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Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management
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Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Jun 23, 2016.

INTRODUCTION — Fluoropyrimidines, such as fluorouracil (FU) and capecitabine, are a mainstay of chemotherapy regimens for a wide variety of malignancies. Worldwide, FU is the third most commonly used chemotherapeutic agent used to treat solid malignancies, including those arising in the head and neck, esophagus, stomach, colon, rectum, anus, and breast [1,2]. In addition, fluoropyrimidines are frequently used concurrently with external beam radiation therapy because of their radiosensitizing properties. Fluoropyrimidines also possess a number of important toxicities, which vary according to dose and schedule [3]. (See 'Effect of schedule and dose' below.)

Fluoropyrimidine-related cardiotoxicity, which was first reported in 1969 [4], is an uncommon but potentially lethal side effect. At present, FU is the second most common chemotherapeutic agent associated with cardiotoxicity, after anthracyclines [5,6]. Despite this, fluoropyrimidine-associated cardiotoxicity remains a poorly defined entity, particularly in regards to the underlying mechanism and optimal management. The most common clinical manifestation is angina but myocardial infarction, arrhythmias, heart failure, acute pulmonary edema, cardiac arrest, pericarditis, and asymptomatic electrocardiogram (ECG) changes are all reported. As with the other fluoropyrimidine-related toxicities, the incidence varies according to the schedule and route of administration.

Recognition of fluoropyrimidine cardiotoxicity is clinically important. Repeated administration may lead to potentially avoidable permanent damage and even death. On the other hand, premature cessation of effective chemotherapy because of unrelated cardiac events may reduce chemotherapy effectiveness and may even compromise cancer cure.

This topic will cover the incidence, clinical manifestations, mechanisms, and management of cardiotoxicity related to fluoropyrimidine therapy. Cardiotoxicity related to anthracyclines and other non-anthracycline anticancer agents is presented elsewhere. (See "Cardiotoxicity of anthracycline-like chemotherapy agents" and "Cardiotoxicity of nonanthracycline cancer chemotherapy agents".)

INCIDENCE AND RISK FACTORS

Fluorouracil — The reported incidence of fluorouracil (FU)-related cardiotoxicity ranges from 1 to 19 percent [5-15], although most series report a risk of 8 percent or less. The variability in incidence rates may be due in part to differences in the definition of cardiotoxicity, but risk estimates may also be influenced by the method of FU administration, the presence of underlying coronary artery disease (CAD), the use of concurrent radiation therapy (RT) or anthracyclines, and how intensively patients were monitored.

The highest rates of cardiotoxicity have been observed in carefully monitored patients, as reflected by the following reports:

One study evaluated 102 consecutive patients receiving FU, all of whom were monitored using 12-lead electrocardiogram (ECG), echocardiography, and radionuclide ventriculography prior to the first cycle and continuous Holter monitoring during the FU infusion; the same examinations were repeated three months later after the discontinuation of chemotherapy [10]. Reversible symptoms of angina pectoris lasting up to 12 hours were observed in 19 patients (19 percent) within 24 hours of starting FU, and these lasted up to 12 hours after cessation of treatment. Most symptomatic patients had accompanying ECG changes. In addition, both bradycardia and ventricular extrasystoles were significantly more frequent during treatment than when assessed in the three months following therapy.

Asymptomatic ECG changes and arrhythmias, as well as increases in plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), during FU chemotherapy have also been described, suggesting the possibility of subclinical cardiotoxicity [7,10,11,16]. However, the clinical significance of these findings remains uncertain.

Effect of schedule and dose — As with other FU-associated toxicities, the risk of cardiotoxicity is also dependent on the schedule and route of administration. In general, risk appears higher with infusional (both long-term and short-term schedules) as opposed to bolus FU regimens:

With bolus regimens, the incidence of cardiotoxicity is between 1.6 and 3 percent [5,6].

With continuous infusional regimens of five days or longer, the reported range of risk is 2 to 18 percent [8,9,15,17,18].

The risk with short-term infusional regimens is intermediate and variable:

In one series of 106 patients receiving short-term infusional FU as a component of the FOLFOX regimen (table 1), nine (8.5 percent) developed chest pain during treatment [11]. The onset was during courses 1, 2, 6, and 8 in three, four, one, and one patient(s), respectively.

In a second report, the risk of cardiotoxicity was significantly higher with continuous versus short-term infusional FU (13 of 205 versus 7 of 317, 6.3 versus 2.2 percent, p < 0.012) [18].

Rarely, myocardial ischemia has been reported with topical [19] or intraperitoneal [8] administration of FU.

The relationship between cardiotoxicity and FU dose is unclear; the available data are sparse:

In one study of patients receiving infusional FU, there was no relationship between dose (which ranged from <600 to >1500 mg/m2 daily) and risk of FU-related cardiotoxicity [15].

Several studies have shown a correlation between FU plasma levels and the biologic effects of FU treatment, both efficacy and toxicity [20]. However, the majority of studies examining the benefits of pharmacokinetically-guided dosing of FU have not reported a significant difference in cardiotoxicity rates with higher versus lower exposure levels to FU [21-27]. One possible exception is a randomized trial in which 208 patients receiving a weekly eight-hour infusion of FU with leucovorin were randomly assigned to standard dosing according to body surface area versus pharmacokinetically-guided dosing [28]. Patients undergoing pharmacokinetically-guided dosing had fewer episodes of cardiotoxicity (2 of 90 versus 6 of 96). However, the numbers are very small. Further data are needed in this area. (See "Dosing of anticancer agents in adults", section on 'Therapeutic drug monitoring'.)

Only one study has examined plasma circulating levels of FU in patients presenting with cardiotoxicity following FU administration [29]. Of the 13 patients who presented with cardiotoxicity during a period of four years, all had received continuous infusion of FU. The area under the curve of concentration X time (AUC) for patients with cardiotoxicity was in the same range of that of patients without other types of significant gastrointestinal or hematological toxicity. It was concluded that circulating FU levels probably do not correlate with cardiotoxicity.

Capecitabine — Capecitabine is an orally available fluoropyrimidine carbamate that is metabolized to FU in tissues, such as tumors, that express high levels of thymidine phosphorylase. Daily administration of capecitabine mimics continuous infusion FU, and the incidence of cardiac toxicity with capecitabine is within the range of that reported with infusional FU (3 to 9 percent) [18,30-32]. Furthermore, patients who previously experienced cardiotoxicity with FU may have recurrent toxicity with capecitabine. (See 'Rechallenge' below.)

Other potential risk factors — A number of other potential risk factors for fluoropyrimidine cardiotoxicity have been suggested, including underlying heart disease, older age, concomitant administration of other drugs with cardiac side effects and RT. However, the available data on all of these risk factors are conflicting, and the predictive accuracy of these risk factors is not sufficient to provide any clinically useful means of identifying patients who are at a high enough risk for cardiotoxicity to justify withholding treatment.

Known history of cardiac disease and cardiac risk factors — Underlying heart disease, including coronary artery disease, structural heart disease, and cardiomyopathy, has been associated with a higher risk for fluoropyrimidine cardiotoxicity in many [5,15,33,34] but not all [11,17,18,30] studies [35]. Furthermore, despite the association of cardiotoxicity with underlying heart disease in many reports, most cases of cardiotoxicity occur in patients without prior heart disease, and preexisting cardiac disease is not predictive for cardiotoxicity. These issues can be illustrated by the following observations:

In two reports utilizing multivariate analysis to assess the independent contribution of risk factors for fluoropyrimidine cardiotoxicity, preexisting cardiac disease of any type was a significant risk factor in one [15] but not the other [11].

In a series of 106 patients receiving short-term infusional FU for colorectal cancer, nine developed cardiotoxicity, only one of whom had a prior history of cardiovascular disease; seven other patients with a prior history of significant cardiovascular disease did not develop cardiotoxicity during treatment [11]. Similarly, in another study of 102 consecutive patients receiving FU, reversible anginas lasting up to 12 hours were observed in 19 patients, none of whom had known coronary artery disease [10]. Furthermore, there was no evidence of coronary artery disease in the six patients with severe symptoms in whom coronary angiography was carried out.

In a review of 377 published cases of fluoropyrimidine-associated cardiotoxicity, only 14 percent of patients had a history of known heart disease, while known risk factors for cardiac disease were found in 37 percent [8]. Smoking was the most common.

Age — Older age is thought to be a risk factor for fluoropyrimidine cardiotoxicity, but the data are conflicting [5,8,33]. As an example, in a review of 668 patients treated with FU or capecitabine, 29 developed cardiotoxicity during treatment, 21 of whom were older than 55 [33]. However, in another report of 1083 patients receiving a fluoropyrimidine, the incidence of cardiotoxicity was not different in those younger than versus older than 55 (7 of 420 versus 10 of 663, 1.4 versus 1/6th percent) [5].

Concomitant administration of other chemotherapeutic agents and radiation therapy — Concomitant administration of other chemotherapeutic agents with cardiac side effects may increase the risk of FU cardiotoxicity [15,18,33,36-38], although this is not a universal finding [5,15,17]. A systematic review [35] concluded that combination regimens in general were not associated with a significantly higher risk of FU cardiotoxicity but that higher rates had been observed when FU was used in conjunction with cisplatin or leucovorin [18,37]. There are no published data addressing rates of cardiotoxicity when fluoropyrimidines are combined with an anthracycline.

Prior or concomitant RT may play a role in this cardiac toxicity as FU is a radiosensitizer and may enhance radiation-induced small vessel thrombosis [8,33]. However, most reports remain anecdotal and have not been statistically confirmed.

DPYD polymorphisms — The influence of polymorphisms in dihydropyrimidine dehydrogenase (DPD), the initial and rate-limiting enzyme in FU catabolism, on cardiotoxicity is unclear. Severe toxic reactions to FU (myelosuppression, diarrhea, stomatitis, and neurotoxicity, which can be fatal) are associated with decreased levels of DPD enzyme activity, and several genetic variations in the gene encoding DPD (DPYD) result in decreased DPD enzyme activity. (See "Enterotoxicity of chemotherapeutic agents", section on 'DPD deficiency'.)

There are case reports of DPYD mutations in patients who developed FU cardiotoxicity [39]. However, whether inheritance of these polymorphisms increases the risk for fluoropyrimidine cardiotoxicity is unclear:

DPD enzyme deficiency was found in 19 of 53 patients treated with FU in one of five French institutions and who developed unanticipated FU-related toxicity [40]. However, only one of these was manifest as cardiotoxicity. Milano et al. in 1999 examined the relationship between DPD deficiency and cardiotoxicity in a study of 53 patients who experienced unanticipated toxicity during therapy with FU [40]; DPD deficiency was discovered in 19, only one of whom manifested as cardiotoxicity (5 percent).

Another study of 487 patients treated with an FU-based regimen found DPD deficiency in 18; only four of these patients (2 percent) developed severe (grade 3 or 4) cardiotoxicity [41]. (See "Common terminology criteria for adverse events", section on 'Cardiac'.)

CLINICAL PRESENTATION — The most common clinical manifestation of fluoropyrimidine cardiotoxicity is chest pain, which can be either nonspecific or anginal and is usually associated with electrocardiographic (ECG) changes [9,11,30-32,42-49]. Symptoms may occur at rest or be effort related [14].

Serum biomarkers of cardiac injury (troponins, the MB isoenzyme of creatine kinase [CK-MB], N-terminal pro-brain natriuretic peptide [NT-proBNP], or B-type natriuretic peptide [BNP] levels) may or may not [8,32] be elevated.

Less commonly, patients may present with palpitations, dyspnea, diffuse pleuritic pain, supraventricular arrhythmias such as atrial fibrillation, and hypotension. In rare cases, myocardial infarction, bradycardia, ventricular fibrillation and ventricular tachycardia, myocarditis and heart failure [38,50-54], sudden death, and pericarditis have been reported. Mortality rates in patients who develop fluoropyrimidine cardiotoxicity have ranged from 2.2 to 13.3 percent [9,10,18,42,55-58].

The types of cardiac toxicity that have been associated with capecitabine are similar to those reported with fluorouracil (FU) [30]. The spectrum of cardiotoxicity associated with FU and capecitabine can be illustrated by a pooled analysis of 377 evaluable cases of fluoropyrimidine-induced cardiotoxicity; the mode of administration was continuous infusion in 72 percent, bolus infusion in 23 percent, intermediate duration infusional therapy in 3 percent, and oral in 2 percent [8]. Cardiac events occurred within 72 hours of the first cycle of the fluoropyrimidine in 69 percent of cases. Clinical symptoms included the following:

Angina – 45 percent

Myocardial infarction – 22 percent

Arrhythmias – 23 percent

Acute pulmonary edema – 5 percent

Cardiac arrest – 1.4 percent

Pericarditis – 1.4 percent

ECG evidence of ischemia or ST-T changes were recorded in 69 percent of patients, but cardiac enzymes were elevated in only 12 percent. In this review, 8 percent of the patients presenting with FU-induced cardiotoxicity died initially, and 13 percent of those reexposed to FU after an episode of fluoropyrimidine cardiotoxicity died [8].

Isolated ST-T wave changes without anginal symptoms are commonly observed in patients who undergo continuous ambulatory ECG monitoring [9,16,42]. Other changes seen on ambulatory monitoring of patients receiving FU include transient asymptomatic bradycardia [52] and prolongation of the corrected QT (QTc) interval with torsade de pointes [10,34,53].

Fluoropyrimidine cardiotoxicity tends to occur most commonly during the first cycle of administration [8,15,30]. The median time to initiation of symptoms is 12 hours following infusion initiation with a range between 3 and 18 hours [44], although in animal studies, median time to symptom onset has been more variable and has been noted as late as 48 hours into the infusion. Symptoms may develop during later cycles. As an example, in a report of 106 patients receiving short-term infusional FU as a component of the FOLFOX regimen (table 1), nine developed chest pain during treatment, and the onset was during courses 1, 2, 6, and 8 in three, four, one, and one patient(s), respectively [11].

Symptoms and ECG changes may disappear quickly after drug discontinuation or last several days.

MECHANISMS AND PATHOGENESIS — The underlying mechanism of toxicity is not established and is likely to be multifactorial [59]. The mechanism that is best supported by preclinical and clinical data is coronary vasospasm.

A possible mechanism to explain fluoropyrimidine cardiac effects is coronary vasospasm [7,9,51,60-64], which is supported by in vitro evidence of concentration-dependent vasoconstriction by fluorouracil (FU) on vascular smooth muscle cells in preclinical models [61], the documentation of coronary artery spasm angiographically following intravenous (IV) FU, and some cases of successful prophylaxis with calcium channel antagonists [62,65-67]. However, some characteristics of fluoropyrimidine cardiotoxicity are inconsistent with this hypothesis:

Vasospasms have not been consistently documented angiographically during symptomatic attacks, and reintroduction of FU in patients with a prior adverse cardiac effect has not resulted in coronary spasm as evidenced by coronary angiography [68,69].

In some patients with suspected FU-related cardiotoxicity, vasospasm has failed to be elicited with ergonovine provocation [70].

Echocardiography has demonstrated a reduced ejection fraction and significant akinesia of the left myocardium during attacks, and the global akinesia did not correspond to the segmental distribution of the major coronary arteries [9].

Vasodilator drugs are not consistently protective. (See 'Preventive strategies' below.)

Other pathophysiologic mechanisms probably contribute, including myocarditis [71], a direct myocardial toxic effect attributed to the antimetabolite effects of the drug, leading to a toxic cardiomyopathic picture [11,72], or a thrombogenic effect due to endothelial injury [73-76]. However, as FU is rapidly cleared from the bloodstream after bolus administration with a half-life of 15 to 20 minutes, a direct effect of the drug seems unlikely to be the cause of cardiotoxicity. However, the metabolite of FU, alpha-fluoro-beta-alanine (FBAL), is further catabolized into fluoroacetate, which is known to be highly cardiotoxic [77,78]. The lack of reported cardiac toxicity from fluoropyrimidines administered with the dihydropyrimidine dehydrogenase (DPD) enzyme inhibitors eniluracil and gimeracil lends further support to the possibility that metabolic pathways leading to FBAL generation may be a significant pathophysiologic component of cardiotoxicity [79-81]. (See 'Other oral fluoropyrimidines' below.)

Others evoke a takotsubo type of cardiomyopathy, a transient regional myocardial dysfunction that is precipitated by physical or emotional stress and thought to be related to exaggerated sympathetic stimulation [51,53,82-84]. The electrocardiograms (ECGs) of patients with presumed takotsubo cardiomyopathy often reveal ST-segment elevation, and cardiac enzymes are frequently mildly elevated, with a characteristic pattern of left ventricular dysfunction, mimicking an acute myocardial infarction. (See "Clinical manifestations and diagnosis of stress (takotsubo) cardiomyopathy".)

Finally, individual sensitivity to cardiotoxicity might result from inherited variations in the enzyme pathways involved in the catabolism of fluoropyrimidines, leading to variable levels of cardiotoxic degradation products. (See 'DPYD polymorphisms' above.)

MANAGEMENT — Fluoropyrimidine treatment should be immediately discontinued if symptoms develop suggestive of cardiotoxicity. Cardiac symptoms usually resolve with termination of fluorouracil (FU) treatment and antianginal treatment (eg, topical nitrates, calcium channel blockers) [8,33], and the cardiotoxicity appears to be completely reversible after cessation of therapy. In the review cited above, 69 percent of patients responded to conservative antianginal therapy; however, as noted above, 8 percent died [8].

The next step is to establish whether the cardiac symptoms can reasonably be attributed to the fluoropyrimidine.

Establishing the diagnosis — Recognition of fluoropyrimidine cardiotoxicity is clinically important. Repeated administration may lead to potentially avoidable permanent damage and even death. On the other hand, premature cessation of effective chemotherapy because of unrelated cardiac events may reduce chemotherapy effectiveness and may even compromise cancer cure.

Unfortunately, there is no test to definitively establish the diagnosis of fluoropyrimidine-induced cardiotoxicity. The association has been based primarily on increased incidence of cardiotoxicity in patients receiving fluoropyrimidines, the temporal relationship of cardiac effects to fluoropyrimidine administration, and reproducibility of symptoms with rechallenge. However, rechallenge can be fatal, and it is not generally pursued unless there are real questions as to the attribution of the cardiotoxicity to the drug, and only then in the absence of appropriate therapeutic alternatives to the continued use of a fluoropyrimidine.

Presentation with chest pain — For most patients with suspected fluoropyrimidine-induced chest pain in whom continued treatment with a fluoropyrimidine is thought to be preferable over a change to a non-fluoropyrimidine-containing regimen, diagnostic coronary arteriography is indicated to exclude another concomitant process that could account for an acute coronary syndrome presentation and to guide treatment decisions. Coronary computed tomography angiography (CCTA) is an alternative for patients deemed to be at low risk for native coronary artery disease (CAD).

Electrocardiogram (ECG) abnormalities lack sensitivity for the diagnosis of fluoropyrimidine-induced cardiac ischemia. In a systematic review of published studies addressing the incidence, manifestations, and predisposing factors for fluoropyrimidine cardiotoxicity, new onset ECG changes were present on single ECG acquisition in 6 to 33 percent of patients [35]. The most common ECG changes were ST deviations (0 to 25 percent), while arrhythmias were present in up to 21 percent of cases.

Although cardiac markers may be elevated [53,85,86], serial assessments of markers of myocyte injury (eg, troponins, MB isoenzyme of creatine kinase [CK-MB] fraction, N-terminal pro-brain natriuretic peptide [NT-proBNP] or B-type natriuretic peptide [BNP] levels) are not a sensitive marker for fluoropyrimidine cardiotoxicity, suggesting that, in many cases, the myocardial injury is not severe enough to cause significant necrosis [11,16,32,34,35,87,88].

Echocardiogram may disclose global left ventricular (LV) hypokinesis [9,53,89] or be completely normal.

Assessment of the coronary arteries is needed to assess the presence of native CAD. The most definitive test, particularly for patients with high-risk features (such as refractory angina, malignant arrhythmias, or shock), is coronary angiography. In most cases, coronary angiography will reveal normal coronary arteries or minor CAD [53,54,89,90]. If the coronary arteries are normal (or if the extent of CAD is thought not to be clinically significant), a presumptive diagnosis of fluoropyrimidine cardiotoxicity can be made. Issues related to management of antineoplastic therapy in these cases are discussed below. (See 'Management of antineoplastic therapy in individuals with presumed fluoropyrimidine cardiotoxicity' below.)

Noninvasive cardiovascular testing (eg, CCTA) may be an appropriate method to screen for CAD in patients who are at low risk for having CAD according to guidelines of the American College of Cardiology/American Heart Association (ACC/AHA) (table 2). In appropriately selected patients, CCTA has a strong negative predictive value (≥95 percent) for excluding the likelihood of major adverse cardiac events. Indications and limitations of CCTA (which include the potential for significant radiation exposure) are discussed in detail elsewhere. If the study is positive, diagnostic coronary angiography is indicated. (See "Noninvasive testing and imaging for diagnosis in patients at low to intermediate risk for acute coronary syndrome" and "Noninvasive coronary imaging with cardiac computed tomography and cardiovascular magnetic resonance", section on 'Radiation exposure' and "Radiation dose and risk of malignancy from cardiovascular imaging".)

The role of other forms of noninvasive testing, such as exercise stress testing, is unclear. There are extremely little data in the literature about this, and in our view, there is no convincing evidence that a negative exercise stress test rules out the possibility of fluoropyrimidine cardiotoxicity. These tests should not be considered a valid evaluation for the presence of fluoropyrimidine-induced cardiotoxicity.

An important point is that the presence of significant CAD at the time of cardiac catheterization does not eliminate the possibility that the fluoropyrimidine contributed to the chest pain. For patients in whom continued fluoropyrimidine therapy is preferred over a switch to a non-fluoropyrimidine-based regimen, revascularization according to standard guidelines is a reasonable approach, followed by a reattempt to administer the fluoropyrimidine, preferably with close monitoring. This approach may improve the patients' overall prognosis by increasing their ability to tolerate therapy [91]. If chest pain once again develops, then the presumptive diagnosis of fluoropyrimidine cardiotoxicity can be made.

The more difficult cases are those where non-critical or non-significant CAD (eg, 50 percent stenosis) is identified, and the decision as to the attribution of chest pain in these cases may be difficult. Provocative tests (ergonovine, acetylcholine, and hyperventilation) have been performed in the catheterization laboratory in an attempt to confirm the diagnosis. However, at present, the issue of provocative testing is extremely controversial. Guidelines on invasive testing/coronary angiography from the ACC/AHA do not specifically address this subject [92]. A more recent ACC/AHA statement did address provocative testing, but assigned it only a class IIB recommendation (benefit ≥ risk, with additional studies needed) and a level of evidence of only "C," and even then, only for those patients with no significant angiographic CAD and no documentation of transient ST-segment elevation when clinically relevant symptoms possibly explained by coronary artery spasm are present [93]. The lack of mention of coronary provocation testing in these guidelines has been noted, and although pharmacologic provocation testing is not frequently performed, some authors emphasize its safety, with comparable results when using ergonovine or acetylcholine [94,95]. The ACC/AHA statement does note that a higher level of expertise and careful monitoring are needed when provocation testing is performed, and this should only be done by expert groups. In our view, provocative testing is indicated for suitable patients as long as the requisite expertise is available in the catheterization laboratory. (See "Vasospastic angina", section on 'Role of coronary arteriography'.)

Other presentations — Patients may less commonly present with symptoms other than chest pain, particularly arrhythmias or heart failure. Temporal association with drug administration, and a lack of prior history of heart failure or arrhythmias are key to distinguish these symptoms as potentially related to the fluoropyrimidine. Even in the absence of overt heart failure, LV dysfunction (typically segmental wall motion abnormalities) is reported in a substantial number of cases of fluoropyrimidine cardiotoxicity (36 percent in one series [9]). Most reports of LV dysfunction and arrhythmias are described within 72 hours of drug administration. (See 'Clinical presentation' above.)

Rhythm changes are mostly benign, though malignant ventricular arrhythmias are rarely described [96].

The pattern of LV dysfunction may be important. Both global and segmental dysfunction have been described in association with fluoropyrimidine therapy, as has the particular segmental dysfunction pattern of stress-induced cardiomyopathy (which is also referred to as takotsubo cardiomyopathy or apical ballooning syndrome) [85]. Although the echocardiogram can be highly suggestive of apical ballooning syndrome, CAD still needs to be excluded with coronary arteriography. (See "Clinical manifestations and diagnosis of stress (takotsubo) cardiomyopathy".)

In most cases, there is relatively prompt improvement in the arrhythmias and LV dysfunction after discontinuation of the fluoropyrimidine [38,50-54].

Management of antineoplastic therapy in individuals with presumed fluoropyrimidine cardiotoxicity — The management of antineoplastic therapy in patients with presumed fluoropyrimidine cardiotoxicity depends on a number of factors, including the intent of therapy (ie, curative versus palliative), the availability of effective alternative non-fluoropyrimidine-containing regimens, and the availability of alternative fluoropyrimidines with a more favorable cardiotoxicity profile (eg, UFT and S-1).

Rechallenge — Rechallenging patients who are thought to have fluoropyrimidine-related cardiac toxicity is controversial. Recurrence rates are as high as 90 percent in several small series [8,9,32,42,58,97-99], and fatalities are reported (13 percent in one systematic review of the published literature [8]). Prophylactic strategies using nitrates or calcium channel blockers are not uniformly effective. In general, even though rechallenge may, in some cases, be successful [100,101], it is not recommended for most patients.

The decision to rechallenge must include a careful weighing of the risks against the possible benefits of retreatment in each individual patient. Rechallenge may reasonably considered in the following scenarios:

For patients who present with fluoropyrimidine-induced chest pain, are found to have significant CAD on diagnostic coronary angiography, and undergo revascularization in an attempt to improve the ability to tolerate therapy, rechallenge could reasonably be attempted if the benefits of drug continuation are felt to outweigh the risks.

For other highly selected patients with no significant CAD for whom there are no other reasonable therapeutic alternatives and in whom the risk to benefit ratio of continuing the fluoropyrimidine is thought to favor significant benefit, rechallenge (preferably with bolus rather than infusional FU) can be attempted.

If it is attempted, pretreatment for at least 48 hours using aspirin and both a calcium channel blocker (eg, diltiazem starting at 90 mg twice daily and titrated to 180 mg twice daily, if tolerated) and scheduled long-acting nitrates (eg, isosorbide dinitrate uptitrated to the highest possible dose based upon blood pressure), detailed informed consent, and careful observation on an inpatient unit with continuous ECG monitoring are advisable during drug infusion. FU administration should be immediately discontinued if any symptoms or signs of a cardiac event occur. In such cases, we avoid beta-blockers, given concerns for unopposed alpha receptor activation in any situation of potential increased adrenergic state (eg, pain, anxiety).

Change treatment schedule — For some patients, a switch from infusional to bolus FU may allow treatment to be successfully resumed [53,100,102-105]. The incidence of FU cardiotoxicity is lower with a bolus schedule than with a continuous infusion schedule or oral capecitabine. Based upon observations from the pooled analysis and individual case reports [8,54,103,106], we have successfully used this strategy for six patients who developed cardiotoxicity while receiving infusional FU or capecitabine and who were felt to require the drug because of a lack of other chemotherapeutic options [104].

In contrast, a switch over to capecitabine is not recommended for patients who develop cardiotoxicity while receiving infusional FU, as recurrent toxicity is frequently reported [97,98,104].

An important point is that the experience with this strategy is limited to few case reports, and bolus FU has also been associated with cardiotoxicity. (See 'Effect of schedule and dose' above.)

If this is attempted, patients should be pretreated with aggressive prophylaxis (pretreatment for at least 48 hours using aspirin and both a calcium channel blocker [eg, diltiazem starting at 90 mg twice daily and titrated to 180 mg twice daily, if tolerated] and scheduled long-acting nitrates [eg, isosorbide dinitrate uptitrated to the highest possible dose based upon blood pressure]), detailed informed consent, careful observation on an inpatient unit with continuous ECG monitoring, and immediate discontinuation of FU administration if any symptoms or signs of a cardiac event occur.

Dose reduction — Dose reduction is not an effective means of mitigating fluoropyrimidine-induced cardiotoxicity, and it cannot be recommended.

As noted above, the dose dependence of FU cardiotoxicity is unclear. (See 'Effect of schedule and dose' above.)

The majority of the data on the efficacy and safety of fluoropyrimidine dose reduction in combination with antianginal prophylaxis derive from case studies reporting varying results in small series of patients [8,32,33,100]. In a pooled analysis, cardiac symptoms were reproducible with rechallenge in 47 percent, and symptoms were elicited when the same patients were treated with lower doses [8]. Furthermore, 13 percent of those reexposed to FU died.

Preventive strategies — Taken together, the available evidence suggests only limited benefit from prophylactic treatment with either nitrates or calcium channel blockers prior to rechallenge, and we suggest not pursuing this approach for most patients.

There are conflicting results in the literature about the role of antianginal therapy (calcium channel blockers or nitrates) in preventing symptoms with fluoropyrimidine retreatment [6,8,18,43,65,68,69,72,100,104,107-111]. There are no randomized trials assessing the benefit of this approach. However, many retrospective studies document the failure of either of these prophylactic strategies to mitigate fluoropyrimidine cardiotoxicity:

In the review cited above, 68 percent of patients responded to conservative antianginal therapy, but prophylactic coronary vasodilators had limited efficacy in patients who were rechallenged with FU [8].

In one study of seven patients manifesting cardiac toxicity after administration of FU, prophylactic nitroglycerin failed to prevent ECG changes suggestive of myocardial ischemia during repeat infusion [72].

A similar lack of protective efficacy was seen with nifedipine 60 mg/day and diltiazem 80 mg/day administered with simultaneous intravenous nitroglycerin at therapeutic doses [107,108].

Another group prophylactically treated 58 patients receiving infusional FU as a component of induction chemotherapy for advanced head and neck cancer with verapamil 120 mg three times a day [43]. Signs of ischemia appeared in a similar percentage of patients as in a historical cohort treated similarly without prophylaxis (12 versus 13 percent), leading the authors to conclude that calcium channel blockade was not protective.

Other oral fluoropyrimidines — Oral fluoropyrimidines with a lower incidence of cardiotoxicity include UFT and S-1.

UFT – UFT is a 1:4 molar combination of the FU prodrug ftorafur (Tegafur) with uracil (which competitively inhibits the degradation of FU, resulting in sustained plasma and intratumoral concentrations). Where available, UFT may be considered for patients who have cardiotoxicity from FU or capecitabine. Angina, arrhythmias, heart failure, myocardial infarction, and cardiac arrest are reported less frequently (<1 percent) with UFT than with FU or capecitabine [79-81,112,113].

However, there are no prospective or retrospective studies on large numbers of patients with fluoropyrimidine-induced cardiotoxicity who were retreated using UFT; the experience with this strategy is limited to isolated case reports, many of which support the safety of this approach [17,30,114,115]. However, at least one case report documents a fatality in one such case [17].

UFT is available in Japan and other Asian countries, South America, and Spain, but not the United States.

S-1 – S-1 is an oral fluoropyrimidine that includes three different agents: ftorafur, gimeracil (5-chloro-2,4 dihydropyridine, a potent inhibitor of dihydropyrimidine dehydrogenase [DPD]), and oteracil (potassium oxonate, which inhibits phosphorylation of intestinal FU, thought responsible for treatment-related diarrhea). It is theorized that cardiotoxicity rates will be lower with this agent because of the inhibitory influence of gimeracil on DPD, which catalyzes the degradation of FU into alpha-fluoro-beta-alanine (FBAL) [77,116]. In fact, there are no published reports of cardiotoxicity with S-1 [117-122]. Nevertheless, it is important to note that DPD inhibition is not complete, and the experience with S-1 in patients with prior FU- or capecitabine-induced cardiotoxicity is limited to case reports [77].

S-1 is available in several Asian countries and most of Europe, but not in the United States.

Other treatment options

Switch to a non-fluoropyrimidine-containing chemotherapy regimen — Where it is feasible, a switch to a non-fluoropyrimidine-containing chemotherapy regimen is the preferred strategy.

This is most often successful for patients with metastatic disease. As an example, for patients with metastatic colorectal cancer, potentially effective non-fluoropyrimidine-containing regimens include irinotecan alone, irinotecan plus oxaliplatin, cetuximab or panitumumab (for patients with RAS wild-type tumors), trifluridine-tipiracil, regorafenib, and ramucirumab. Outside of the United States, options include raltitrexed as monotherapy or in combination regimens [110,114,123-125], S-1 and UFT (oral fluoropyrimidines with a lower risk of cardiotoxicity), and combinations of UFT with irinotecan (TEGAFIRI), oxaliplatin (TEGAFOX, UFOX) [126-129], or mitomycin [130]. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials".)

Particular challenges in treating gastrointestinal cancers — Unfortunately, for patients treated in the adjuvant or neoadjuvant setting for gastrointestinal cancer, a switch to a non-fluoropyrimidine-containing regimen is more problematic since fluoropyrimidines are an integral component of most effective regimens.

This is a particularly difficult issue for two settings: patients receiving adjuvant treatment for colorectal cancer, especially in the United States, and those receiving radiation therapy (RT) with radiosensitizing doses of a fluoropyrimidine.

Adjuvant therapy colorectal cancer — Globally, the standard therapy for resected node-positive disease is an oxaliplatin and fluoropyrimidine-containing regimen. For patients with node-negative disease who are deemed at high enough risk to warrant adjuvant chemotherapy, a fluoropyrimidine-based therapy is typically recommended. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer" and "Adjuvant chemotherapy for resected stage II colon cancer" and "Adjuvant therapy for resected rectal adenocarcinoma".)

For patients with fluoropyrimidine-related cardiotoxicity, the available options depend on geographic location. Outside of the United States, where available, UFT, S-1, and raltitrexed are all options:

Based upon the results of randomized trials, six months of UFT plus leucovorin (LV) is a standard approach for adjuvant chemotherapy of stage III colon cancer in Japan, and where available, S-1 is an acceptable alternative to UFT/LV for stage III disease. (See 'Other oral fluoropyrimidines' above and "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'UFT and S-1'.)

Both S-1 and UFT/LV have been combined with oxaliplatin in metastatic colorectal cancer [128,131], but there are no data in the adjuvant setting.

In addition, raltitrexed as a single agent has documented activity in a randomized phase III trial compared with LV-modulated FU [132]. In contrast, experience with raltitrexed plus oxaliplatin is limited [125,133,134].

Unfortunately, UFT, S-1, and raltitrexed are not available in many regions, including the United States.

As a result, the optimal approach for patients in the Unites States who develop FU-induced cardiotoxicity remains a challenge. One option is challenge with an FU bolus-containing regimen, such as the Roswell Park weekly regimen of LV-modulated FU [135,136] or, for patients who need oxaliplatin, FLOX (FU plus LV and oxaliplatin) [136]. However, if this approach is attempted, we suggest aggressive prophylaxis (pretreatment for at least 48 hours with aspirin and both a calcium channel blocker [eg, diltiazem starting at 90 mg twice daily and titrated to 180 mg twice daily, as tolerated] and scheduled long-acting nitrates [eg, isosorbide dinitrate uptitrated to the highest possible dose based upon blood pressure]), along with detailed informed consent, careful observation on an inpatient unit with continuous ECG monitoring, and immediate discontinuation of FU administration if any symptoms or signs of a cardiac event occur.

Radiosensitization during external beam RT — Infusional FU and capecitabine are used in a variety of gastrointestinal cancers (rectum, anus, esophagus, pancreas, stomach) to enhance the effects of external beam radiation therapy (RT).

In some cases, an alternative non-fluoropyrimidine-based radiosensitizing regimen (such as weekly carboplatin and paclitaxel for esophageal cancer or gemcitabine for pancreatic cancer) can be offered. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus", section on 'CROSS trial' and "Treatment for potentially resectable exocrine pancreatic cancer", section on 'Gemcitabine-based approaches'.)

If there are no other options and continuation of a radiosensitizer is thought to be clinically important, another option is switching to a bolus FU regimen [104]. However, the available data on the safety of this method are scant, and cardiotoxicity may still develop in patients treated with bolus FU. This approach should only be undertaken using aggressive prophylaxis (pretreatment for at least 48 hours with aspirin and both a calcium channel blocker [eg, diltiazem starting at 90 mg twice daily and titrated to 180 mg twice daily, as tolerated] and scheduled long-acting nitrates [eg, isosorbide dinitrate uptitrated to the highest possible dose based upon blood pressure]), along with a detailed informed consent, careful observation on an inpatient unit with continuous ECG monitoring, and immediate discontinuation of FU administration if any symptoms or signs of a cardiac event occur. (See 'Change treatment schedule' above.)

Other treatment modalities — Patients who are not candidates for other chemotherapy agents or who have an organ-limited disease should be assessed for local and/or direct therapy. Such options may include surgical resection, radiofrequency ablation (RFA), yttrium-90 (Y-90) radioembolization, transarterial chemoembolization (TACE), and others [137-140]. Selection of the patient and weighing risk versus benefits should be addressed in each patient.

Is there an antidote? — The antitumor effects and systemic toxicities associated with FU are related to its metabolite fluorouridine triphosphate (FUTP). Uridine is a naturally occurring pyrimidine nucleoside that augments cellular uridine triphosphate (UTP) pools and competes with FUTP for incorporation into the host ribonucleic acid (RNA) of hematopoietic progenitor and gastrointestinal mucosal cells, thereby attenuating FU/FUTP toxicity in normal tissues [141-144]. In preclinical and clinical studies, sustained uridine concentrations of at least 50 micromol/L are required to confer protection from the toxic effects of FU/FUTP on normal tissues. However, there are no data examining the utility of uridine to reverse FU-related cardiotoxicity. Furthermore, the low oral bioavailability, risk of fever and phlebitis, and the requirement of central venous access for parenteral administration limit its clinical utility.

Uridine triacetate is an orally active prodrug of uridine and is efficiently absorbed from the gastrointestinal tract and deacetylated, yielding uridine and acetate [145-148]. In contrast to oral uridine, uridine acetate is not a substrate for the catabolic enzyme uridine phosphorylase and does not require the pyrimidine transporter for absorption from the gastrointestinal tract. Consequently, administration has a higher oral bioavailability than uridine itself. Uridine triacetate was approved by the US Food and Drug Administration in December 2015 for emergency use following FU or capecitabine overdose for patients who exhibit early onset, severe, or life-threatening toxicity affecting the cardiac or central nervous system; and/or early onset, unusually severe adverse reactions (eg, gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of FU or capecitabine administration, such as might occur in a DPD-deficient patient. Use of this agent might be considered in a patient with severe toxicity, including fluoropyrimidine-related cardiac toxicity that persists despite discontinuation of the drug and initiation of antianginal therapy. Its utility in other settings is unclear. (See "Enterotoxicity of chemotherapeutic agents", section on 'Uridine triacetate'.)

SUMMARY AND RECOMMENDATIONS

Fluoropyrimidine cardiotoxicity is an infrequent but potentially lethal side effect. Despite the frequency of use of fluoropyrimidines to treat a variety of cancers, fluoropyrimidine-associated cardiotoxicity remains a poorly defined entity, particularly in regards to the underlying mechanism and optimal management. Recognition of fluoropyrimidine cardiotoxicity is clinically important. Continued administration may lead to potentially avoidable permanent damage and even death. On the other hand, premature cessation of effective chemotherapy because of unrelated cardiac events may compromise cancer cure. (See 'Introduction' above.)

Cardiotoxicity may be more frequent with infusional as compared with bolus regimens of fluorouracil (FU). The incidence of cardiac toxicity with capecitabine is within the range of that reported with infusional FU. Although several potential risk factors for fluoropyrimidine cardiotoxicity have been suggested (including underlying heart disease, older age, concomitant administration of other drugs with cardiac side effects, and radiation therapy [RT]), the available data on all of these risk factors is conflicting, and the predictive accuracy of these risk factors is not sufficient to provide any clinically useful means of identifying patients who are at a high enough risk for cardiotoxicity to justify withholding treatment. (See 'Incidence and risk factors' above.)

The most common clinical manifestation of fluoropyrimidine cardiotoxicity is chest pain, which can be either nonspecific or anginal and is usually associated with electrocardiographic (ECG) changes. Symptoms may occur at rest or be effort-related. Symptoms tend to occur most often in the first cycle of administration, but they can be delayed. Serum biomarkers of cardiac injury may or may not be elevated. Less commonly, patients may present with palpitations, dyspnea, diffuse pleuritic pain, supraventricular arrhythmias, and hypotension. In rare cases, myocardial infarction, bradycardia, ventricular fibrillation and ventricular tachycardia, myocarditis and heart failure, sudden death, and pericarditis have been reported. (See 'Clinical presentation' above.)

The underlying mechanism of fluoropyrimidine cardiotoxicity is not established but is likely to be multifactorial. The mechanism that is best supported by preclinical and clinical data is coronary vasospasm. (See 'Mechanisms and pathogenesis' above.)

Fluoropyrimidine treatment should be immediately discontinued if symptoms develop suggestive of cardiotoxicity. Cardiac symptoms usually resolve with termination of FU treatment and antianginal treatment (eg, topical nitrates, calcium channel blockers) [8,33], and the cardiotoxicity appears to be completely reversible after cessation of therapy. (See 'Management' above.)


The next step is to establish whether the cardiac symptoms can reasonably be attributed to the fluoropyrimidine. Unfortunately, there is no test to definitively establish the diagnosis of fluoropyrimidine-induced cardiotoxicity. (See 'Establishing the diagnosis' above.)

For most patients with suspected fluoropyrimidine-induced chest pain in whom continued treatment with a fluoropyrimidine is thought to be preferable over a change to a non-fluoropyrimidine-containing regimen, diagnostic coronary arteriography is indicated to exclude another concomitant process that could account for an acute coronary syndrome presentation and to guide treatment decisions. For patients undergoing diagnostic coronary arteriography, provocative testing is indicated for suitable patients as long as the requisite expertise is available in the catheterization laboratory. Coronary computed tomography angiography is a reasonable alternative to coronary arteriography for patients deemed to be at low risk for native coronary artery disease (CAD). (See 'Presentation with chest pain' above.)


For patients who present with heart failure or arrhythmias, the temporal association with drug administration and a lack of prior history of heart failure or arrhythmias are key to distinguishing these symptoms as potentially related to the fluoropyrimidine. Both global and segmental dysfunction have been described, as has the particular segmental dysfunction pattern of stress-induced (Takotsubo) cardiomyopathy (or apical ballooning syndrome). In most cases, discontinuation of the fluoropyrimidine is followed by prompt improvement in left ventricular function and resolution of the arrhythmia. (See 'Other presentations' above.)

The management of antineoplastic therapy in patients with presumed fluoropyrimidine cardiotoxicity depends on a number of factors, including the intent of therapy (ie, curative versus palliative), the availability of effective alternative non-fluoropyrimidine-containing regimens, and geographic location. (See 'Other oral fluoropyrimidines' above.)

In general, rechallenge with FU or capecitabine is not recommended for most patients. Recurrence rates are as high as 90 percent in several small series, and fatalities are reported. Prophylactic strategies using nitrates or calcium channel blockers are not uniformly effective. The decision to rechallenge must include a careful weighing of the risks against the possible benefits of retreatment in each individual patient. Rechallenge may reasonably considered in the following scenarios:

For patients who present with fluoropyrimidine-induced chest pain, are found to have significant CAD on diagnostic coronary angiography, and undergo revascularization in an attempt to improve the ability to tolerate therapy, rechallenge could reasonably be attempted if the benefits of drug continuation are felt to outweigh the risks.

For other highly selected patients with no significant CAD for whom there are no other reasonable therapeutic alternatives and in whom the risk to benefit ratio of continuing the fluoropyrimidine is thought to favor significant benefit, rechallenge (preferably with bolus rather than infusional FU) can be attempted. (See 'Change treatment schedule' above.)

If rechallenge is attempted, patients should be treated with aggressive prophylaxis (pretreatment for at least 48 hours using aspirin and both a calcium channel blocker [eg, diltiazem starting at 90 mg twice daily and titrated to 180 mg twice daily if tolerated] and scheduled long-acting nitrates [eg, isosorbide dinitrate uptitrated to the highest possible dose based upon blood pressure]), detailed informed consent, careful observation on an inpatient unit with continuous ECG monitoring, and immediate discontinuation of FU administration if any symptoms or signs of a cardiac event occur.


For patients with metastatic disease treated with palliative intent, the preferred strategy in most cases is to switch to a non-fluoropyrimidine-containing chemotherapy regimen or a different treatment modality. (See 'Other treatment options' above.)


Management of patients treated in the adjuvant or neoadjuvant setting is more challenging, and decisions must be individualized. Decision-making is especially difficult for patients being treated in the adjuvant setting for colorectal cancer (see 'Adjuvant therapy colorectal cancer' above):

Where available, treatment with the oral thymidylate synthesis inhibitor raltitrexed carries with it minimal cardiotoxicity risk, but there are case reports of fatalities when raltitrexed is administered to patients with fluoropyrimidine-induced cardiotoxicity. It must be used cautiously. (See 'Switch to a non-fluoropyrimidine-containing chemotherapy regimen' above.)

UFT and S-1 are oral FU prodrugs in combination with a dihydropyrimidine dehydrogenase (DPD) inhibitor, and there is a lower intrinsic risk of cardiotoxicity, especially with S-1. Where available, these agents are a reasonable substitute for FU and capecitabine, although experience in patients who have fluoropyrimidine-related cardiotoxicity is limited to case reports and small series. (See 'Other oral fluoropyrimidines' above and 'Adjuvant therapy colorectal cancer' above.)

For patients treated in the United States, where none of these three drugs are available, the best approach is uncertain. One option is challenge with an FU bolus-containing regimen, such as the Roswell Park weekly regimen of leucovorin-modulated FU [135,136] or, for patients who need oxaliplatin, FLOX (FU plus leucovorin and oxaliplatin) [136]. However, if this approach is attempted, patients should be treated with aggressive prophylaxis (pretreatment for at least 48 hours using aspirin and both a calcium channel blocker [eg, diltiazem starting at 90 mg twice daily and titrated to 180 mg twice daily if tolerated] and scheduled long-acting nitrates [eg, isosorbide dinitrate uptitrated to the highest possible dose based upon blood pressure]), detailed informed consent, careful observation on an inpatient unit with continuous ECG monitoring, and immediate discontinuation of FU administration if any symptoms or signs of a cardiac event occur.

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