Toxicity of 5-Fluorouracil
John S. Macdonald, MD
Professor of Medicine, and Chief, Gastrointestinal Oncology
Service, St. Vincents Comprehensive Cancer Center, New York, New York
July 1, 1999
Fluorouracil (5-FU) is a relatively unique drug in oncology
because administration in different doses and schedules results in
dramatically different patterns of qualitative toxicity. In the 41
years 5-FU has been available to the clinical oncologist, a wide
variety of doses and schedules of this agent have been used.
Infusional schedules are associated with less myelosuppression but
may have more gastrointestinal and skin toxicity. Bolus schedules
cause myelotoxicity, and bolus schedules including calcium folinate
are associated with diarrhea, mucositis, and, in some schedules,
myelosuppression. The availability of various doses and schedules of
5-FU for administration allows clinicians to choose a 5-FU regimen
with the most acceptable pattern of toxicity for individual cases.
Also, the study of 5-FU in various groups of patients has
demonstrated that relatively increased drug toxicity may be expected
in patients above the age of 70 years and in female patients.
[ONCOLOGY 7(Suppl 3): 33-35, 1999]
Fluorouracil(Drug information on fluorouracil) (5-FU) is a remarkable drug that has been available for
41 years and has become the mainstay of chemotherapy for
gastrointestinal cancer.[1-7] It is one of a minority of drugs in
clinical medicine for which the qualitative spectrum of toxicity
changes dramatically when the drug is used in different doses and
schedules (Table 1). These
different methods of administration have been demonstrated to produce
significantly different toxicity patterns, particularly when bolus
schedules are compared to infusional schedules. For example, bolus
single-agent 5-FU given weeklywhich was, in the past, the
standard schedule and route of administration for this drug in
gastrointestinal canceris associated with myelosuppression as
its major toxicity, with mucositis and diarrhea being minor
toxicities. The major toxic event caused by 5-FU administered by
96-hour high-dose infusion is mucositis. Low-dose (250 to 300
mg/m²/d) continuous infusion of 5-FU is associated with little
myelosuppression but results in an unusual toxicity: palmar-plantar
dysesthesia, more commonly known as hand-foot syndrome. Finally, the
commonly used 5-FU/calcium folinate regimens, depending on the doses
and schedules, may produce the combination of mucositis, diarrhea,
and myelosuppression or, in weekly high-dose regimens, diarrhea as
the only significant toxicity.
Toxicity of 5-fluorouracil may also vary with the characteristics of
the patient. For example, in a large adjuvant colon cancer study, it
has been demonstrated that older patients (> 70 years) are more
likely to experience mucositis and myelosuppression from 5-FU/calcium
folinate regimens (Table 2).
It is also possible that the relatively rare neurotoxicity is more
common in older patients receiving 5-FU. Gender is another risk
factor for 5-FU toxicity. Female patients have a statistically higher
incidence of all 5-FU toxicities(Table
3). The latter finding may be associated with some degree of
decreased 5-FU catabolism in women. Fluorouracil toxicity may be
exacerbated by drugs that inhibit the major enzyme responsible for
5-FU metabolismdihydropyrimidine dehydrogenasesuch as the
irreversible inactivator 776C85 and the nucleic acid uracil.
Uracil acts as a competitive inhibitor of dihydropyrimidine
dehydrogenase and does not irreversibly inactivate the enzyme.
Strategies to treat or prevent 5-FUrelated toxicities include
general supportive measures and specific strategies, such as
prevention of mucositis by the use of oral ice chips, and treatment
of severe 5-FUrelated diarrhea with the somatostatin(Drug information on somatostatin) analog octreotide(Drug information on octreotide) (Sandostatin).
1. Petrelli N, Herrera L, Rustum Y, et al: A prospective randomized
trial of 5-fluorouracil vs 5-fluorouracil and high-dose leucovorin vs
5-fluorouracil and methotrexate in previously untreated patients with
advanced colorectal carcinoma. J Clin Oncol 5:1559-1565, 1987.
2. Blanke C, Kasimis B, Schein P, et al: Phase II study of
trimetrexate, fluorouracil, and leucovorin for advanced colorectal
cancer. J Clin Oncol 15:915-920, 1997.
3. Wadler S, Schwartz L, Goldman M, et al: Fluorouracil and
recombinant alfa-2a-interferon: An active regimen against advanced
colorectal carcinoma. J Clin Oncol 7:1769-1775, 1989.
4. Poon M, OConnell M, Wieand H, et al: Biochemical modulation
of fluorouracil with leucovorin: Confirmatory evidence of improved
therapeutic efficacy in advanced colorectal cancer. J Clin Oncol
5. Lokich J, Ahlgren J, Gullo J, et al: A prospective randomized
comparison of continuous infusion fluorouracil with a conventional
bolus schedule in metastatic colorectal carcinoma: A Mid-Atlantic
Oncology Program study. J Clin Oncol 7:425-432, 1989.
6. Leichman C, Fleming T, Muggia F, et al: Phase II study of
fluorouracil and its modulation in advanced colorectal cancer: A
Southwest Oncology Group study. J Clin Oncol 13:1303-1311, 1995.
7. Hansen R, Ryan L, Anderson T, et al: Phase III study of bolus vs
infusion fluorouracil with or without cisplatin in advanced
colorectal cancer. J Natl Cancer Inst 88:668-674, 1996.
8. The Meta-Analysis Group in Cancer: Toxicity of fluorouracil in
patients with advanced colorectal cancer: Effect of administration
schedule and prognostic factors. J Clin Oncol 16:3537-3541, 1998.
9. Hodi FS, Catalano P, Macdonald JS, et al: Age as a factor
influencing the toxicity of adjuvant chemotherapy for colorectal
cancer. Abstract presented at 2nd International Conference on
Gastrointestinal Oncology, Cologne, Germany, 1994.
10. Baker S, Khor S, Adjei A, et al: Pharmacokinetic, oral
bioavailability, and safety study of fluorouracil in patients treated
with 776C85, an inactivator of dihydropyrimidine dehydrogenase. J
Clin Oncol 14:3085-3096, 1996.
11. Pazdur R, Lassere Y, Diaz-Canton E, et al: Phase I trial of
uracil-tegafur (UFT) plus oral leucovorin: 28 day schedule. Cancer
Invest 16:145-151, 1998.