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

Abstract

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)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015)(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 ¼ .21). The most common events were angina without ischemia (5-FU: 1.6%, capecitabine: 1.3%, p ¼ .53), angina with ischemia on ECG (5-FU: 0.9%, capecitabine: 0.8%, p ¼ .53), unspecified chest pain (5-FU: 0.9%, capecitabine: 0.6%, p ¼ .34), ST-elevation myocardial infarction (5-FU: 0.5%; capecitabine: 0.4%, p ¼ .76) and non-ST-elevation myocardial infarction (5-FU: 0.7%, capecitabine: 0.5%, p ¼ .50). Cardiac arrest or sudden death occurred in 0.5 and 0.4%, respectively (p ¼ 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 ¼ .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.

Cardiotoxicity from Capecitabine Chemotherapy: Prospective Study of Incidence at Rest and During Physical Exercise

“…EST was planned after at least 10 days of treatment to increase its sensitivity because FP cardiotoxicity is more frequent in prolonged therapies. 16 , 24 , 42 We observed more cases of stress-induced cardiotoxicity than rest cardiotoxicity (26 vs. 6). In 12 cases the toxicity was evident after a workload of < 4.6 Metabolic Equivalents of Task (METs), corresponding to activities as digging, making beds, walking upstairs, washing windows, mowing the lawn, painting a wall, bicycling at 10 km/h.…”

“… 5 , 8 , 15 , 19-27 Retrospective studies (based on symptoms reported in the clinical charts) report an incidence of 4.3-7%. 13 , 21 , 24-26 Two prospective studies based on symptoms found 5.5-6.5% of capecitabine cardiotoxicity, 9 , 10 while other prospective studies including ECG found rates of 8.5-35% fluoropyrimidine cardiotoxicity. 8 , 14-16 , 23 , 27 , 28 Some of these studies, however, included in the term “cardiotoxicity” ECG changes of little, if any, clinical significance, as asymptomatic sinus bradycardia or PR and QT changes.…”

“…Of note, the same group found an incidence of 4-5% only in two retrospective studies based on symptoms and published in the past years. 21 , 24 …”

Metastatic colorectal cancer: Advances in the folate-fluoropyrimidine chemotherapy backbone

“…Cardiotoxicity is an uncommon but important side effect of 5-FU and capecitabine, seen in about 5% of patients, and encompasses a wide spectrum of effects, including electrocardiogram changes to myocardial infarction and cardiogenic shock, which may lead to anything from dose reduction, interruption of planned chemotherapy regimens to, albeit rarely, sudden death [58]. 5-FU re-challenge may be undertaken with vigilant cardiac monitoring and the combined use of calcium channel blockers and nitrates [59].…”

Anticancer Drug-Induced Cardiotoxicity: Insights and Pharmacogenetics

“…However, the risk of developing trastuzumab cardiotoxicity has been seen to increase in patients who receive concurrent anthracycline therapy [ 90 , 95 , 96 ]. When trastuzumab suppresses ErbB2 signaling, it was reported that it further accelerates the anthracycline’s ability to induce sarcomeric protein breakdown, increasing the chances of cardiac toxicity and heart failure [ 97 ].…”