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6/19/2001

Researchers Urge Caution With Standard Regimen for Metastatic Colorectal Cancer

Kate Traynor

A three-drug regimen used as first-line treatment of metastatic colorectal cancer may be more dangerous for patients than was previously believed, say researchers.

Preliminary data from two studies involving over 2000 patients with metastatic colorectal cancer revealed an unexpectedly high number of deaths in the groups that received the Saltz1 irinotecan–fluorouracil–leucovorin regimen. Between 2.2% and 4.8% of these patients died within 60 days of starting therapy. In contrast, 1.8% of the study participants who received oxaliplatin–fluorouracil–leucovorin or irinotecan–oxaliplatin died during that period.

These figures include early deaths from all causes, including those not necessarily related to treatment, and there was some overlap in the 95% confidence intervals for the rates of death in the treatment groups. Still, the disproportionate number of early deaths associated with the Saltz regimen prompted the safety and review boards of the two multisite studies to recommend against the enrollment of new patients. Noting that the Saltz regimen has become the "standard of care" for metastatic colorectal cancer, the researchers communicated their findings to the editor of the New England Journal of Medicine (NEJM),2 who released the letter early on the journal’s Web site.

In place of the Saltz regimen, which consists of four once-weekly treatments of irinotecan, fluorouracil, and leucovorin repeated in six-week cycles, the researchers recommended a more complex course originally described by Douillard et al.3 The Douillard regimen, which is briefly described in Table 10 of the product labeling for irinotecan (Camptosar [PDF], Pharmacia; see "Regimen 2"), calls for irinotecan to be administered on days 1, 15, and 29 of a six-week course and for leucovorin and fluorouracil to be given on days 1 and 2, 15 and 16, and 29 and 30.

An overview of the Douillard study’s efficacy results appears in Table 2 of irinotecan’s labeling (study 2; study 1 describes the Saltz trial). Also in the irinotecan labeling is a table that seems to describe adverse events in the Douillard study, as reported to FDA (Table 7).

One of the two studies described in the NEJM letter enrolled patients who had advanced colorectal cancer. Deaths in this study were associated with dehydration, neutropenia, or sepsis. In the other study, which involved patients who had first undergone surgery, deaths were related to pulmonary embolism, sepsis, aspiration into the airway, and other causes.

Most of the fatal adverse events mentioned in the letter are also listed as potential complications of irinotecan treatment in the product’s current labeling.

  1. Saltz LB, Cox JV, Blanke C et al., for the Irinotecan Study Group. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000; 343:905-14.
  2. Sargent DJ, Niedzweicki D, O’Connell MJ et al. Recommendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer. N Engl J Med. In press.
  3. Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000; 355:1041-7.