Topics:

Toxicity of 5-Fluorouracil

Toxicity of 5-Fluorouracil

ABSTRACT: 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]


Introduction

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.[8] For example, bolus single-agent 5-FU given weekly—which was, in the past, the standard schedule and route of administration for this drug in gastrointestinal cancer—is 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).[9] 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).[9] 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 metabolism—dihydropyrimidine dehydrogenase—such as the irreversible inactivator 776C85[10] and the nucleic acid uracil.[11] Uracil acts as a competitive inhibitor of dihydropyrimidine dehydrogenase and does not irreversibly inactivate the enzyme. Strategies to treat or prevent 5-FU–related 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-FU–related diarrhea with the somatostatin analog octreotide (Sandostatin).

References

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, O’Connell M, Wieand H, et al: Biochemical modulation of fluorouracil with leucovorin: Confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol 9:1967-1972, 1991.

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.

 
Loading comments...

By clicking Accept, you agree to become a member of the UBM Medica Community.