Dermatological, cardiovascular and neurological morpho-histopathological effects of fluoropyrimidine-based chemotherapy in humans.

Fluoropyrimidines are anticancer drugs used for the treatment solid tumors. Apart from general side effects common to other anticancer drugs, the intravenously administered 5-fluorouracil (5-FU) and the recently developed oral prodrugs can induce toxicity at cardiovascular, neurologic and dermatologic level. Toxic reactions are reversed by treatment interruption, discontinuation and dose reduction, together with supportive therapies. This review examined, from the morpho-histopathological point of view, the main toxic effects induced by fluoropyrimidines. Unlike dermatologic toxicity, which is very rich in histopathological observations because of the easy approach to skin examination, cardio- and neurotoxicity are scarcely documented, considering that most imaging and functional data are poorly altered. Animal models were very useful to support and corroborate data obtained in humans. Fluoropyrimidines can associate with specific cutaneous side effects, such as the hand-foot syndrome (HFS), consisting of symmetrical erythema, dysaesthesia, dryness, rash, swelling and desquamation on palms and soles. At the cardiovascular level, fluoropyrimidines can cause angina pectoris, arrhythmias, palpitation, hypotension, hypertension, malaise and dyspnea, until life-threatening damages, including myocardial infarction and sudden cardiac death. Neurotoxicity is an uncommon but potentially severe side effect, consisting of rare cases of cerebellar alterations with ataxia, as well as multifocal cerebral leukoencephalopathy, with or without seizures, announcing with dizziness, memory deficits, trismus, headache, vertigo, gait disturbances and confusion, until coma. These adverse events are likely due to direct chemotoxic effects of fluoropyrimidine metabolites and most of them can be regarded as allergic reactions triggered by the hapten-like properties of these molecules.