Over the past decades, there has been an increasing number of patients presenting oncologic and cardiologic co-morbidities [1]. A substantial proportion of patients who underwent chemotherapy showed different degrees of cardiac dysfunction. However, prevention of such cardiac morbidities through early diagnosis is still an unmet need. Recently, cardio-oncology has emerged as a new discipline to provide expertise in the development of innovative strategies and interdisciplinary therapies for cardiologic and oncologic co-morbidities [1]. The chemotherapeutic drug 5-fluorouracil (5-FU) and its oral prodrug capecitabine have been reported to induce adverse cardiac effects, despite being considered as tolerable in most cases [2–4]. 5-FU and capecitabine are pyrimidine antimetabolites that have been widely used in the treatment of various malignant diseases. Emerging studies have shown that they can induce a spectrum of adverse cardiac effects including chest pain, dyspnea and hypotension [5–7]. Other clinical presentations include arrhythmias, heart failure, myocardial infarction, cardiogenic shock and sudden death [4–9]. A recent meta-analysis indicates that the incidence of symptomatic cardiotoxicity is 0–20% in patients treated with 5-FU and 3–35% in patients receiving capecitabine [10]. While 5-FU- and capecitabine-associated cardiotoxicity has been widely addressed in the US and European countries, the incidence and risk factors for such cardiotoxicity, to our knowledge, has never been prospectively investigated in Chinese patients. In this study, we aimed to prospectively evaluate the incidence, clinical manifestations and risk factors of 5-FU- and capecitabine-associated cardiotoxicity in patients recruited from multiple centers in China.

In this prospective multicenter study, we evaluated the incidence rates and clinical manifestations of 5-FU- and capecitabine-associated cardiotoxicity in Chinese cancer patients. The highest incidence of symptomatic cardiotoxicity induced by 5-FU and capecitabine was 19.9% [11] and 34.6% [7] respectively in previous studies on other non-Chinese patient populations. In our study, the rates of 5-FU-associated cardiotoxicity was higher than that in previous reports (25.0% vs 19.9%) while cardiotoxicity associated with capecitabine occurred at a rate similar to previous studies (33.8% vs 34.6%). In our study, 4% of patients reported chest discomfort and palpitation whereas around 20% of patients presented arrhythmia. These rates were in a similar range as that reported previously [10]. Polk et al. reported that chest pain and palpitations were common symptoms during fluorouracil treatment with incidence rates from 0 to 18.6% and 0 to 23.1%, respectively, while arrhythmia was present in 0–21% of the patients [10]. Consistent with previous studies, ECG changes were not always associated with chest discomfort but they can reveal silent myocardial ischemia and asymptomatic arrhythmia in patients [12–14]. In our study, a substantial number of patients presented ischemic changes with no complaints of chest discomfort. We speculate that if patients on 5-FU or capecitabine treatment had been equipped with continuous ECG monitoring, the rate of cardiotoxicity observed could have been even higher given that many of ischemic episodes could be transient and silent [15]. Therefore, patients on 5-FU or capecitabine treatment should be closely monitored. In addition, we found a relatively high rate of abnormal ECG findings with around 13% of patients showing ST deviation compared with other studies [7, 16]. We reasoned that the discrepancy in clinical manifestation is partly due to our prospective study design.

5-FU and capecitabine can also cause serious cardiac events such as myocardial infarction and heart failure [4], with the latter also occurring more frequently in our study. In an exploratory step, we found that patients with pre-existing cardiac disease had a significantly higher risk of developing cardiotoxicity during 5-FU or capecitabine treatment, which was in line with previous reports [17, 18]. It should be noted that fluoropyrimidine-associated cardiotoxicity is potentially lethal even in patients without a prior history of cardiac disease. This is supported by the observation that around 5% of patients without prior cardiac disease developed heart failure and myocardial infarction on treatment with fluoropyrimidines. Capecitabine is an orally administered prodrug of 5-FU that is metabolized into the active form 5-FU in vivo through thymidine kinase conversion. Our study suggested that capecitabine is more prone to induce cardiotoxicity compared with 5-FU chemotherapy, consistent with the report of Kosmas et al. [8]. However, reports of other inconsistent results are also noted [9, 19]. We recommend careful monitoring of possible fluoropyrimidine-associated cardiotoxicity throughout the chemotherapy cycles and upon occurrence of cardiotoxicity, effective work-up should be applied, e.g. ECG monitoring, dose reduction of 5-FU or capecitabine, use of sublingual nitrates or calcium antagonists, and change to other chemotherapeutic drugs. Previous study suggested hypertension and chemotherapy cycles were potential risk factors of cardiotoxicity. We found that hypertension was significantly associated with cardiotoxicity in the univariate analysis. Although we failed to find such association in logistic regression model, this may be in part due to hypertension was in collinearity with other risk factors.

Fluoropyrimidine-associated cardiotoxicity has been indicated in a number of studies including ours, yet the pathogenesis is still unknown. Coronary vasospasm, endothelial injury and accumulation of toxic metabolites are the most common hypotheses for fluoropyrimidine-induced cardiotoxicity [20–22]. Guidelines for managing patients who develop cardiotoxicity following fluoropyrimidine treatment are still lacking. Collectively, there is a pressing need for alternative anticancer drugs that could substitute fluoropyrimidine agents for patients at high risk of intolerance towards them. Tegafur/gimeracil/oteracil (S-1) is a combination of three agents, comprising the oral fluoropyrimidine prodrug tegafur, the dehydropyrimidine dehydrogenase (DPD) inhibitor gimeracil (5-chloro-2,4-dihydroxypyridine) and potassium oxonate (OXO), an inhibitor of orotate phosphoribosyl transferase which converts 5-FU to fluorouridine monophosphate [23]. The clinical outcome of S-1 treatment is comparable with the results of 5-FU and capecitabine treatment. In particular, DPD inhibition by gimeracil is considered to significantly reduce F-beta-alanine and other cardiotoxic 5-FU catabolites like F-citrate, when comparing with capecitabine or 5-FU treatment, thus resulting in less cardiotoxicity [24]. However, DPD inhibition by gimeracil is partial and clinical evaluation of S-1-associated cardiotoxicity on a larger scale is still lacking. In a recent study, raltitrexed was found to show good safety in colorectal cancer patients [25]. Raltitrexed is an antifolate thymidylate synthase inhibitor that is also efficacious and safe in other tumor types including gastrointestinal tumor [26], head and neck cancer [27] and hepatocellular carcinoma [28]. Guidelines of both European Society for Medical Oncology (ESMO) and the National Institute for Health and Care Excellence (NICE) recommend that raltitrexed may serve as an alternative to 5-FU and capecitabine, both of which pose cardiotoxicity risk [29, 30]. In a phase III trial, first-line treatment with raltitrexed in combination with cisplatin demonstrated superior overall survival (OS) compared with cisplatin alone in the treatment of malignant pleural mesothelioma [31]. In addition, raltitrexed as first-line treatment of advanced colorectal cancer gave comparable OS as and a better safety profile than the 5-FU-based regimens in three different randomized clinical studies [32–34]. Gravalos et al. have also shown that raltitrexed/oxaliplatin (TOMOX) appears to have similar efficacy as FOLFOX4 and is well tolerated as the first-line treatment for advanced colorectal cancer. However, the two regimens offer different toxicity profiles, especially in grade 3 and 4 neutropenia and leukopenia. The convenient TOMOX regimen could be a useful alternative to fluoropyrimidine-based regimens [34]. Notably however, guidelines on dose reduction of raltitrexed should be strictly followed, especially in patients with impaired renal function, given that nearly half of the raltitrexed dose is excreted via the kidney in patients with normal renal function. The raltitrexed dose should be adjusted according to creatinine clearance with measurements conducted before the start of treatment and before each subsequent cycle [35].

There are several limitations in our study: S1 contains the fluoropyrimidine prodrug tegafur, which was not included in this study. Also, 5 patients (< 1%) were on bevacizumab combination therapy and we cannot exclude the possibility that bevacizumab may induce potential cardiovascular toxicity, with hypertension as the predominant symptom. Moreover, Hawthorne bias may occur in results potentially leading to a lower threshold for initiation of a cardiac work-up. In our study, however, cardiotoxicity was evaluated mainly based on objective indexes such as ECG and the doctor evaluated the overall condition of each patient and tried to reduce the risk of leading patients to a heightened awareness. We may thus have underestimated the incidence of cardiotoxicity in the patients, and further clinical evidence is required to confirm these results.

Cardiotoxicity induced by fluoropyrimidine chemotherapeutic agents in the Chinese population may be underestimated in clinical practice. Close monitoring of patients is recommended, especially for those patients at high risk for cardiotoxicity.