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

Abstract

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.

Introduction

The antimetabolite 5-flourouracil (5-FU) is widely used alone or in combination regimens in the treatment of gastrointestinal, breast and head and neck tumours and its oral prodrug, capecitabine, is approved for treatment of colorectal cancer and metastatic breast cancer. Both 5-FU and capecitabine can induce cardiotoxicity in spite that capecitabine is activated preferentially in tumour cells. Fluorouracil cardiotoxicity presents during the course of chemotherapy and the spectrum of cardiac effects include acute coronary syndromes, arrhythmias, heart failure, hyper- and hypotension, cardiogenic shock and sudden death.[1], [2]

The frequency and clinical manifestations of 5-FU-induced cardiotoxicity has been addressed in several studies during the last 4 decades. More recently, studies of cardiotoxicity from capecitabine have emerged. However, the reported frequency varies greatly in-between studies. It has been hypothesized that the wide variation in frequency and manifestations could be explained by differences in criteria for cardiotoxicity, differences in treatment schedules and differences in susceptibility of patients.[1], [2] Hence, several attempts to identify potential predisposing factors for fluorouracil-induced cardiotoxicity have been made. Accurate estimation of the frequency of cardiotoxicity and identification of predisposing factors is important to identify patients at greatest risk and to guide safe application of these drugs. Therefore, we performed a systematic review of the incidence, manifestations and predisposing factors for cardiotoxicity from systemic 5-FU and capecitabine treatment in cancer patients. We stratified available evidence in: symptoms and clinical manifestations, electrocardiographic changes, changes in biomarkers and cardiovascular function assessed by imaging techniques.