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
CORRESPONDENCE

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
<http://www.nejm.org/content/sargent/#ref-1-1> ) 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
<http://www.nejm.org/content/sargent/#ref-1-2> ) and a regimen of
oxaliplatin and irinotecan. ( 3
<http://www.nejm.org/content/sargent/#ref-1-3> ) 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 <http://www.nejm.org/content/sargent/figs.asp?section=T1> ). 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
<http://www.nejm.org/content/sargent/#ref-1-4> ) 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
<http://www.nejm.org/content/2000/0343/0013/0905.asp> .
Return to Text <http://www.nejm.org/content/sargent/#tref-1-1>
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.
Return to Text <http://www.nejm.org/content/sargent/#tref-1-2>
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.
Return to Text <http://www.nejm.org/content/sargent/#tref-1-3>
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.].
Return to Text <http://www.nejm.org/content/sargent/#tref-1-4>


Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.