Careful Monitoring of Saltz Regimen is Advised

BOSTON—In a letter to the editors of the New England Journal of Medicine, researchers from two cooperative groups call for "vigilant monitoring" of patients receiving the combination of irinotecan (Camptosar), fluorouracil (5-FU), and leucovorin for metastatic colorectal cancer, due to an excess number of deaths observed in patients receiving this combination in two randomized NCI-sponsored trials. They added that specific clinical factors that increase the risk of adverse effects in patients receiving this regimen have not yet been identified.

The Journal released the letter on May 17, 2001, a month before its publication date of June 21, 2001, due to its "potential importance in the treatment of colorectal cancer."

Last year, Saltz et al reported the superiority of the irinotecan/5-FU/leucovorin combination over irinotecan alone or 5-FU/leucovorin in the initial treatment of metastatic colorectal cancer (N Engl J Med 343:905-914, 2000). The FDA subsequently approved the treatment, and many oncologists consider it the standard of care.

Now, researchers conducting North Central Cancer Treatment Group (NCCTG) trial N9741 and Cancer and Leukemia Group B (CALBG) trial C89803 report "an imbalance in the number of deaths occurring within 60 days after the initiation of treatment."

In N9741, which involves patients with advanced disease, there have been 14 deaths in the irinotecan/5-FU/leucovorin arm, compared with 5 each in the oxaliplatin/5-FU/leucovorin arm and the oxaliplatin/irinotecan arm. In the second study, a surgical adjuvant trial, there have been 14 deaths among patients receiving the Saltz combination vs 5 in patients taking 5-FU/leucovorin. The investigators report that on the basis of these data, the data and safety monitoring boards of both trials recommended that enrollments in the studies be suspended.

The letter’s authors—Daniel Sargent, PhD, and Michael O’Connell, MD, Mayo Clinic; Donna Niedzwiecki, PhD, Duke University; and Richard Schilsky, MD, Chicago—state that the Saltz regimen "should continue to be an option in this treatment setting, but in our experience has been associated with an excessive rate of early deaths." They suggest as an alternative the FDA-approved infusion schedule reported by Douillard et al (Lancet 355:372, 2000) and given in the irinotecan package insert.