Dermatological, Cardiovascular and Neurological Morphohistopathological Effects of Fluoropyrimidine-based Chemotherapy in Humans

Background: Fluoropyrimidines are anticancer drugs used for the treatment of solid tumours. 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, which is reversed by treatment interruption, discontinuation, dose reduction and supportive therapies. Objective: To examine, from the morphohistopathological point of view, the main toxic effects induced by fluoropyrimidines. Methods: Pertinent articles were retrieved through PubMed search. Results: Unlike dermatologic toxicity, with evident histopathological observations because of the easy approach to skin examination, cardio- and neurotoxicity are scarcely documented, with most imaging and functional data poorly altered. Animal models are useful to corroborate data obtained in humans. Fluoropyrimidines can associate with specific cutaneous side effects, including the hand-foot syndrome (HFS), with symmetrical erythema, dysaesthesia, dryness, rash, swelling and desquamation on palms and soles. Cardiotoxicity includes angina pectoris, arrhythmias, palpitation, hypotension, hypertension, malaise and dyspnea, until life-threatening damages, with myocardial infarction and sudden 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. Conclusion: Fluoropyrimidines are able to induce specific morphohistopathological changes in tissues.