Cardiotoxicity in the form of cardiac arrhythmia, myocardial infarction, and angina-like symptoms are not rare complications of fluoropyrimidines as 5-Fluorouracil (5FU) and capecitabine (Table
1). The hallmark of cardiotoxicity is the occurrence of coronary vasospasm leading to the electrocardiographic and clinical manifestation of myocardial ischemia. Meyer et al. [
1], in a prospective series of more than 400 patients treated with 5FU continuous infusion (ci), found an incidence of 3 % (9 cases out of all observed patients) during the first course of chemotherapy, and this was one of the first association of type of 5FU administration and risk of cardiotoxicity, with preexisting cardiac disease and concomitant cardiovascular drugs as main risk factors in these 9 patients. From that publication, other series found evidence of cardiac events occurrence during the administration of 5FU ci (or capecitabine) for gastrointestinal malignancies. In particular, myocardial angina or cardiac infarction are the most observed clinical manifestation of 5FU-related cardio-toxicity, and other antimetabolites (e.g., raltitrexed) or bolus 5FU administration could mitigate the risk of these worrisome events [
2,
3]. The exact pathophysiology of these events is not well known, but a cardiac vasospasm seems the main events associated with cardio- toxicity. It has been postulated a role of the 5FU metabolites: in particular 5FU is catabolized to alpha-fluoro-beta-alanine (FBAL) and subsequently to fluoroacetate, the latter suspect in particular as a cardiotoxic substance [
4]. Recently, Italian authors analyzed human cardiomyocytes and endothelial cells to evaluate the effect of 5FU. They observed autophagic features with reactive oxygen species (ROS) elevation as an endothelial response and induction of a senescent phenotype on both cell types treated with 5FU [
5]. By these data and owing to the relative misunderstanding of exact mechanisms involved in the cardio-toxicity of 5FU, there is a rationale for using different inhibitors of thymidylate synthase (TS), commonly prescribed in clinical practice, in particular, raltitrexed. Animal studies of myocardium damage after 5FU administration showed that multifocal hemorrhages, myofiber necrosis, inflammatory reactions including perivascular involvement, pericarditis, valvulitis and vascular changes, were observed. In particular, a single high intravenous dose resulted in hemorrhagic infarction of the ventricle walls, proximal spasms of the coronary arteries and lethal outcome for animals within few hours. In contrast, repeated lower doses resulted in left ventricular hypertrophy, concentric fibrous thickening of the intima of coronary vessels and foci of necrotic myocardial cells [
6]. Whether the differences in histopathological effects were due to different doses, is not understood but could be the basis for an oral (chronic) low dose of antimetabolites as TAS 102 and S-1.
Table 1
Cardiotoxicity of capecitabine, 5-Fluorouracil, TAS 102 and S1
Capecitabine | | | Unstable angina pectoris, angina pectoris, myocardial ischemia, atrial fibrillation, cardiac arrhythmia, tachycardia, Palpitation | Ventricular fibrillation, QT prolongation, torsade de pointes, bradycardia, vasospasm |
5-fluorouracil | | Chest pain | Myocardial infarction, myocardial ischemia, cardiac arrhythmia, myocarditis, heart failure, dilated cardiomyopathy | Cardiac arrest, sudden cardiac death |
TAS-102 | | | | Myocardial infarction, myocardial ischemia, chest pain, bradycardia, tachycardia |
S1 | | | Cardiac failure, acute myocardial infarction, pericardial effusion, atrial fibrillation, angina pectoris, cardiac fibrillation, tachycardia, palpitations | |