade 3 [severe] diarrhea was more common during treatment with CPT-l 1/5-FU/Ly than during treatment with 5-FU/Ly. Grade 4 [life-threatening] diarrhea was infrequent in the two groups. Grade 3 or 4 mucositis were infrequent. Grade 4 neutropenia and neutropenic fever were more frequent during treatment with CPT-1 1/5-FU/Ly. Toxic effects were predictable, reversible, non-cumulative and manageable. The combination of CPT-1115-FU/Ly is superior to 5-FU/Ly alone as first-line therapy for patients with locally advanced and metastatic colorectal cancer, offering statistically significant better response rate, PFS and OS and a comparable toxicity