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5-Fluorouracil Toxicity
Old or New?
B. J. Kennedy,
Department of Medicine, University of Minnesota Medical School, Fairview-University Medical
Center, Minneapolis, Minnesota.
See referenced original article on pages 1129 –34,
this issue.
Address for reprints: B. J. Kennedy, M.D., Department of Medicine, Fairview-University Medical
Center, 240 Delaware Street SE, Box 286, Minneapolis, MN 55455.
Received July 1, 1999; accepted July 6, 1999.
© 1999 American Cancer Society
n this issue of Cancer, Fata et al. describe 5-fluorouracil (5-FU) and
leucovorin-induced small bowel toxicity manifested by extensive
ulceration and inflammation of the small bowel with no involvement
of the colon.1 It appears that history repeats itself, but often with a
new twist.
5-FU was developed in a basic science laboratory, intensively
studied biochemically, screened through animal tumors, and brought
forth for clinical evaluation in human tumors.2,3 It became apparent
that 5-FU was able to produce objective remissions in a variety of
malignant tumors. It was expected that 5-FU would be damaging to
any cells with a high replication rate and, consequently, would damage the mucosa of the small bowel along with the oral mucosa, hair
follicles, nails, etc. It would not be unexpected that a denudation of
small bowel mucosa might invoke both epithelial regeneration and
increased DNA synthesis and accompanying neovascular proliferation.
At a meeting of clinical investigators in 1958 at the National
Cancer Institute, the toxicity of the drug was deemed too great for
extensive human use, but a few investigators regarded it as potentially
useful. This exciting development of the antitumor activity of 5-FU
initiated the new era of cytotoxic cancer chemotherapy.
The clinical toxicity cited in early reports included stomatitis,
esophagopharyngitis, diarrhea, dermatologic changes, alopecia,
hematopoietic depression, fever, and death. Neurotoxicity and cardiotoxicity later were added. The mucosal changes involved the
entire gastrointestinal tract. A pseudomembranous enterocolitis
occurred with shredding of the intestinal mucosa.4 With severe
mucosal damage, adynamic ileus occurred. On recovery of function, shreds of sloughed mucosal tissue were passed in the feces
(Fig. 1).
The dose of 5-FU initially was adjusted to 15 mg/kg/day for 5 days
with a daily dose not to exceed 1 g. Subsequently, this dose was
reduced to 12 mg/kg/day with resulting tolerable toxicity. The doses
employed in the current study1 did not exceed the earlier modified
dose schedule. Leucovorin has been combined with 5-FU to increase
tumor cell sensitivity. Allergic reactions have been noted with leucovorin.
Does the current study represent a new phenomenon or simply
CANCER October 1, 1999 / Volume 86 / Number 7
toxicity. 5-FU has interfered notoriously with mucosal
cell growth. Dosage schedules have varied; even in the
late 1950s prolonged infusion of 5-FU produced less
The current article by Fata et al.1 represents a
reminder that 5-FU does cause gastrointestinal mucosal damage (directly or indirectly) and awareness of
this phenomenon and its complications by oncologists is necessary.
FIGURE 1. Appearance of the small bowel with complete sloughing of the
intestinal mucosa in a patient dying of 5-fluorouracil toxicity in 1958.
an early, limited manifestation of early reports of gastrointestinal toxicity? Has leucovorin modified the
gastrointestinal toxicity? Most likely, as the authors
state, the described phenomenon is multifactorial. Patients with partial or complete deficiency of pyrimidine catabolic enzymes are likely to develop severe
toxicity from 5-FU administration.5,6 Study of the activity of the enzymes might have predictive value for
Fata F, Ron IG, Kemeny N, O’Reilly E, Klimstra D, Kelsen DP.
5-fluorouracil-induced small bowel toxicity in patients with
colorectal carcinoma. Cancer 1999; 86:1129 –34.
Heidelberger C, Chaudhuri NK, Danneberg P, Mooren D, Greisback L, Duschinsky R, et al. Fluorinated pyrimidines, a new
class of tumor inhibitory compounds. Nature 1957;179:663– 6.
Curreri AR, Ansfield FJ, McIver FA, Waisman HA, Heidelberger C. Clinical studies with 5-fluorouracil. Cancer Res
1958;18:478 – 84.
Theologides A, Kennedy BJ. Toxic manifestations of 5-fluorouracil in advanced cancer. Clin Res 1959;7:395.
Tuchman M, Stoeckeler JS, Kiang DT, O’Dea RF, Ramnaraine ML, Mirkin BL. Familial pyrimidinemia and pyrimidurea
associated with severe fluorouracil toxicity. N Engl J Med
Diasio RB, Beavers TL, Carpenter JT. Familial deficiency of
dihydropyrimidine dehydrogenase. Biochemical basis for
familial pyrimidinemia and severe 5-fluorouracil-induced
toxicity. J Clin Invest 1988;81:47–51.
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