Mucositis with fluorouracil

Fluorouracil Inhibition of the enzyme thymidylate synthase, the rate-limiting step in thymidine formation. Dose-limiting Myelosuppression and mucositis with bolus administration Diarrhea and hand-foot syndrome with continuous infusion Additional toxicities Skin discoloration, nail changes, photosensitivity, and neurologic toxicity... 

The toxicities of 5-fluorouracil vary with the schedule and mode of administration. Nausea is usually mild if it occurs at all. Myelosuppression is most severe after intravenous bolus administration, with leukopenia and thrombocytopenia appearing 7 to 14 days after an injection. Daily injection or continuous infusion is most likely to produce oral mucositis, pharyngitis, diarrhea, and alopecia. Skin rashes and nail discoloration have been reported, as have photosensitivity and increased skin pigmentation on sun exposure. Neurological toxicity is manifested as acute cerebellar ataxia that may occur within a few days of beginning treatment. 

Metzger, G., Massari, C., Etienne, M.C., Comisso, M., Brienza, S., Touitou, Y., Milano, G., Bastian, G., Misset, J.L., Levi, F. Spontaneous or imposed circadian changes in plasma concentrations of 5-fluorouracil coadministered with folinic acid and oxaliplatin relationship with mucosal toxicity in patients with cancer. Clin. Pharmacol. Ther. 1994, 56 190-201. 

Sorensen JB, Skovsgaard T, Bork E, Damstrup L, Ingeberg S. Double-blind, placebo-controlled, randomized study of chlorhexidine prophylaxis for 5-fluorouracil-based chemotherapy-induced oral mucositis with nonblinded randomized comparison to oral cooling (cryotherapy) in gastrointestinal malignancies. Cancer 2008 112(7) 1600-6. 

Two-thirds of patients treated with cyclophosphamide orally for 4 months plus intravenous 5-fluorouracil and methotrexate for breast cancer developed Barrett s epithelium (16), perhaps as a result of esophagitis, rather than through mucosal re-epithelialization by undifferentiated stem cells (17). 

The dose and duration of protracted infusional fluorouracil is hmited by mucositis, diarrhea, and/or palmar-plantar erythrodysesthesia. Typically, palmar-plantar dysesthesia begins several weeks to months after starting treatment. Although the dysesthesia abates within several weeks of discontinuing the infusion, it rapidly recurs when the infusion is resumed. Five patients who developed palmar-plantar dysesthesia during infusion of fluorouracil were treated with oral pyridoxine, 50 or 150 mg/day, once it reached moderate severity (149). The severity of the skin toxicity improved, with resolution of pain in four of the five patients, despite continued administration of fluorouracil. The abihty of pyridoxine to modulate fluorouracil-induced cutaneous toxicity is currently undergoing evaluation in the randomized trial (150). 

McCarthy GM, Awde JD, Ghandi H, Vincent M, Kocha WI. Risk factors associated with mucositis in cancer patients receiving 5-fluorouracil. Oral Oncol 1998 34(6) 484-90. 

Overall, response rates and survival outcomes with weekly and daily regimens of bolus fluorouracil plus LD- or HD-leucovorin appear comparable. Leucovorin doses greater than 20 mg/m do not appear to increase overall survival, but rather add to the toxicity of either daily or weekly regimens of fluorouracil. Weekly (HD-leucovorin) treatment schedules are associated with a higher incidence of diarrhea, the primary dose-limiting toxicity, whereas mucositis and leukopenia are relatively infrequent. Mucositis tends to be dose-limiting and leukopenia is more common with the daily (LD-leucovorin) treatment schedule. 

Gastrointestinal Oral mucositis is a dose-limiting adverse reaction to fluorouracil. It affects 40% of patients overall and is grade 3/4 in about 15% [83 , 84 ]. Prophylactic use of a chlorhexidine mouthwash or topical cooling with crushed ice can reduce the severity of symptoms [85 ]. Diarrhea is also common and affects up to 40-50% of patients, particularly with bolus regimens with leucovorin and in combination therapy with oxaliplatin [86 ]. In one phase... 

Gastrointestinal Stomatitis, diarrhea, and nausea are significantly less common with capecitabine than fluorouracil and affect 24%, 48% and 38% of patients respectively (all grades). Grade 3/4 diarrhea affects 23% of patients and may require dosage modification [102 ] the median time to occurrence is 34 days. Severe mucositis is uncommon and is reported in 2% of patients. 

Fluorouracil Pyrimidine Colorectal, pancreatic, breast Thymidylate synthase inhibitor Acral erythema maculopap. rash inj. site reaction CD St Anaph diarrhea myelosuppression GI mucositis Palmar-plantar dermatitis risk factor. Diag.—IDT and patch (with care) IgE-mediated Direct cytotoxic effect... 

Ferreira TM, Leonel AJ, Melo MA, et al. Oral supplementation of butyrate reduces mucositis and intestinal permeability associated with 5-Fluorouracil administration. Lipids. 2012 47 669—678. 

Thatcher et al. (1980) combined weekly intramuscular injections of retinol with adriamycin, bleomycin, S-fluorouracil, and methotrexate for the treatment of 25 patients with advanced squamous cell carcinoma of the head and neck. No effect on response rate or duration by the addition of vitamin A can be determined however, the authors state diat the addition of retinol may have ameliorated drug-induced mucositis. 

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