Clinical Study
Chemotherapy 2011;57:381–387 Received: March 28, 2011
DOI: 10.1159/000331645
Clinical and Electrocardiography Changes
in Patients Treated with Capecitabine
Dogan Koca a Tarik Salman a Ilkay Tugba Unek a Ilhan Oztop a Hulya Ellidokuz b
Murat Eren c Ugur Yilmaz a
a
Division of Medical Oncology, Department of Internal Diseases, Medical Faculty, b Department of Preventive
Oncology, Institute of Oncology, and c Department of Cardiology, Medical Faculty, Dokuz Eylül University,
Izmir, Turkey
Key Words
Capecitabine ⴢ Heart ⴢ Side effects
Abstract
Background: We aimed to identify the incidence of cardiac
events with capecitabine treatment. Methods: The study in-
cluded 52 patients (median age 59 years) with cancer treated
at our Medical Oncology Clinic between 2009 and 2010. Car-
diac events from capecitabine treatment were classified into
4 groups: cardiac symptoms, physical signs, electrocardiog-
raphy (ECG) findings, and severe adverse cardiac effects. Re-
sults: The patients received either single-agent capecita-
bine or a combination chemotherapy including capecita-
bine. After initiation of capecitabine, 18 patients (34.6%) had
new onset cardiovascular symptoms, 6 (11.5%) had new on-
set physical signs and 17 (32.6%) had new onset ECG find-
ings. New onset ECG findings included prolonged corrected
QT interval (n = 10, 19.2%) and prolonged PR interval (n = 3,
5.8%). Severe adverse capecitabine-induced cardiac side ef-
fects were observed in 5.8% of the patients, but none of the
patients had myocardial infarction or died. Conclusion: Car-
diac events are not rare during capecitebine treatment and
patients should be followed closely to avoid cardiac morbid-
ity and mortality. Copyright © 2011 S. Karger AG, Basel
© 2011 S. Karger AG, Basel
0009–3157/11/0575–0381$38.00/0
Fax +41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/che
Accepted after revision: August 6, 2011
Published online: October 12, 2011
Introduction
Capecitabine is an orally administered fluoropyrimi-
dine carbamate; it is an antimetabolite and the prodrug
of 5-fluorourocil (5-FU). The drug is absorbed in the in-
testines with a bioavailability of 80%. It is converted to
metabolically active substrate 5-FU. It is widely used for
the treatment of various malignancies – colorectal can-
cers and breast cancer being the most common types.
The most frequent toxic effects of capecitabine are diar-
rhea and hand-foot syndrome. Other side effects include
myelosuppression, febrile neutropenia, mucositis, alope-
cia, nausea, vomiting, and transient and asymptomatic
bilirubin increases [1, 2].
Cardiac side effects of capecitabine are an important
problem and resemble those of 5-FU, as capecitabine is
converted in vivo to 5-FU. Although the mechanism of
the cardiotoxicity of capecitabine is not well understood,
it is thought that capecitabine and its metabolites may
cause vasoconstriction (which can be relieved by nitrates),
vascular spasms, endothelial injury and myocarditis, all
of which result in cardiac damage. Other factors that ex-
acerbate the cardiac toxicity of capecitabine are a history
of cardiac ischemia or arrhythmia, a history of mediasti-
nal irradiation and a history of cardiotoxic drug use [3].
Dr. Dogan Koca, MD
Division of Medical Oncology, Department of Internal Diseases
Medical Faculty, Dokuz Eylül University, Inciraltı
TR–35340 Izmir (Turkey)
Tel. +90 232 412 4801, E-Mail dogankoca @ hotmail.com
 Although cardiac side effects of 5-FU are well known,
research on capecitabine is limited and requires further
examination [4]. Capecitabine use is increasing because
it is usually more convenient than 5-FU. As such, deter-
mination of the cardiac side effects of this widely used
drug is as important as its use [5].
As important achievements are recently being realized
in cancer treatment, with the combination of chemother-
apy, radiotherapy and surgery, advances in chemothera-
py amplified this success. Since both the extension of the
cancer patients’ lifespan and the cardiac side effects that
might occur with the newly used agents directly affect the
expected lifespan of the patient, the protection of cancer
patients against cardiac side effects becomes as important
as the treatment of cancer [6, 7]. In the present study, we
aimed to identify the incidence of cardiac events with
capecitabine treatment.
Materials and Methods
Patient Population
The study included cancer patients treated with single-agent
capecitabine or a combination chemotherapy with capecitebine at
the Department of Internal Medicine, Division of Medical Oncol-
ogy Clinic, Faculty of Medicine, Dokuz Eylül University, Izmir,
Turkey, between June 2009 and June 2010. None of these patients
had been treated with capecitabine before study entry. A history
of cardiac disease was not an exclusionary criterion for the study,
and all patients with an indication for capecitabine treatment
were included.
Evaluation of Patients before Treatment
After determining the cardiovascular medical history of the
patients and performing cardiovascular system and physical ex-
aminations, 12-lead electrocardiography (ECG) was performed
in all patients. Capecitabine was started in patients in whom car-
diac pathology was not observed. Patients with a cardiovascular
problem were referred to the Cardiology Department, and the
recommended cardiac tests and treatments were performed. The
patients that were cleared for capecitabine treatment by the Car-
diology Department began the treatment.
Capecitabine Treatment
Capecitabine was given in 21-day cycles as a 2-week on 1-week
off regimen. In patients receiving capecitabine monotherapy, the
dose was 2,500 mgⴢm–2ⴢday–1, and for those taking capecitabine
in combination with other drugs, the dose was 2,000 mgⴢm–2ⴢ
day–1. The dosage of the other drugs was as follows: docetaxel 75
mgⴢm–2 for 21 days; oxaliplatin 130 mgⴢm–2 for 21 days; vinorel-
bine 25 mgⴢm–2 on the 1st and 8th day of a 21-day interval; irino-
tecan 180 mgⴢm2 for 21 days; lapatinib 1,250 mgⴢday–1.
Evaluation of Cardiac Side Effects
Patients were monitored for cardiac events 1 h before starting
capecitabine treatment and during the first 4 h of capecitabine
382 Chemotherapy 2011;57:381–387
Table 1. Patient characteristics
Features Patients
n %
Gender
Female 39 75.0
Male 13 25.0
Disease
Breast cancer 32 61.5
Colon cancer 18 34.6
Gastric cancer 2 3.9
treatment; the first examination was at least 1 h after the treat-
ment had begun. During capecitabine treatment, cardiac exami-
nations were performed on the 4th, 21st and 24th day. Cardiac
evaluation was based on patient complaints, physical examina-
tion, ECG, and when needed, echocardiography (ECHO). Cardiac
side effects after the start of capecitabine treatment were divided
into 4 groups: cardiac symptoms, physical signs, ECG findings
and severe adverse cardiac effects. PR interval values between 120
and 200 ms were accepted as normal for ECG evaluation. Cor-
rected QT (QTc) values 1 440 ms were accepted as prolonged. Sta-
ble or unstable angina pectoris, myocardial ischemia, myocardial
infarction and cardiac arrhythmias were considered severe ad-
verse cardiac effects. When severe adverse cardiac effects defi-
nitely attributable to capecitabine were observed, capecitabine
treatment was discontinued and the required cardiac therapies
were planned and started.
Statistical Analysis
Statistical data analysis was performed using SPSS version 15.0
for Windows. The t test was used to analyze the means of 2 groups,
the Mann-Whitney U test was used to compare independent
group medians, and the ␹2 test was used to compare independent
group ratios. p values !0.05 were accepted as statistically signifi-
cant.
Results
Patient Characteristics
The present study included 52 patients (median age 59
years) who underwent capecitabine treatment. Among
the patients, 39 (75%) were females and 13 (25%) were
males. Overall, 32 patients (61.5%) had metastatic breast
cancer, 18 (34.6%) had metastatic colon cancer and 2
(3.9%) had metastatic gastric cancer (table 1).
Treatment plans for the patients were designed ac-
cording to standard protocols. In total, 18 (34.6%) pa-
tients received capecitabine as monotherapy and 34
(65.4%) had capecitabine in combination with other
Koca /Salman /Unek /Oztop /Ellidokuz /
Eren /Yilmaz
Table 2. Treatment protocols Table 3. ECG findings before capecitabine treatment

Features Patients Findings Patients

n % n %

Treated with capecitabine monotherapy 18 34.6 All important ECG findings 37 71.2
Treated with capecitabine in combination Nonspecific ST-T changes 13 25
with other drugs 34 65.4 Sinus tachycardia 10 19.2
Capecitabine+docetaxel 17 32.6 Prolonged PR interval 6 11.5
Capecitabine+oxaliplatine 8 15.3 Prolonged QTc interval 5 9.6
Capecitabine+vinorelbine 1 1.9 First-degree AV block 5 9.6
Capecitabine+irinotecan 1 1.9 Negative T wave 5 9.6
Capecitabine+lapatinib 7 13.4 Old myocardial infarction 4 7.7
First-line capecitabine treatment 26 50 ST segment depression 4 7.7
Second-line capecitabine treatment 16 30.8 Atrial premature beats 3 5.8
Third-line capecitabine treatment 10 19.2 Poor R wave progression 3 5.8
History of thoracic irradiation 29 55.7 Left bundle branch block 3 5.8
History of anthracycline therapy 30 55.7 Ventricular premature beats 2 3.8
History of trastuzumab treatment 9 17.3 Aneurysmatic ST segment elevation 2 3.8
Left anterior fascicular hemiblock 2 3.8
Low voltage 2 3.8
Right bundle branch block 1 1.9
Left ventricle hypertrophy signs 1 1.9
drugs. Docetaxel, oxaliplatin, vinorelbine, irinotecan and
AV = Atrioventricular.
lapatinib were the drugs used in combination with
capecitabine. Overall, 26 patients (50%) had capecitabine
treatment as first-line chemotherapy, 16 (30.8%) as sec-
ond-line therapy and 10 patients (19.2%) had capecitabine
Table 4. New onset symptoms, physical signs and ECG findings
as third-line therapy (table 2). after starting capecitabine treatment
Overall, 29 of the patients (55.7%) had thoracic irra-
diation before this study, 30 (55.7%) had previously un- Sign/symptom Patients
dergone a chemotherapy regimen that contained anthra-
n %
cycline, and 9 (17.3%) had trastuzumab treatment before
this study (table 2). New onset complaints 18 34.6
Palpitation 12 23.0
Cardiac Evaluation of the Patients before Angina pectoris 5 9.6
Dyspnea 4 7.6
Capecitabine Treatment
New onset signs on physical examination 6 11.5
In total, 12 patients (23.0%) had cardiovascular system Tachycardia 3 5.8
symptoms before capecitabine treatment; 8 patients had Hypotension 2 3.8
palpitations and 7 patients had dyspnea – the 2 most fre- Hypertension 1 1.9
quent symptoms before capecitabine treatment. Overall, New onset ECG findings 16 30.8
At least 1 h after capecitabine treatment 2 3.8
16 of the patients (30.8%) had a history of cardiovascular
On the 4th day of capecitabine treatment 12 23.0
disease. The most frequent previous cardiac diseases On the 21st day of capecitabine treatment 5 9.6
were hypertension (n = 11) and myocardial infarction due On the 24th day of capecitabine treatment 6 11.5
to coronary arterial disease (n = 6); 10 of these patients
had used antihypertensive medications and 3 used anti-
hyperlipidemic drugs in combination with antihyperten-
sives. portant ECG findings before capecitabine treatment. Fre-
Physical examination of 16 patients (26.9%) was posi- quent findings were nonspecific ST-T abnormality (n =
tive for cardiovascular system signs before starting 13, 25.0%) and sinus tachycardia (n = 10, 19.2%; table 3).
capecitabine treatment. Among these physical signs, Additionally, ECHO was performed in 11 patients (21.1%),
tachycardia (n = 5) and pretibial edema (n = 4) were the and pathological cardiovascular signs were observed in 5.
most frequent. Among the patients, 37 (71.8%) had im- Left ventricle systolic and diastolic dysfunction, along

Capecitabine and the Heart Chemotherapy 2011;57:381–387 383

Table 5. ECG findings during capecitabine treatment

Newly detected ECG findings At 1–4 h after On the On the On the Total of signs
treatment start 4th day 21st day 24th day
n %

Sinus tachycardia 2 5 1 3 11 21.1

Sinus bradycardia 1 1 1.9
ST segment depression 3 1 1 5 9.6
Left axis deviation 2 1 3 5.8
Nonspecific ST-T changes 1 1 1 1 4 7.6
Biphasic T waves 1 1 1.9
Negative T waves 1 1 1 3 5.8
Low voltage 1 1 1.9
Premature atrial beat 1 1 2 3.8
Premature ventricular beat 1 1 2 3.8
Prolonged QTc interval 7 3 10 19.2
Prolonged PR interval 2 1 3 5.8
Median progress of the QTc interval based on ECG, ms 418 420 416 415 52 100.0
Median progress of the PR interval based on ECG, ms 158 152 153 151 52 100.0

QTc values >440 ms were accepted as prolonged. PR interval values between 120 and 200 ms were accepted as normal for ECG
evaluation.

with septal hypokinesia was observed in 1 patient, and
mild left ventricle hypokinesia was noted in the other 4
patients. Nonetheless, capecitabine treatment was not
contraindicated in any of the patients.
Cardiac Evaluation of the Patients after Capecitabine
Treatment
Patients had cardiac examinations during the first 4 h
of capecitabine treatment; the first examination was at
least 1 h after the treatment had begun. During capecitabi-
ne treatment, cardiac examinations were performed on
the 4th, 21st and 24th day. These examinations showed
that 18 patients (34.6%) had new onset cardiovascular
symptoms, 6 (11.5%) had new onset physical signs and 17
(32.6%) had new onset ECG signs (table 4). The patients’
new onset ECG findings are shown in table 5. QTc inter-
vals increased due to capecitabine treatment in 10 pa-
tients (19.2%), shown in table 5. After capecitabine treat-
ment, the PR interval in 3 patients (5.8%) was prolonged.
On the 4th day of treatment, the QTc interval was pro-
longed in 2 patients that also had prolonged PR intervals.
The patients’ PR intervals based on ECG are shown in
table 5.
Evaluation of capecitabine-induced adverse cardiac
side effects showed that there were no significant differ-
ences in cardiovascular symptoms or cardiac physical
signs, as compared to before treatment (p = 0.189 and
0.077, respectively); however, differences in new onset
ECG findings and ECG findings before treatment were
statistically significant (p = 0.001). Another important
finding was that these differences occurred more fre-
quently on the 4th day of treatment (p = 0.016, 0.011 and
0.031, respectively)
Capecitabine-induced severe adverse cardiac side ef-
fects were noted in 3 patients (5.8%). One patient present-
ed to hospital due to angina and dyspnea, which began on
the 4th day of capecitabine treatment. Physical examina-
tion showed tachycardia and hypotension, and ECG
showed ST segment depression with a prolonged QTc in-
terval. Another patient presented with palpitations on the
21st day of treatment and was observed to be rhythmic
and tachycardic on physical examination. ECG showed
ST depression and negative T waves on anterior precor-
dial derivations. The third patient presented with dys-
pnea on the 4th day of treatment. The patient was rhyth-
mic, tachycardic and hypotensive on physical examina-
tion. ECG showed sinus tachycardia and a prolonged QTc
interval. Capecitabine treatment was discontinued in all
3 of these patients. During follow-up, all abnormal car-
diovascular system findings, physical examination find-
ings, symptoms and ECG findings improved. Severe ad-
verse cardiac side effects, such as myocardial infarction
and death, did not occur.

384 Chemotherapy 2011;57:381–387 Koca /Salman /Unek /Oztop /Ellidokuz /

Eren /Yilmaz
 Factors That Influenced Adverse Cardiac Side Effects
More of the patients with abnormal ECHO findings
before capecitabine treatment had new onset cardiovas-
cular complaints (p = 0.022), more patients with a history
of thoracic irradiation had ECG abnormalities after treat-
ment (p = 0.036), more breast cancer patients had pro-
longed QTc intervals (at the statistical limit; p = 0.055),
and among the breast cancer patients, more of those with
a history of trastuzumab treatment had prolonged QTc
intervals (p = 0.043).
Discussion
Capecitabine treatment is becoming more common
because it is easy to use and can be more convenient than
5-FU. Cardiac toxicity of chemotherapeutics might cause
significant morbidity and mortality. As data on the ad-
verse cardiac effects of capecitabine are limited, we pro-
spectively evaluated 52 patients scheduled for capecitabi-
ne treatment. Overall, 18 patients (34.6%) had new onset
cardiovascular symptoms, 6 (11.5%) had new onset phys-
ical signs and 17 (32.6%) had new onset ECG findings.
More patients with abnormal ECHO findings before
capecitabine treatment had new onset cardiovascular
complaints, more patients with a history of thoracic ir-
radiation had ECG abnormalities after treatment, more
breast cancer patients had prolonged QTc intervals, and
among the breast cancer patients, more of those with a
history of trastuzumab treatment had prolonged QTc
intervals. Overall, 3 patients (5.8%) had severe adverse
cardiac side effects that resulted in discontinuation of
capecitabine; however, none of the patients had fatal car-
diac side effects such as myocardial infarction or death.
Cardiac side effects of capecitabine are similar to those
of 5-FU and the two drugs cause cardiac toxicity by much
the same mechanism, as capecitabine is converted to
5-FU in vivo. First, we considered to explicate the cardiac
side effects caused by 5-FU in order to better understand
the adverse cardiac side effects of capecitabine that cause
vasoconstriction, vascular spasm, endothelial injury and
myocarditis [3].
Treatment with 5-FU has been commonly used in on-
cology since it was first introduced in 1957 [8]. Cardio-
toxicity due to 5-FU is the second most frequent cause of
chemotherapeutic-related cardiac toxicity after anthra-
cyclines [9]. Cardiac side effects of capecitabine vary from
angina to myocardial infarction [10, 11]. The incidence of
5-FU-induced cardiac toxicity is about 1.2–7.6%, and the
incidence of life-threatening toxicity is !1% [12]. Thick-
Capecitabine and the Heart
ening of intramyocardial arteriolar walls, myocardial ne-
crosis, ventricular hypertrophy and increased apoptosis
in myocardial and epicardial cells, as well as vasospasm
cause cardiac toxicity in 5-FU treatment [13]. Infusion of
5-FU, concomitant leucovorin use [14], combining 5-FU
with other drugs, and radiotherapy increase the risk of
cardiac toxicity [15]. The primary treatment of 5-FU-in-
duced cardiac toxicity is discontinuation of the drug [16],
and administration of calcium channel blockers such as
verapamil or nitrates are suggested for treatment [17].
ECG is an effective tool for determining the cardiac
side effects of 5-FU [18] and ECG testing is routinely per-
formed before treatment [19]. Extreme ECG findings and
concomitant symptoms are significant indicators for the
underlying coronary arterial disease. At the same time,
these findings could be an indicator for expansive athero-
sclerosis such as peripheral artery disease and high blood
pressure. In addition, ECG findings, which are very im-
portant for the diagnosis of cardiac diseases, are at the
same time very important for the monitoring of the ap-
plied treatments. Therefore, changes in ECG findings are
paid greater attention [20, 21]. 5-FU-induced cardiac tox-
icity can be easily determined based on the typical ECG
findings combined with chest pain, palpitations, nausea
and sweating [9]. Another important testing method is
the use of a Holter monitor [22]. In patients who had pre-
viously received a chemotherapy regimen with anthracy-
cline or transtuzumab, or mediastinal radiotherapy, the
cardiac toxicity risk increases with the usage of anti-
metabolite group chemotherapy medications. Therefore,
ECHO examination of those patients takes an important
place in the monitoring [7]. Besides, the monitoring of the
serum troponin level in those patients could also be a very
important indicator [23].
Although reports on cardiac side effects of 5-FU are
common, the literature does not contain any studies con-
cerning effects associated with capecitabine [4]. Cardiac
toxicity of capecitabine is as important as its use, as it is
commonly and easily used when 5-FU is contraindicated
[5]. For example, the incidence of 5-FU-induced cardiac
toxicity is reported to be 1.2–18.0%, whereas the inci-
dence of capecitabine-induced cardiac toxicity is yet to be
reported [21, 22].
Capecitabine-induced cardiac side effects and their
frequency are similar to those observed with infusion of
5-FU [14]. Capecitabine causes adverse cardiac side ef-
fects similar to those of 5-FU via coronary vasospasm,
direct cytotoxic endothelial injury, immunoallergic reac-
tions and thrombus formation. Clinical equivalents are
chest pain, ischemic ECG findings, myocardial infarc-
Chemotherapy 2011;57:381–387 385
tion, ventricular arrhythmias and death [24–26]. As with
5-FU, the cardiac side effects of capecitabine are more
common in patients with a history of cardiac ischemia
and arrhythmia, a history of mediastinal irradiation and
a history of cardiotoxic drug use [3]. Together with a rare
cardiac toxicity, capecitabine is an agent which might
cause side effects that might even reach to severe and pro-
longed acute coroner syndrome and it should not be ad-
ministered to patients with a cardiotoxicity history due
to fluoropyrimidine analogous medication [25]. A his-
tory of anthracycline or other cardiotoxic drug use, or
concomitant use of these drugs with capecitabine, in-
creases the risk of adverse cardiac side effects. In case se-
vere cardiac side effects occur, it is possible to eliminate
them via stopping the capecitabine. Along with that,
while combining capecitabine with other chemotherapy
medication, the patient must be monitored carefully and,
if possible, such a combination should be avoided [27–29].
Moreover, patients with a history of cardiovascular dis-
ease and/or renal failure are more prone to the adverse
cardiac side effects of capecitabine [30]. Capecitabine is
not contraindicated in patients with cardiovascular dis-
ease, but such patients must be observed closely due to the
increased risk of adverse cardiac side effects [31].
When capecitabine-induced adverse cardiac side ef-
fects occur, they manifest as chest pain, arrhythmia and
myocardial infarction and result in death in 11.3% of pa-
tients [32]. In cases of capecitabine-induced adverse car-
diac side effects in which fluoropyrimidines are indicat-
ed, 5-FU or raltitrexed may be used [31]. As raltitrexed is
not a common drug, 5-FU is frequently used, adminis-
tered as bolus, and is combined with nitrates or calcium
channel blockers. Whereas the nitrates are better in the
treatment of myocardial ischemia, addition of calcium
channel blockers could be more effective in the preven-
tion of recurrences [33].
The usage of ECHO and the treadmill stress test,
which are found effective in reduction of morbidity and
mortality rates in patients treated with fluoropyrimidine,
in the pretreatment phase and during monitoring, takes
an important place in the diagnosis and treatment of car-
diac diseases which constitute a significant problem for
cancer patients, whose lifespan is extended through de-
veloping cancer treatments [6, 7, 22]. In our study, ECHO
and the treadmill stress test were not routinely applied to
each patient in pretreatment assessment. ECHO was ap-
plied only to patients of the Cardiology Department
where it is necessary to evaluate who has previously re-
ceived treatments containing anthracycline or trastu-
zumab. Among these, the fact that the treadmill stress
386 Chemotherapy 2011;57:381–387
test was not routinely used might be a shortcoming, but
we do not regard the absence of ECHO as a significant
shortcoming because in the previous study on 5-FU con-
ducted by our clinic [15], it was emphasized that there was
no significant change in ECHO.
Since most patients received capecitabine in combina-
tion with other chemotherapeutic drugs, it is not possible
to conclude that all the observed cardiac side effects were
due to capecitabine alone. To determine the adverse car-
diac side effects of capecitabine more precisely, addition-
al studies are needed in which capecitabine is used as
monotherapy.
As the severe cardiac event incidence is found to be
5.8% in our study, the patients whom we treated with
capecitabine had never undergone fluoropyrimidine
treatment and 34.6% of the patients received capecitabine
as monotherapy. Although in one important study where
Ng et al. [29] determined a higher rate of severe cardiac
event incidence, i.e. 6.5%, it is observed that one patient
who died while receiving the first cure treatment had a
severe cardiac disease, another patient died at home, and
31% of the patients had been treated with 5-FU or
capecitabine, and capecitabine was combined with other
agents (oxaliplatine). Therefore, the higher ratio deter-
mined in the study of Ng et al. [29] might have been due
to the administration of combined treatment.
In our study, 5.8% of the patients experienced
capecitabine-induced severe cardiac side effects. A his-
tory of cardiac disease did not negatively affect capecitabi-
ne treatment; however, patients with abnormal ECHO
findings had a greater risk of developing cardiovascular
system signs during capecitabine treatment. Moreover,
patients with a history of thoracic irradiation and those
with a history of trastuzumab treatment more frequently
experienced capecitabine-induced adverse cardiac side
effects on the 4th day of treatment with ECG abnormali-
ties.
In conclusion, the patients who are to be treated with
capecitabine should be carefully assessed in terms of car-
diac diseases, usage of cardiotoxic medications and me-
diastinal RT history, and capecitabine must either be ap-
plied carefully in this group of patients or, if possible, not
be used at all. Since it causes nonspecific complaints and
minor changes in ECG for other patients, it is a safe med-
ication in cardiac terms and its usage is recommended.
Koca /Salman /Unek /Oztop /Ellidokuz /
Eren /Yilmaz
 References
1 Saif MW, Chu E: Antimetabolites; in DeVita
VT, Lawrence TS, Rosenberg SA (eds): De-
Vita, Hellman, and Rosenberg’s Cancer:
Principles and Practice of Oncology. Phila-
delphia, Lippincott Williams & Wilkins,
2008, vol 1, pp 427–437.
2 Taguchi T, Nakayama T, Masuda N, Yo-
shidome K, Akagi K, Nishida Y, Yoshikawa
Y, Ogino N, Abe C, Sakamoto J, Noguchi S,
Kinki Breast Cancer Study Group: Study of
low-dose capecitabine monotherapy for met-
astatic breast cancer. Chemotherapy 2010;
56:166–170.
3 Yahalom J, Portlock CS: Cardiac toxicity; in
DeVita VT, Lawrence TS, Rosenberg SA
(eds): DeVita, Hellman, and Rosenberg’s
Cancer: Principles and Practice of Oncology.
Philadelphia, Lippincott Williams &
Wilkins, 2008, vol 1, pp 2678–2688.
4 Scott PA, Ferchow L, Hobson A, Curzen NP:
Coronary spasm induced by capecitabine
mimicks ST elevation myocardial infarction.
Emerg Med J 2008;25:699–700.
5 Coughlin S, Das S, Lee J, Cooper J:
Capecitabine induced vasospastic angina.
Int J Cardiol 2008;130:e34–e36.
6 Yeh ET, Bickford CL: Cardiovascular com-
plications of cancer therapy: incidence,
pathogenesis, diagnosis, and management. J
Am Coll Cardiol 2009;53:2231–2247.
7 Monsuez JJ, Charniot JC, Vignat N, Artigou
JY: Cardiac side-effects of cancer chemo-
therapy. Int J Cardiol 2010;144:3–15.
8 Timour Q, Lombard-Bohas C, Slim R, Barel
C, Bui-Xuan B, Tabib A, Bricca G, Malonne
H, Vial T, Iordescu D, Descotes J: Cardiotox-
icity of 5-fluorouracil: report of 6 cases.
Therapie 2002;57:302–306.
9 Anand AJ: Fluorouracil cardiotoxicity. Ann
Pharmacother 1994;28:374–378.
10 Kuropkat C, Griem K, Clark J, Rodriguez ER,
Hutchinson J, Taylor SG 4th: Severe cardio-
toxicity during 5-fluorouracil chemothera-
py: a case and literature report. Am J Clin
Oncol 1999;22:466–470.
11 Sclafani F, Carnaghi C, Colombo P, Bozza-
relli S, De Vincenzo F, Rimassa L, Giorgetti
PL, Santoro A: Case report of acute aortic
dissection during treatment with capecitabi-
ne for a late recurrence of breast cancer. Che-
motherapy 2010;56:203–207.
Capecitabine and the Heart
12 Alter P, Herzum M, Soufi M, Schaefer JR,
Maisch B: Cardiotoxicity of 5-fluorouracil.
Cardiovasc Hematol Agents Med Chem
2006;4:1–5.
13 Tsibiribi P, Bui-Xuan C, Bui-Xuan B, Lom-
bard-Bohas C, Duperret S, Belkhiria M,
Tabib A, Maujean G, Descotes J, Timour Q:
Cardiac lesions induced by 5-fluorouracil in
the rabbit. Hum Exp Toxicol 2006; 25: 305–
309.
14 Kosmas C, Kallistratos MS, Kopterides P,
Syrios J, Skopelitis H, Mylonakis N, Karabe-
lis A, Tsavaris N: Cardiotoxicity of fluoropy-
rimidines in different schedules of adminis-
tration: a prospective study. J Cancer Res
Clin Oncol 2008;134:75–82.
15 Meydan N, Kundak I, Yavuzsen T, Oztop I,
Barutca S, Yilmaz U, Alakavuklar MN: Car-
diotoxicity of de Gramont’s regimen: inci-
dence, clinical characteristics and long-term
follow-up. Jpn J Clin Oncol 2005;35:265–270.
16 Teixeira L, Barry S, Debourdeau P, Cohen A,
Tournigand C: Cardiotoxicity of 5-fluoro-
uracil. Bull Cancer 2004; 91(suppl 3):154–
158.
17 Alter P, Herzum M, Schaefer JR, Maisch B:
Coronary artery spasm induced by 5-fluoro-
uracil. Z Kardiol 2005;94:33–37.
18 Oztop I, Gencer M, Okan T, Yaren A, Altekin
E, Turker S, Yilmaz U: Evaluation of cardio-
toxicity of a combined bolus plus infusional
5-fluorouracil/folinic acid treatment by
echocardiography, plasma troponin I level,
QT interval and dispersion in patients with
gastrointestinal system cancers. Jpn J Clin
Oncol 2004;34:262–268.
19 Luján J, García De Burgos F, Jordán A, García
M, Reyes F, Espinosa MD: Angina related to
5-fluorouracil. Rev Esp Cardiol 2002; 55:
764–767.
20 De Bacquer D, De Backer G, Kornitzer M,
Blackburn H: Prognostic value of ECG find-
ings for total, cardiovascular disease, and
coronary heart disease death in men and
women. Heart 1998;80:570–577.
21 Zairis MN, Manousakis SJ, Adamopoulou
EN, Makrygiannis SS, Glyptis MP, Beldekos
DJ, Patsourakos NG, Olympios CD, Prekates
AA, Foussas SG: Continuous 12-lead elec-
trocardiographic ST monitoring and long-
term prognosis after successful coronary
stenting. Am Heart J 2006;151:892–897.
Chemotherapy 2011;57:381–387
22 Yilmaz U, Oztop I, Ciloglu A, Okan T, Tekin
U, Yaren A, Somali I, Alacacioglu A, Kirimli
O: 5-Fluorouracil increases the number and
complexity of premature complexes in the
heart: a prospective study using ambulatory
ECG monitoring. Int J Clin Pract 2007; 61:
795–801.
23 Cardinale D, Sandri MT: Role of biomarkers
in chemotherapy-induced cardiotoxicity.
Prog Cardiovasc Dis 2010;53:121–129.
24 Goldsmith YB, Roistacher N, Baum MS:
Capecitabine-induced coronary vasospasm.
J Clin Oncol 2008;26:3802–3804.
25 Frickhofen N, Beck FJ, Jung B, Fuhr HG, An-
drasch H, Sigmund M: Capecitabine can in-
duce acute coronary syndrome similar to
5-fluorouracil. Ann Oncol 2002;13:797–801.
26 Arbea L, Coma-Canella I, Martinez-Monge
R, García-Foncillas J: A case of capecitabine-
induced coronary microspasm in a patient
with rectal cancer. World J Gastroenterol
2007;13:2135–2137.
27 Gianni L, Herman EH, Lipshultz SE, Minot-
ti G, Sarvazyan N, Sawyer DB: Anthracy-
cline cardiotoxicity: from bench to bedside.
J Clin Oncol 2008;26:3777–3784.
28 Telli ML, Hunt SA, Carlson RW, Guardino
AE: Trastuzumab-related cardiotoxicity:
calling into question the concept of revers-
ibility. J Clin Oncol 2007;25:3525–3533.
29 Ng M, Cunningham D, Norman AR: The
frequency and pattern of cardiotoxicity ob-
served with capecitabine used in conjunc-
tion with oxaliplatin in patients treated for
advanced colorectal cancer (CRC). Eur J
Cancer 2005;41:1542–1546.
30 Jensen SA, Sørensen JB: Risk factors and pre-
vention of cardiotoxicity induced by 5-fluo-
rouracil or capecitabine. Cancer Chemother
Pharmacol 2006;58:487–493.
31 van Halteren HK, Liem AH, Planting AS:
Myocardial ischaemia as a result of treat-
ment with capecitabine. Ned Tijdschr Ge-
neeskd 2007;151:1469–1473.
32 Manojlovic N, Babic D, Stojanovic S, Filipo-
vic I, Radoje D: Capecitabine cardiotoxicity,
case reports and literature review. Hepato-
gastroenterology 2008; 55:1249–1256.
33 Wijesinghe N, Thompson PI, McAlister H:
Acute coronary syndrome induced by
capecitabine therapy. Heart Lung Circ 2006;
15:337–339.
387
Copyright: S. Karger AG, Basel 2012. Reproduced with the permission of S. Karger AG, Basel. Further
reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright
holder.