1099 E D I T O R I A L 5-Fluorouracil Toxicity Old or New? B. J. Kennedy, M.D. Department of Medicine, University of Minnesota Medical School, Fairview-University Medical Center, Minneapolis, Minnesota. I 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 1100 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 toxicity. 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. REFERENCES 1. 2. 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 3. 4. 5. 6. 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 1985;313:245–9. 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.