5‐Fluorouracil–induced small bowel toxicity in patients with colorectal carcinoma

Abstract

The report by Fata et al.1 and the historical commentary by Kennedy2 document the well-known toxicity associated with fluoropyrimidine therapy, a diarrheal syndrome that may be life-threatening and can lead to death. Fata et al. indicate that the anatomic lesions in the cases reported were located in the small intestine, implying that this is not the usual site of the injury and that the mechanism of 5-fluorouracil (5-FU)–induced injury is related to vasospasm. With regard to the anatomic localization of a lesion in the small intestine, it is likely that this is, in fact, the most common site of 5-FU–induced intestinal ulceration and secondary diarrhea. Tritiated thymidine studies of the intestinal tract indicate that the proliferative activity of the cells in the small intestine is higher than in the large intestine and the movement of the crypt cells to the tip of the villus occurs over a shorter time interval for the small versus the large intestine. Therefore, the glandular cells of the small intestine would at least conceptually be more sensitive to the cell cycle specific action of the fluoropyrimidine antimetabolites. Furthermore, a 5-FU–induced lesion in the large intestine has not been specifically described in the literature, although Kennedy refers to a “pseudomembranous enterocolitis” from a 1959 report and suggests that the entire gastrointestinal tract may be subjected to mucosal damage by 5-FU. Although the diarrheal syndrome associated with the fluoropyrimidines has not been studied prospectively and has not been routinely evaluated with intestinal assessment with radiologic or endoscopic investigations, a previously reported case study by our group did demonstrate that floxuridine infusion induced radiographic lesions in the small intestine not unlike those seen with Crohn disease3 and was reversible with drug withdrawal. These cases were similar to those described by Fata et al. Additional aspects of the fluoropyrimidine-induced intestinal syndrome relate to the specific fluoropyrimidine used, the drug schedule of administration, and the concomitant use of leucovorin for biomodulation. Floxuridine (5FUdR) is more commonly associated with diarrhea than 5-FU for unknown reasons, although the pharmacokinetic and pharmacodynamic differences between the two fluoropyrimidine analogues is well established. In terms of the drug schedule, 5-FU administered by protracted venous infusion (PVI) is uncommonly, if only rarely, associated with diarrhea. On the other hand, bolus 5-FU results in diarrhea as a major gastrointestinal toxicity. These clinical observations suggest that infusional 5-FU may be mechanistically or pharmacologically different from bolus 5-FU in terms of cellular effect, as suggested by Sobrero and Bertino,4 in which bolus 5-FU effects RNA and infusional 5-FU effects DNA synthesis and the pattern and frequency of toxicity may therefore differ. Finally, what is the role of leucovorin modulation in inducing the intestinal lesion? Early studies from Roswell Park and subsequently by the Gastrointestinal Tumor Study Group and others5 established that leucovorin modulation and 5-FU administration resulted in a dose-limiting “cholera-like” syndrome of diarrhea and secondary dehydration. Furthermore, in the Phase I trials of infusional 5-FU with concomitant leucovorin, diarrheal toxicity was commonly observed.6 It would appear, then, that 5-FU biomodulation with leucovorin increases the frequency and severity of 5-FU–induced diarrhea (in both bolus and infusional schedules of 5-FU), but the specific mechanism is unclear. Vasospastic effects or alterations in fibrinolytic activity seem unlikely, and it is possible that leucovorin modulation of 5-FU results in an “FUdR”-like effect in the mucosal lining cells of the small intestine, leading to mucosal ulceration and resulting in diarrhea. I suspect that the diarrheal toxicity associated with 5-FU is almost always related to a small intestinal lesion and that the incidence and intensity is related to the schedule of 5-FU administration and the use or nonuse of concomitant leucovorin modulation. Jacob Lokich M.D.*, * The Cancer Center of Boston, Boston, Massachusetts