Fluorouracil, adverse reactions

Fluoroquinolones, 12.250, 18.271 Fluorouracil, adverse reactions, 23.476 Folic acid, dietary supplementation, 19.369 safety aspects, 27.407 Formoterol, tolerance, 24.187 Fragrances, contact allergy, 20.149... 

The adverse reactions following treatment with combination leucovorin/5-fluorouracil in descending order of occurrence are stomatitis (75%), nausea, leukopenia (69%), diarrhea, vomiting, alopecia (42%), dermatitis, anorexia, fatigue, thrombocytopenia, infection, and constipation (3%). 

Nervous system Fluorouracil can cause acute nervous system toxicity. Acute cerebellar syndrome affects up to 5% of patients and is usually self-limiting after withdrawal. It can occur within weeks to months of starting fluorouracil and presents with ataxia, nystagmus, and dysarthria [77, 78 ]. An encephalopathy can occur rarely and is often associated with markedly raised ammonia concentrations in the absence of underlying liver disease. Ischemic stroke has also been reported and the risk appears to be increased when fluorouracil is combined with cisplatin [60, 79 ]. Other rare adverse reactions include oculomotor disturbances, focal dystonia, parkinsonian syndrome, peripheral neuropathy, and seizures [80 ]. Dihydropyrimidine dehydrogenase deficiency also increases the risk of nervous system toxicity [81" ]. 

Sensory systems Excessive lacrimation is common with fluorouracil and affects 30% of patients [82 ]. Other ocular adverse reactions include blurred vision, ocular irritation and pain, photophobia, conjunctivitis, circu-morbital edema, ectropion, keratitis, and tear duct stenosis. Most patients can be managed symptomatically with methylcellulose or dexamethasone eye drops. Occasionally fluorouracil may need to be withdrawn and the symptoms usually resolve in 1-2 weeks [18 ]. Optic neuropathy is rare [79 ]. 

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... 

Susceptibility factors Women and patients over 70 years of age are more likely to have more severe adverse reactions to fluorouracil-based therapy [91, 92 ]. 

Capecitabine is a tumor-selective oral fluoropyrimidine. It has been approved by the FDA and NICE for the treatment of colorectal cancer in both the adjuvant and metastatic settings and for patients with breast cancer after anthracycline and taxane therapy [93 ,94 ]. It has also been approved by NICE for advanced gastric cancer as part of platinum-based therapy [95 ]. In a randomized phase III study of adjuvant capecitabine versus fluorouracil -I- leucovorin, efficacy was similar between the groups but grade 3/4 adverse reactions were significantly less common in those who were given capecitabine [96 ]. The starting dose is usually 1000-1250 m m bd for 14 days, followed by 7 days rest. 

Diarrhea is a dose-limiting adverse reaction to uracil-ftorafur. However, it is less toxic than bolus fluorouracil and causes significantly less myelosuppression and mucositis [108 , 109 "]. Other common adverse reactions include nausea, vomiting, fatigue, and hyperbilirubinemia. Hand-foot syndrome is very rare. 

Susceptibility factors Genetic Polymorphisms of orotate phosphoribosyltransferase (OPRT), related to fluorouracil metabolism, predict more severe adverse reactions, including grade 3/4 diarrhea [110 ]. 

Fluorouracil is a pyrimidine analogue (see Chapter 27, Section II.b.3). Topical application may be used for malignant and premalignant skin conditions, including actinic keratosis. Adverse effects include local inflammatory and allergic reactions. Photosensitivity reactions during and for up to 2 months after treatment may become manifest. 

Reduced folates are co-factors for the 5-fluorodeoxy-uridine monophosphate-thymidilate synthetase reaction. Leucovorin (calcium fohnate) therefore potentiates the toxicity of 5-fluorouracil, and fatal adverse effects have been reported in patients over 65 years of age receiving high-dose treatment with leucovorin simultaneously with fluorouracil. This has led some groups to recommend that initial dose levels of fluorouracil should be lowered by 20% and that therapy be stopped temporarily at the first sign of distal gastrointestinal adverse effects (SEDA-15, 414). 

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