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Adjuvant chemotherapy, combining oxaliplatin (Eloxatin) with 5-fluorouracil (5-FU; including regimens employing either continuous infusions or bolus schedules of 5-FU), lengthens disease-free and overall survival in patients with stage III colorectal cancer. Because combining irinotecan (Camptosar) with 5-FU plus leucovorin improves response rates and lengthens survival in patients with metastatic colorectal cancer, researchers evaluated whether irinotecan plus 5-FU is beneficial in the adjuvant setting after curative surgery for stage III node-positive disease.
In the CALGB 89803 trial, researchers compared conventional bolus 5-FU plus leucovorin with or without addition of irinotecan. After resection of stage III colon cancer, 1264 patients were assigned randomly to receive a conventional regimen (FL; weekly 5-FU [500 mg/m2] plus leucovorin [500 mg/m2], administered for 6 consecutive weeks followed by 2 weeks of rest, for 4 cycles) or an experimental regimen (IFL; weekly irinotecan [125 mg/m2] and 5-FU [500 mg/m2] plus leucovorin [20 mg/m2], administered for 4 consecutive weeks, followed by 2 weeks of rest, for 5 cycles). The primary endpoint was overall survival. The study design included early reporting of overall survival to allow for interim futility analyses.
Toxicity was significantly greater for IFL than for FL, including higher incidences of neutropenia and febrile neutropenia. The death rate was significantly higher during the 6 months of study therapy in the IFL arm than in the FL arm (2.8% vs. 1.0%; P=0.008). Therapy-related deaths during the study were caused largely by neutropenic sepsis or vascular thromboembolic events. The overall survival futility boundary was crossed at the fifth interim analysis. No differences were found at 3 years for IFL compared with FL in the probability of overall survival (0.80 and 0.81), disease-free survival (0.66 and 0.69), or relapse-free survival (0.68 and 0.71); similarly, no differences were seen in 5-year outcomes.
Saltz LB et al. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: Results of CALGB 89803. J Clin Oncol 2007 Aug 10; 25:3456.
Comment
The CALGB 89803 trial results are important and should influence treatment of colorectal cancer patients in both adjuvant and advanced-disease settings. Despite better response and survival rates for IFL among patients with metastatic colorectal cancer, IFL was no more effective than FL in the adjuvant setting. This negative result mirrored those in two earlier European adjuvant trials of irinotecan plus continuous-infusion 5-FU (termed FOLFIRI), which failed to lengthen disease-free survival after surgical resection: ACCORD and PETACC3. Based on the results of three negative trials, irinotecan should not be used in the adjuvant setting, because it adds no benefit when combined with either bolus or continuous-infusion 5-FU. The irinotecan data contrast with the response and survival benefits for the combination of 5-FU and oxaliplatin, which are seen in both advanced-disease and adjuvant settings — the current findings reinforce oxaliplatin plus 5-FU as the standard of care for adjuvant chemotherapy. Given the toxicity of IFL, including a high rate of toxic deaths, this regimen also should not be used as a therapy in patients with advanced disease; because of its superior toxicity profile, FOLFIRI is the preferred irinotecan-based regimen.