Real-life incidence of cardiotoxicity and associated risk factors in sarcoma patients receiving doxorubicin.

BACKGROUND: Anthracycline induced cardiotoxicity is well recognized but only few data exist in sarcoma patients. This study retrospectively aimed to analyze sequential Cadmium Zinc Telluride (CZT)-multigated equilibrium radionuclide angiography (ERNA) for monitoring left ventricular ejection fraction (LVEF) and to assess the real-life incidence of cardiotoxicity in sarcoma patients receiving doxorubicin based chemotherapy. MATERIALS AND METHODS: A retrospective analysis was performed on all sarcoma patients referred to Herlev University Hospital between 2012 and 2015. Cardiotoxicity was defined as a decline in LVEF of > 10% percentage point to a LVEF < 50% as compared to baseline. Early cardiotoxicity was defined as < 1 year and late cardiotoxicity as ≥ 1 year. Recovery of cardiotoxicity was defined as a LVEF ≥ 50%. RESULTS: A total of 149 patients were referred, 75 (50%) sarcoma patients were included. The main reason for exclusion was that only one CZT-ERNA had been performed in 50 (68%) of the patients. Twenty-three (31%) of the patients experienced cardiotoxicity, 11 (48%) were female, mean age was 56.9 years. Early cardiotoxicity was observed in 16 (70%) of the patients and 11 (48%) experienced clinical symptoms of cardiotoxicity at diagnosis. Recovery of LVEF was seen in 12 (55%) of the patients and persistent recovery in 10 (45%). The diastolic blood pressure at baseline was positively and significantly associated with a higher risk of developing cardiotoxicity (Relative Risk (RR): 1.039 (95% CI= 1.001 - 1.079; p = 0.042)). The median survival was 1.4 years (range 0.5 - 2.2 years) for patients with metastatic disease versus 3.9 years (range 1.5 - 6.4 years) (p = 0.009) for localized disease at baseline. CONCLUSION: Cardiotoxicity is a relative frequent complication in sarcoma patients treated with doxorubicin based chemotherapy and the diastolic blood pressure at baseline was significantly associated with a higher risk of developing cardiotoxicity.

Myocardial Ischemia Induced by 5-Fluorouracil: A Prospective Electrocardiographic and Cardiac Biomarker Study.

BACKGROUND: Cardiotoxicity induced by 5-fluorouracil (5-FU) is well known but poorly understood. In this study, we undertook ECG recording (Holter) and analyses of the biomarkers troponin and copeptin in patients receiving 5-FU to increase our understanding of the cardiotoxicity. SUBJECTS, MATERIALS, AND METHODS: Patients with colorectal or anal cancer that received first-time treatment with 5-FU-based chemotherapy were prospectively included. Holter recording, clinical evaluation, 12-lead electrocardiogram, and assessment of plasma concentrations of troponin I and copeptin were performed before (control) and during 5-FU treatment (intervention). RESULTS: A total of 108 patients were included, 82 with colorectal and 26 with anal cancer. The proportion of patients with myocardial ischemia on Holter recording was significantly higher during the first 5-FU infusion (14.1%) than before (3.7%; p = .001). The ischemic burden per day (p = .001), the number of ST depression episodes per day (p = .003), and the total duration of ischemic episodes per day (p = .003) were higher during the first 5-FU infusion than before, as was plasma copeptin (p < .001), whereas plasma troponin I was similar (p > 0.999). Six patients (5.6%) developed acute coronary syndromes and two (1.8%) developed symptomatic arrhythmias during 5-FU treatment. CONCLUSION: 5-FU infusion is associated with an increase in the number of patients with myocardial ischemia on Holter recording. According to biomarker analyses, 5-FU is associated with an increase in copeptin, but rarely with increases in cardiac troponin I. However, 5%-6% of the patients developed acute coronary syndromes during treatment with 5-FU. IMPLICATIONS FOR PRACTICE: Symptomatic 5-fluorouracil (5-FU) cardiotoxicity occurs in 0.6%-19% of patients treated with this drug, but a small electrocardiographic (Holter) study has revealed silent myocardial ischemia in asymptomatic patients, suggesting a more prevalent subclinical cardiac influence. This study demonstrated a significant increase in the number of patients with myocardial ischemia on Holter recording during 5-FU treatment and an increase in ischemic burden. Cardiac biomarker analyses suggested that 5-FU infusion results in endogenous stress (increased copeptin) but rarely induces myocyte injury (no change in troponin). These findings suggest a more prevalent cardiac influence from 5-FU and that Holter recording is an important tool in the evaluation of patients with suspected cardiotoxicity from 5-FU.

Incidence and risk markers of 5-fluorouracil and capecitabine cardiotoxicity in patients with colorectal cancer.

Background: Fluoropyrimidines are mainstay chemotherapeutics in the treatment of gastrointestinal cancers and are also used to treat breast cancer and head and neck cancers. However, 5-flourouracil (5-FU) and capecitabine may induce cardiotoxicity that mostly presents as acute coronary syndromes. We compared the incidence of cardiotoxicity induced by 5-FU and capecitabine in patients with colorectal cancer and sought to identify risk markers for cardiotoxicity.Methods: We reviewed all consecutive patients with colorectal cancer who received 5-FU or capecitabine at one institution in the neoadjuvant (2007-2016), adjuvant (2000-2016) or metastatic setting (2007-2016).Results: Totally, 995 patients received 5-FU and 1241 received capecitabine. The incidence of cardiotoxicity induced by 5-FU was 5.2% [95% confidence interval (CI): 3.8-6.6%] and 4.1% (95% CI: 3.0-5.2%) induced by capecitabine (p = .21). The most common events were angina without ischemia (5-FU: 1.6%, capecitabine: 1.3%, p = .53), angina with ischemia on ECG (5-FU: 0.9%, capecitabine: 0.8%, p = .53), unspecified chest pain (5-FU: 0.9%, capecitabine: 0.6%, p = .34), ST-elevation myocardial infarction (5-FU: 0.5%; capecitabine: 0.4%, p = .76) and non-ST-elevation myocardial infarction (5-FU: 0.7%, capecitabine: 0.5%, p = .50). Cardiac arrest or sudden death occurred in 0.5 and 0.4%, respectively (p = 1). No risk markers for cardiotoxicity induced by 5-FU were identified. In the capecitabine group, ischemic heart disease was a risk marker (odds ratio: 2.9, 95% CI: 1.2-7.0, p = .016).Conclusions: Five percent of patients treated with 5-FU developed cardiotoxicity and 4% treated with capecitabine. Ischemic heart disease was a risk marker for cardiotoxicity induced by capecitabine.

Short and long term radiation induced cardiovascular disease in patients with cancer.

Radiation-induced cardiovascular disease is well described as a late effect in cancer patients treated with radiation therapy. Advancements in surgery, radiotherapy, and chemotherapy have led to an increasing number of cancer survivors with resultant long-term side effects related to their cancer treatments. In this review, we describe the short- and long-term cardiovascular consequences of mediastinal radiotherapy and discuss the optimal cardiovascular assessments and diagnostic tools in asymptomatic and symptomatic patients.

Incidence and risk factors for capecitabine-induced symptomatic cardiotoxicity: a retrospective study of 452 consecutive patients with metastatic breast cancer.

OBJECTIVES: Case reports of capecitabine cardiotoxicity resemble those seen with intravenous 5-fluorouracil (5-FU) with chest pain as the predominant manifestation, but few studies of capecitabine cardiotoxicity are available. We aimed to determine the incidence of symptomatic cardiotoxicity from capecitabine in patients with breast cancer and to identify risk factors. METHODS: We reviewed medical records of consecutive women with breast cancer treated with capecitabine (1000 mg/m2 two times per day) from 2002 to 2012 at one institution. RESULTS: 22 of 452 patients (4.9%) (95% CI 2.9% to 6.9%) had symptoms of cardiotoxicity (chest pain: n=13, dyspnoea: n=9, palpitations: n=2). 11 patients had changes on ECG (atrial fibrillation: n=5, ST deviations: n=3, T-wave abnormalities: n=2 and QTc prolongation: n=1). 2 patients (0.4%) sustained acute myocardial infarction. 1 patient (0.2%) developed cardiac arrest with lethal outcome. 4 of 6 patients (66%) retreated with capecitabine had recurrent symptoms at retreatment. Cardiac comorbidity (p=0.001), hypercholesterolaemia (p=0.005) and current smoking (p=0.023) were risk factors for cardiotoxicity in univariate analyses and remained significant when adjusted for age. Patients with cardiac comorbidity were 5.5 times (95% CI 2.0 to 14.8) more likely to develop cardiotoxicity. In the subgroup of patients with apparently no cardiac comorbidity, the incidence of cardiotoxicity was lower (3.7%) and hypercholesterolaemia (p=0.035) and current smoking (p=0.020) were risk factors of cardiotoxicity. CONCLUSIONS: The incidence of cardiotoxicity from capecitabine resembles that of intravenous 5-FU (≈5%). Cardiac comorbidity, hypercholesterolaemia and current smoking were associated with development of cardiotoxicity.

A systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity.

BACKGROUND: Cardiotoxicity is a serious side effect to treatment with 5-fluorouracil (5-FU), but the underlying mechanisms are not fully understood. The objective of this systematic review was to evaluate the pathophysiology of 5-FU- induced cardiotoxicity. METHODS: We systematically searched PubMed for articles in English using the search terms: 5-FU OR 5-fluorouracil OR capecitabine AND cardiotoxicity. Papers evaluating the pathophysiology of this cardiotoxicity were included. RESULTS: We identified 27 articles of 26 studies concerning the pathophysiology of 5-FU-induced cardiotoxicity. The studies demonstrated 5-FU-induced: hemorrhagic infarction, interstitial fibrosis and inflammatory reaction in the myocardium; damage of the arterial endothelium followed by platelet aggregation; increased myocardial energy metabolism and depletion of high energy phosphate compounds; increased superoxide anion levels and a reduced antioxidant capacity; vasoconstriction of arteries; changes in red blood cell (RBC) structure, function and metabolism; alterations in plasma levels of substances involved in coagulation and fibrinolysis and increased endothelin-1 levels and N-terminal-pro brain natriuretic peptide levels. Based on these findings the proposed mechanisms are: endothelial injury followed by thrombosis, increased metabolism leading to energy depletion and ischemia, oxidative stress causing cellular damage, coronary artery spasm leading to myocardial ischemia and diminished ability of RBCs to transfer oxygen resulting in myocardial ischemia. CONCLUSIONS: There is no evidence for a single mechanism responsible for 5-FU-induced cardiotoxicity, and the underlying mechanisms might be multifactorial. Further research is needed to elucidate the pathogenesis of this side effect.

Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: a systematic review of incidence, manifestations and predisposing factors.

PURPOSE: To systematically review the incidence, manifestations and predisposing factors for cardiovascular toxicity in cancer patients treated with systemic 5-fluorouracil or capecitabine. DESIGN: 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. CONCLUSION: 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.