title: Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: a systematic review of incidence, manifestations and predisposing factors.
abstract: OBJECTIVE
  To systematically review the incidence, manifestations and predisposing factors for cardiovascular toxicity in cancer patients treated with systemic 5-fluorouracil or capecitabine.
  
  
  METHODS
  We searched PubMed, EMBASE and Web of science for studies with ≥ 20 cancer patients evaluating cardiovascular toxicity of 5-fluorouracil and capecitabine. We hand searched the reference lists of all included studies. Study selection and assessment of risk of bias were performed by two authors independently.
  
  
  RESULTS
  We identified 30 eligible studies (1 meta-analyses of 4 RCTs, 18 prospective and 11 retrospective). Symptomatic cardiotoxicity occurred in 0-20% of the patients treated with 5-fluorouracil and in 3-35% with capecitabine. The most common symptom was chest pain (0-18.6%) followed by palpitations (0-23.1%), dyspnoea (0-7.6%) and hypotension (0-6%). Severe clinical events such as myocardial infarction, cardiogenic shock and cardiac arrest occurred in 0-2%. Mortality rates ranged from 0 to 8%. Asymptomatic cardiac influence was demonstrated on ECG, in NT-proBNP measurements and with ultrasonic cyclic variation of integrated backscatter. Predisposing factors were mostly tested in univariate analyses. Preexisting cardiac disease was a risk factor in some studies, but there were divergent results. There was some evidence for increased cardiotoxicity during continuous infusion schedules and with concomitant cisplatin treatment. The effects of previous or current chest-radiotherapy were ambiguous.
  
  
  CONCLUSIONS
  Larger studies suggest an incidence of symptomatic cardiotoxicity of 1.2-4.3% during fluorouracil treatment, however subclinical cardiac influence are common. Possible risk factors are cardiac co-morbidity, continuous infusion schedules and concomitant cisplatin treatment, but existing evidence are of insufficient quality.
authors.affiliation: Department of Cardiology, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2730 Herlev, Denmark. Electronic address: anne.polk@hotmail.com.
authors.forename: Anne
authors.initials: A
authors.lastname: Polk
authors.forename: Merete
authors.initials: M
authors.lastname: Vaage-Nilsen
authors.forename: Kirsten
authors.initials: K
authors.lastname: Vistisen
authors.forename: Dorte L
authors.initials: DL
authors.lastname: Nielsen
mesh_terms: D000069287:Capecitabine; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005472:Fluorouracil / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006331:Heart Diseases / Q000139:chemically induced*; D006801:Humans; D011446:Prospective Studies; D012189:Retrospective Studies
chemical_list: D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil
keywords: 5-fluorouracil; Capecitabine; Cardiotoxicity; Systematic review