Correspondence
Recommendation for Caution with Irinotecan, Fluorouracil, and Leucovorin for Colorectal Cancer
N Engl J Med 2001; 345:144-146July 12, 2001
- Article
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 leucovorin2 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 1Table 1
Number and Rate of Deaths from Any Cause within 60 Days after the Initiation of Treatment in Studies N9741 and C89803.). 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 reported 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.
4 ReferencesDaniel J. Sargent, Ph.D.
Mayo Clinic, Rochester, MN 55905Donna Niedzwiecki, Ph.D.
Duke University Medical Center, Durham, NC 27710Michael J. O'Connell, M.D.
Mayo Clinic, Rochester, MN 55905Richard L. Schilsky, M.D.
Cancer and Leukemia Group B, Chicago, IL 60604-11041
Saltz LB ,Cox JV ,Blanke C , et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000;343:905-914
Full Text | Web of Science | Medline2
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;18:2938-2947
Web of Science | Medline3
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;17:1751-1759
Web of Science | Medline4
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;355:1041-1047[Erratum, Lancet 2000;355:1372.]
CrossRef | Web of Science | Medline
To the Editor:
In their letter, Sargent et al. highlight the potential danger of combining bolus-therapy irinotecan and fluorouracil for the treatment of colon cancer. High rates of grade 3 (severe) or grade 4 (life-threatening) neutropenia and diarrhea in the study by Saltz et al. were the principal factors responsible. Infused fluorouracil is more commonly used in Europe, since the incidence of neutropenia and diarrhea is much lower with this approach than with bolus regimens of fluorouracil.1
We have exploited the potential synergy of combining irinotecan and infused fluorouracil in a simplified schedule given every two weeks that is similar to the schedule used by Douillard et al.2: irinotecan at a dose of 180 mg per square meter of body-surface area given over a period of 30 minutes was followed by an infusion of 175 mg of l-folinic acid (leucovorin) and an initial bolus of fluorouracil at a dose of 400 mg per square meter and then by a 46-hour infusion of fluorouracil at a dose of 2800 or 2400 mg per square meter.
The protocol was used as first-line or second-line therapy for metastatic colorectal cancer in a pilot study that has now been incorporated into two of the groups in an ongoing Medical Research Council randomized trial (CR08-FOCUS). Eighty-two patients received a median of 8 cycles (range, 1 to 12). Initially, the 46-hour infusion of fluorouracil was set at a dose of 2800 mg per square meter, but two deaths related to neutropenia and diarrhea occurred among the first four patients. Thereafter, the dose was reduced to 2400 mg per square meter, and there were no further life-threatening toxic effects, although there were five hospitalizations (three for neutropenia, one for diarrhea, and one for dehydration). The toxic effects among all patients are summarized in Table 1Table 1
Incidence of Grade 3 or 4 Adverse Effects..The ongoing trial has thus far accrued 475 patients (one third of whom have been assigned to receive this modified regimen). No deaths or other undue toxic effects have so far occurred. These results show again that irinotecan may be given safely with high doses of infused fluorouracil without compromising the density of the dose.
2 ReferencesJonathan A. Ledermann, M.D., F.R.C.P.
Pauline Leonard, M.B., M.R.C.P.
University College London, London W1W 7BS, United Kingdom
j.ledermann@ucl. ac. uk Matthew Seymour, M.D., F.R.C.P.
Cookridge Hospital, Leeds LS16 6QB, United Kingdom1
de Gramont A ,Bosset JF ,Milan C , et al. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer. J Clin Oncol 1997;15:808-815
Web of Science | Medline2
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;355:1041-1047[Erratum, Lancet 2000;355:1372.]
CrossRef | Web of Science | Medline
Author/Editor Response
Dr. Miller, one of the authors of the article by Saltz et al., replies:
To the Editor: Sargent et al. have reported their preliminary estimates of 60-day rates of death from any cause in two ongoing studies of the treatment of colorectal cancer with irinotecan, fluorouracil, and leucovorin. Although we share the authors' concern regarding these observations, we would caution that the underlying circumstances or causes of these deaths have not yet been thoroughly reviewed. We are working with Sargent et al. and with other involved parties to obtain the necessary information to permit a more complete understanding of these events. These analyses will help us to determine which underlying circumstances might have contributed to the deaths and which measures might be most effective in preventing such outcomes in the future.
We reported the data on deaths from all causes in the form of a Kaplan–Meier survival plot. As was the case with the investigator-reported rates of death from toxic effects, the rates of death from all causes at 60 days in our study did not differ significantly between the 225 patients in the group treated with irinotecan, fluorouracil, and leucovorin and the 219 patients in the group given fluorouracil and leucovorin (6.7 percent vs. 7.3 percent).
We concur with Sargent et al. that this regimen has been shown to provide an overall survival benefit for patients with metastatic colorectal cancer. We strongly support and endorse their recommendations that “vigilant monitoring of all patients who are receiving this combination of irinotecan, fluorouracil, and leucovorin is called for.” Careful selection of patients, monitoring of patients for toxic effects, and appropriate dose modifications have always been, and will continue to be, cornerstones of the safe and effective use of all chemotherapy regimens.
Langdon L. Miller, M.D.
Pharmacia, Peapack, NJ 07977- Citing Articles (64)
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Full Text64
Maxine D. Fisher, Leonard Saltz, Richard Goldberg, Richard Schilsky. (2001) Recommendation for Irinotecan, 5-Fluorouracil, and Leucovorin as First-Line Therapy for Colorectal Cancer. Clinical Colorectal Cancer 1:2, 82-84
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