Notice: Because of its
potential importance in the treatment of colorectal cancer, this letter to the
editor is being released before its publication date. The final version of the
letter will be published on June 21. (Notice posted May 17, 2001.)
The New England Journal
of Medicine
Recommendation for Caution with Irinotecan,
Fluorouracil, and Leucovorin for Colorectal Cancer
To the Editor:
In the September 28 issue of the Journal,
Saltz et al. (1)
reported the superiority of the chemotherapy combination of irinotecan,
fluorouracil, and leucovorin over irinotecan alone or fluorouracil and
leucovorin in the initial treatment of metastatic colorectal cancer. The
results of this large clinical trial indicated that the three-drug combination
was tolerable and not associated with a significantly increased incidence of
toxicity as compared with the other two forms of treatment. The incidence of
treatment-related death was approximately 1 percent during the study. The Food
and Drug Administration (FDA) has approved this regimen of irinotecan,
fluorouracil, and leucovorin for the initial treatment of metastatic colorectal
cancer, and many oncologists have now adopted it as the standard of care. We
are writing to report an unexpectedly high rate of death associated with the
use of the identical drug combination in two separate cooperative-group
clinical trials sponsored by the National Cancer Institute.
Trial N9741 is being conducted in the
setting of metastatic colon cancer. In this trial, the regimen of irinotecan, fluorouracil,
and leucovorin described by Saltz et al. is being compared with a regimen of
oxaliplatin, fluorouracil, and leucovorin (2) and a regimen of
oxaliplatin and irinotecan. (3) Trial C89803, an
adjuvant study involving patients with resected stage III colon cancer, is
comparing fluorouracil and leucovorin with the irinotecan, fluorouracil, and
leucovorin regimen. Both trials are being conducted throughout the United
States and Canada.
An analysis of the current data from each
study reveals an imbalance in the number of deaths occurring within 60 days
after the initiation of treatment (Table 1). In
the study of patients with advanced disease (N9741), 12 of the 14 deaths in the
group assigned to the regimen of irinotecan, fluorouracil, and leucovorin had
several characteristics in common: dehydration (resulting from diarrhea,
nausea, and vomiting), neutropenia, and sepsis (alone or in combination with
shock), leading to death. Thirteen of the 14 deaths occurred during the first
six-week cycle of chemotherapy or immediately afterward. In the surgical adjuvant
study (C89803), the reported causes of 14 deaths in the group assigned to
receive irinotecan, fluorouracil, and leucovorin included pulmonary emboli (in
3 patients); sepsis (in 3); aspiration (in 3); myocardial infarction (in 1);
dehydration and neutropenia (in 1); a cerebrovascular accident (in 1); bowel
ischemia, infarct, or both (in 1); and unknown (in 1).
On the basis of these data, the respective
independent data and safety monitoring boards of the North Central Cancer
Treatment Group and Cancer and Leukemia Group B recommended suspension of
enrollment in trials N9741 and C89803. In each trial, dose modifications were
made in an attempt to ameliorate the toxic effects of this regimen. Vigilant
monitoring of all patients who are receiving this combination of irinotecan,
fluorouracil, and leucovorin is called for because specific clinical factors
that increase the risk of adverse effects have not yet been identified.
The regimen used by Saltz et al. has been
shown to improve survival in patients with advanced colorectal cancer, and
combination therapy with irinotecan, fluorouracil, and leucovorin should
continue to be an option in this treatment setting, but in our experience has
been associated with an excessive rate of early deaths. An alternative is the
FDA-approved infusional schedule reported by Douillard et al. (4) and described in the
irinotecan package insert.
Daniel J. Sargent, Ph.D.
Mayo Clinic
Rochester, MN 55905
Donna Niedzwiecki, Ph.D.
Duke University Medical Center
Durham, NC 27710
Michael J. O'Connell, M.D.
Mayo Clinic
Rochester, MN 55905
Richard L. Schilsky, M.D.
208 S. LaSalle St., Suite 2000
Chicago, IL 60604-1104
References
1. Saltz LB, Cox JV, Blanke C, et al.
Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med
2000;343:905-14.
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2. de Gramont A, Figer A, Seymour M, et
al. Leucovorin and fluorouracil with or without oxaliplatin as first-line
treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938-47.
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3. Wasserman E, Cuvier C, Lokiec F, et al.
Combination of oxaliplatin plus irinotecan in patients with gastrointestinal
tumors: results of two independent phase I studies with pharmacokinetics. J
Clin Oncol 1999;17:1751-9.
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4. 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. [Erratum, Lancet 2000;355:1372.].
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Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.