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

<b>Background:</b> 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. <b>Methods:</b> 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). <b>Results:</b> 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 (<i>p</i> = .21). The most common events were angina without ischemia (5-FU: 1.6%, capecitabine: 1.3%, <i>p</i> = .53), angina with ischemia on ECG (5-FU: 0.9%, capecitabine: 0.8%, <i>p</i> = .53), unspecified chest pain (5-FU: 0.9%, capecitabine: 0.6%, <i>p</i> = .34), ST-elevation myocardial infarction (5-FU: 0.5%; capecitabine: 0.4%, <i>p</i> = .76) and non-ST-elevation myocardial infarction (5-FU: 0.7%, capecitabine: 0.5%, <i>p</i> = .50). Cardiac arrest or sudden death occurred in 0.5 and 0.4%, respectively (<i>p</i> = 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, <i>p</i> = .016). <b>Conclusions:</b> 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.

**背景：** 氟嘧啶类药物（fluoropyrimidines）是胃肠道恶性肿瘤一线化疗药物，同时也可用于乳腺癌及头颈部恶性肿瘤的治疗。然而，5-氟尿嘧啶（5-flourouracil）与卡培他滨（capecitabine）可能诱发心脏毒性，此类毒性多以急性冠脉综合征为主要临床表现。本研究比较了结直肠癌患者中5-氟尿嘧啶与卡培他滨诱导心脏毒性的发生率，并尝试明确心脏毒性的风险标志物。
**方法：** 本研究回顾性分析了某医疗机构2007-2016年新辅助治疗阶段、2000-2016年辅助治疗阶段或2007-2016年转移性治疗阶段中，所有接受5-氟尿嘧啶或卡培他滨治疗的连续性结直肠癌患者。
**结果：** 共计995例患者接受5-氟尿嘧啶治疗，1241例接受卡培他滨治疗。5-氟尿嘧啶诱导的心脏毒性发生率为5.2%[95%置信区间（confidence interval, CI）：3.8%~6.6%]，卡培他滨诱导的心脏毒性发生率为4.1%（95%CI：3.0%~5.2%），组间差异无统计学意义（p=0.21）。最常见的心脏不良事件包括：无缺血表现的心绞痛（5-氟尿嘧啶组：1.6%，卡培他滨组：1.3%，p=0.53）、心电图提示缺血性心绞痛（5-氟尿嘧啶组：0.9%，卡培他滨组：0.8%，p=0.53）、未明确病因的胸痛（5-氟尿嘧啶组：0.9%，卡培他滨组：0.6%，p=0.34）、ST段抬高型心肌梗死（ST-elevation myocardial infarction）：5-氟尿嘧啶组0.5%，卡培他滨组0.4%（p=0.76）以及非ST段抬高型心肌梗死（non-ST-elevation myocardial infarction）：5-氟尿嘧啶组0.7%，卡培他滨组0.5%（p=0.50）。心脏骤停或猝死的发生率分别为0.5%与0.4%（p=1）。本研究未发现5-氟尿嘧啶诱导心脏毒性的风险标志物；在卡培他滨组中，缺血性心脏病为心脏毒性的风险标志物（优势比：2.9，95%CI：1.2~7.0，p=0.016）。
**结论：** 接受5-氟尿嘧啶治疗的患者中，约5%会出现心脏毒性，而接受卡培他滨治疗的患者中这一比例约为4%。缺血性心脏病是卡培他滨诱导心脏毒性的风险标志物。