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Cancer Treatment Reviews xxx (2013) xxx–xxx
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Cancer Treatment Reviews
journal homepage: www.elsevierhealth.com/journals/ctrv
Complications of Treatment
Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine:
A systematic review of incidence, manifestations and predisposing factors
Anne Polk a,⇑, Merete Vaage-Nilsen a,2, Kirsten Vistisen b,3, Dorte L Nielsen b,1
a
b
Department of Cardiology, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2730 Herlev, Denmark
Department of Oncology, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2730 Herlev, Denmark
a r t i c l e
i n f o
Article history:
Received 28 December 2012
Received in revised form 6 March 2013
Accepted 11 March 2013
Available online xxxx
Keywords:
5-fluorouracil
Cardiotoxicity
Capecitabine
Systematic review
a b s t r a c t
Purpose: To systematically review the incidence, manifestations and predisposing factors for cardiovascular toxicity in cancer patients treated with systemic 5-fluorouracil or capecitabine.
Design: We searched PubMed, EMBASE and Web of science for studies with P20 cancer patients evaluating cardiovascular toxicity of 5-fluorouracil and capecitabine. We hand searched the reference lists of
all included studies. Study selection and assessment of risk of bias were performed by two authors independently.
Results: We identified 30 eligible studies (1 meta-analyses of 4 RCTs, 18 prospective and 11 retrospective). Symptomatic cardiotoxicity occurred in 0–20% of the patients treated with 5-fluorouracil and in
3–35% with capecitabine. The most common symptom was chest pain (0–18.6%) followed by palpitations
(0–23.1%), dyspnoea (0–7.6%) and hypotension (0–6%). Severe clinical events such as myocardial infarction, cardiogenic shock and cardiac arrest occurred in 0–2%. Mortality rates ranged from 0 to 8%. Asymptomatic cardiac influence was demonstrated on ECG, in NT-proBNP measurements and with ultrasonic
cyclic variation of integrated backscatter. Predisposing factors were mostly tested in univariate analyses.
Preexisting cardiac disease was a risk factor in some studies, but there were divergent results. There was
some evidence for increased cardiotoxicity during continuous infusion schedules and with concomitant
cisplatin treatment. The effects of previous or current chest-radiotherapy were ambiguous.
Conclusion: Larger studies suggest an incidence of symptomatic cardiotoxicity of 1.2–4.3% during fluorouracil treatment, however subclinical cardiac influence are common. Possible risk factors are cardiac comorbidity, continuous infusion schedules and concomitant cisplatin treatment, but existing evidence are
of insufficient quality.
Ó 2013 Elsevier Ltd. All rights reserved.
Introduction
The antimetabolite 5-flourouracil (5-FU) is widely used alone or
in combination regimens in the treatment of gastrointestinal,
breast and head and neck tumours and its oral prodrug, capecitabine, is approved for treatment of colorectal cancer and metastatic
breast cancer. Both 5-FU and capecitabine can induce cardiotoxicity in spite that capecitabine is activated preferentially in tumour
cells. Fluorouracil cardiotoxicity presents during the course of
chemotherapy and the spectrum of cardiac effects include acute
coronary syndromes, arrhythmias, heart failure, hyper- and hypotension, cardiogenic shock and sudden death.1,2
⇑ Corresponding author. Tel.: +45 28 49 75 98.
E-mail addresses: [email protected] (A. Polk), Merete.Vaage-Nilsen@
regionh.dk (M. Vaage-Nilsen), [email protected] (K. Vistisen), dorte.
[email protected] (D.L Nielsen).
1
Tel.: +45 38 68 23 44.
2
Tel.: +45 38 68 96 08.
3
Tel.: +45 38 68 29 76.
The frequency and clinical manifestations of 5-FU-induced cardiotoxicity has been addressed in several studies during the last 4
decades. More recently, studies of cardiotoxicity from capecitabine
have emerged. However, the reported frequency varies greatly inbetween studies. It has been hypothesized that the wide variation
in frequency and manifestations could be explained by differences
in criteria for cardiotoxicity, differences in treatment schedules
and differences in susceptibility of patients.1,2 Hence, several attempts to identify potential predisposing factors for fluorouracilinduced cardiotoxicity have been made. Accurate estimation of
the frequency of cardiotoxicity and identification of predisposing
factors is important to identify patients at greatest risk and to
guide safe application of these drugs. Therefore, we performed a
systematic review of the incidence, manifestations and predisposing factors for cardiotoxicity from systemic 5-FU and capecitabine
treatment in cancer patients. We stratified available evidence in:
symptoms and clinical manifestations, electrocardiographic
changes, changes in biomarkers and cardiovascular function assessed by imaging techniques.
0305-7372/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ctrv.2013.03.005
Please cite this article in press as: Polk A et al. Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: A systematic review of incidence, manifestations and predisposing factors. Cancer Treat Rev (2013), http://dx.doi.org/10.1016/j.ctrv.2013.03.005
2
A. Polk et al. / Cancer Treatment Reviews xxx (2013) xxx–xxx
Methods
Data synthesis
Search strategy
We summarised data using descriptive summary measures. We
did not attempt a meta-analysis because of heterogeneity in design, eligibility criteria, treatment schedules, baseline patient characteristics and outcomes considered among studies.
We searched PubMed (1966 – July 31, 2012), EMBASE (1980 – July
31, 2012) and Web of science (1900 – July 31, 2012) for publications in English on human using the search terms: (1) 5-fluorouracil OR 5-FU OR capecitabine; (2) ((Heart OR cardia OR myocardi)
AND ischemia) OR arrhythmia; (3) cardiotoxi (4) anthracycline
[MeSH]. The final search combined #1 AND (#2 OR #3) NOT #4.
Additionally we hand searched reference lists of retrieved papers.
Eligibility criteria
Studies were included if they met all following criteria: (1) P20
patients; (2) studies on patients with solid cancers; (3) treatment
with systemic 5-FU-infusion or oral capecitabine as monotherapy
or in combination with other chemotherapeutics; (4) studies
reporting the frequency of cardiovascular toxicity. We excluded
studies where cardiac medications were given prophylactic. If
sequential upgrades on same study were published, we selected
the most recent update.
Study selection process
All citations retrieved were reviewed on full citation, abstracts
and indexing terms (where provided in the databases) by two
authors independently (AP and DN). They were rated as ‘‘relevant’’,
‘‘possibly relevant’’ or ‘‘not relevant’’. Full-text publications of all
potentially relevant articles were reviewed for eligibility independently by same two authors. All disagreements in rating or eligibility were resolved by discussion of the full-text articles till
consensus was reached.
Data extraction
One author extracted the following data from all studies meeting eligibility criteria: The exact question addressed by the study,
the number of patients enrolled in the study, dose, duration and
mode of administration of 5-FU or capecitabine, name and dose
of concomitant administered chemotherapeutic drugs, duration
of follow up and cardiovascular profile of cohort participants at
baseline. The outcomes of interest were cardiac adverse effects,
mortality of likely cardiac origin and risk factors for cardiotoxicity.
Assessment of risk of bias
We graded studies as ‘‘randomised controlled trial’’ (RCT), ‘‘prospective study’’ (a priori fixed selection criteria) with or without a
control group or ‘‘retrospective study’’ (of register data, medical
charts etc.). We assessed the risk of bias within studies according
to predefined criteria: (1) cohort consecutively sampled (selection
bias); (2) adequate follow-up (attrition bias); (3) blinding of outcome assessors to treatment and duplicate outcome assessment
(detection bias); (4) all pre-specified outcomes reported (outcome
reporting bias); (5) adjustment for possible confounders i.e. cardiovascular co-morbidity and treatment with other potentially cardiotoxic drugs; (6) predefined criteria for outcomes measured; (7)
systematically assessment of outcomes; (8) well-described patient
characteristics. Point 1–5 evaluated internal validity and 6–8
external validity. Assessment of risk of bias was done at study-level
by two authors (AP and DN). The risk of bias across studies was assessed graphically by plotting the incidence of cardiotoxicity and
mortality in relation to study size (patient number).
Results
Results of literature search
The search strategy retrieved 1351 publications after duplicates
were removed (Fig. 1). On the basis of full citation, abstracts and
indexing terms 1313 publications were excluded. Of the remaining
38 publications, which were retrieved in full text for detailed
examination, 31 met eligibility criteria. Hand searching the reference lists of retrieved papers identified one additional relevant
publication. From the 32 papers 30 different studies were identified. One retrospective study (3) could include patients from cohorts of 3 prospective studies.4–6 However, these studies did not
evaluate the same types of outcome measure (symptoms, ECG
changes, echocardiography etc.) and are therefore included in different sections of the review.
Description of the studies
The studies were published between 1978 and 2012 and were
performed in 25 different reference centers (Table 1). Twenty-five
studies investigated cardiotoxicity of 5-FU, two studies investigated cardiotoxicity of capecitabine and three studies included
both patients treated with 5-FU and capecitabine. In total, 7973 patients were treated with 5-FU and 1386 patients were treated with
capecitabine. Studies of 5-FU included a median of 68 (range 22–
593) patients in prospective studies and a median of 346 (range
140–1350) patients in retrospective studies. Studies of capecitabine included a median of 153 (range 52–832) patients. Mean or
median age of the patients ranged from 47 to 67 years. Most commonly, the site of primary cancer was gastrointestinal, breast or
head and neck, however, in 9 studies of 5-FU patients with neuroendocrine, lung, prostate, cervix, pancreatic, hepatic, bladder or biliary tumours were included.
5-FU was administered as bolus infusion in 1766 patients, continuous infusion in 2432 patients and intermediate infusion in 461
patients, while the mode of administration was not reported for
3304 patients. 5-FU was given as a single agent to 1553 patients,
in combination with other chemotherapeutics in 3303 patients
whereas it was not reported for 3114 patients. Combination regimens varied extensively. The co-administered drugs included leucovorin, anthracyclines, oxaliplatin, cyclophosphamide, cisplatin,
mitomycin, etoposide, interferon, paclitaxel, methotrexate, vincristine, peptichemio (a peptide complex of m-L-phenylalanine mustard), gemcitabine and irinotecan. Various dosing regimens for
both 5-FU and co-administered drugs were used. Capecitabine
was administered in doses of 1000–2500 mg/m2/day as a 2-week
on 1-week off regimen. It was either given as a single agent
(1118 patients) or in combination (268 patients) with oxaliplatin,
docetaxel, carboplatin, vinorelbine, irinotecan or lapatinib (only
in 7 patients).
Baseline cardiovascular status of the patients varied extensively
in-between studies of both 5-FU and capecitabine. The prevalence
of patients with previous myocardial infarction or pre-existing cardiovascular disease ranged from 0% to 28% and risk factors for
ischemic heart disease were present in 0–64% of the patients.
Please cite this article in press as: Polk A et al. Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: A systematic review of incidence, manifestations and predisposing factors. Cancer Treat Rev (2013), http://dx.doi.org/10.1016/j.ctrv.2013.03.005
A. Polk et al. / Cancer Treatment Reviews xxx (2013) xxx–xxx
3
Fig. 1. Flow of literature search, study identification and study selection.
Assessment of risk of bias within studies
One study was a meta-analyses of 4 RCTs,7 18 were prospective cohort studies4–6,8–24 and 11 were retrospective cohort studies.3,25–34
Two prospective studies included a control group.21,22 Of the retrospective studies, 725,26,28,29,32–34 included all patients treated in a
given period whilst this was unclear for 4 studies.3,27,30,31 Follow
up was adequate in 14 studies,6–8,11–14,16,19,20,22–24,26 inadequate in
2 studies18,32 and unclear in 14 studies.3–5,9,10,15,17,21,25,27–31,33,34
The risk of detection bias was high in most studies as blinding of
outcome assessors were only reported for 5 studies6,11,13,20,30 and
multiple outcome assessors were used for some outcomes in 4
studies.4,6,17,20 In the two studies21,22 with a control group outcome
assessors were not blinded to the intervention. The risk of outcome
reporting bias was low in 22 studies3–18,20,22–26,29,30 where all prespecified outcomes were reported and not applicable for 7 studies19,27,28,31–34 where no outcomes were pre-specified. Eleven studies4–7,11,13,17–19,24,26,30 adjusted for the possible influence of
cardiovascular co-morbidity by restriction of the study cohort or
with statistical methods. Two studies16,28 reported previous antineoplastic treatment with potentially cardiotoxic drugs and three
studies16,18,31 reported previous thoracic radiotherapy, but none
of these studies made any adjustments based on this information.
External validity varied among most studies. An objective
definition for outcome criteria was reported in 12
studies3,7,9–11,13,14,17,20,22,24–26 and for some parameters in 3 studies.6,16,28 Systematically assessment of outcomes was performed
in 16 studies.4–9,11–16,18,20–24,30 For 17 studies3,7,8,11–24,32 patient
characteristics was well-described. Duration of follow-up was
reported in 3 studies.6,8,13
Studies of symptomatic cardiotoxicity
The incidence of symptomatic cardiotoxicity was evaluated in
23 studies3,7,8,10–13,15–20,23,25–29,31–34 (21 5-FU, 5 capecitabine). It
ranged from 0% to 20% in patients treated with 5-FU and from 3%
to 35% in patients receiving capecitabine (Table 2). Chest pain
was the most frequently reported symptom. It occurred with an
incidence of 0–18.6%, often with contemporary ischemic changes
in the electrocardiogram. Palpitations (0–23.1%), dyspnoea (0–
7.6%) and hypotension (0–6%) were also frequent symptoms while
heart failure was infrequent (0–0.7%). Serious cardiac events such
as myocardial infarction, cardiogenic shock and cardiac arrest occurred in 0–2%. The mortality rate ranged from 0–8% in studies
of 5-FU and 0–0.7% in studies of capecitabine.
Studies of electrocardiographic manifestations
In 9 studies4,6,8,12,15,16,20,23,30 single ECGs were recorded in all
patients at predefined time points during treatment and in 3 studies20,23,24 continuous electrocardiographic (Holter) monitoring
were performed (Table 3). The studies included a median of 50 patients (22–102) and treatment was 5-FU-infusion in 9 studies and
capecitabine in one study.
New onset electrocardiographic abnormalities were present on
single ECG acquisition in 6–33% of the patients. The most common
abnormalities were ST-deviations in 0–25%, whilst arrhythmias
were present in 0–21%. The arrhythmias included sinus tachycardia, sinus bradycardia, atrial fibrillation and ventricular fibrillation.
Continuous electrocardiographic (Holter) monitoring demonstrated complex ventricular arrhythmia in 22% and premature ectopic beats in 70% in the study by Yilmaz et al.24, whilst STdeviations were the major finding present in 68% in the study by
Rezkalla et al.20
One study demonstrated prolonged Pmax and increased Pdispersion.4 Significantly prolonged QTc was demonstrated by Wacker et al.23 3 months from baseline whilst Orditura et al.30 could
not demonstrate any alterations in QTc shortly after the beginning
of therapy. In the study by Oztop et al.6 QTmax and QTdispersion
increased as early as 24 h after induction of chemotherapy and
progressed through subsequent cycles.
Cardiac biomarkers and other biomarkers
Three studies assessed plasma troponin I or T levels during 5-FU
therapy.6,9,21 Of these, 2 found no significant changes in troponin
Please cite this article in press as: Polk A et al. Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: A systematic review of incidence, manifestations and predisposing factors. Cancer Treat Rev (2013), http://dx.doi.org/10.1016/j.ctrv.2013.03.005
Design
Khan et al.28
(2012)
Koca et al.16
(2011)
Jensen
et al.13,14
(2010,
2012)
Salepci
et al.21
(2010)
Participants
Treatment
No.
Female/
male
Age, median
(range)
Pre-treatment CVD profilea
Site of primary cancer
Regimen (No. of patients)
Mode of
administration
Retrospective
301
226/75
Previous anthracyclines: 58%
NR
52
39/13
Breast, colon, gastric
Prospective
106
59/47
64 (37–81)
Previous XRT: 56%
Previous anthracyclines: 56%
CVD or symptoms: 31%
Previous AMI: 12%
ECG abnormalities: 72%
CVD: 7.5%
Risk factors for IHD: P47%
5-FU mono. (2)
5-FU comb. (299)
CAP mono. (18)
CAP comb. (34)
NR
Prospective
Mean 47 (18–
81)
NR
Colorectal
5-FU comb. (106)
CI
Prospective
with control
group
59 (31 in the
study group, 28
controls)
Study group:
57 (37–78)
CVD: 0.0%
Study group: Gastric, colon
Study group: 5-FU comb. (30)
BI
Control
group: 60
(37–75)
Mean 67 (56–
70)
Previous AMI: 0.0%
Controls: various
CVD: 0.0%
Colorectal, breast and head and
neck
Control group: platin derivatives,
anthracylines, cyclophaphamide or
gemcitabine
5-FU comb. (590)
PO
Kosmas
et al.17
(2008)
Yilmaz
et al.24
(2007)
Holubec
et al.9
(2007)
Tsibiribi
et al.33
(2006)
Jensen
et al.26
(2006)
Prospective
644
Study
group:
10/21
Control
group:
11/17
NS
Prospective
27
12/15
54 (19–70)
Risk factors for IHD: P 64%
CVD: 0.0%
Risk factors for IHD: 26%
Colon, gastric, esophageal, hepar
CAP mono. (54)
5-FU comb.
CI (209) II
(381)
PO
CI
Prospective
42
NR
52 (34–82)
NR
Colorectal
5-FU comb.
CI
Retrospective,
unclear
1350
NR
NR
CVD: 0.0%
Esophageal, gastric, colon,
pancreas
5-FU
NR
Retrospective
668
NR
NR
NR
Gastrointestinal
CAP mono. (214)
CAP comb. (81)
5-FU mono. (362)
Ng M et al.19
(2005)
Prospective
153
63/90
63 (33–81)
Colorectal
Meydan
et al.3
(2005)
Ceyhan
et al.4,5
(2004)
Retrospective
231
93/138
59 (23–87)
IHD: 2.6%
Other CVD: 7.2%
ECG abnormalities: 22%
Risk factors for IHD: 45%
IHD: 6.5%
Risk factors for IHD: 24%
PO
PO
BI (352) CI
(10)
CI
PO
Prospective
37
11/26
Mean 62 (22–
83)
Oztop et al.6
(2004)
Südhoff
et al.22
(2004)
Wacker
et al.23
(2003)
Prospective
25
22
8/14
63 (44–76)
Prospective
with control
group
Prospective
60 (30 in study
group, 30
controls)
102
23/34
63 (28–87)
32/70
62 (39–78)
History of CVD: 0.0%
Echocardiographic CVD: 0.0%
ECG abnormalities: 0.0%
Riskfactors for CVD: 0.0%
CVD: 0.0%
Antiarrhythmic agents: 0.0%
CVD or previous AMI: 20% of cases and 6.7%
of controls
IHD: 12.5%
Cardiac medications: 18%
5-FU comb. (11)
CAP comb. (153)
Gastrointestinal, pancreas,
gallbladder, breast,
neuroendocrine, head and neck
Colorectal, gastric breast, lung
carcinoid, nasopharyngeal
5-FU comb.
CI
CI
5-FU comb.
CI
Gastrointestinal
5-FU comb.
CI
Gastrointestinal, lung, lymphoma,
head and neck
Study group: 5-FU comb. (30)
Controls: platin derivatives,
anthracylines or cyclophaphamide
5-FU mono. (69)
5-FU combb (33)
BI (21) CI (9)
Digestive tract, nasopharynx
CI (82) BI (20)
A. Polk et al. / Cancer Treatment Reviews xxx (2013) xxx–xxx
Reference
(year)
4
Please cite this article in press as: Polk A et al. Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: A systematic review of incidence, manifestations and predisposing factors. Cancer Treat Rev (2013), http://dx.doi.org/10.1016/j.ctrv.2013.03.005
Table 1
Characteristics of the 30 studies.
Meta-analysis
of 4 RCTs
1425
721/722
MCRC: 64
(29–87)
MBC: Mean
53–56 (26–
78)
66 (45–75)
Balloni
et al.11
(2000)
Prospective
25
9/16
Orditura
et al.30
(1998)
Meyer
et al.18
(1997)
Prospective
43
21/22
18 < 55 years
25 > 55 years
Prospective
483
198/285
Mean 61 (SD:
+/- 12)
Weidmann
et al.34
(1995)
Schöber
et al.32
(1993)
Keefe et al.27
(1993)
Akhtar et al.8
(1993)
De Forni
et al.10
(1992)
Gradishar
et al.25
(1991)
Jeremic
et al.15
(1990)
Rezkalla
et al.20
(1989)
Eskilsson
et al.12
(1988)
Labianca
et al.29
(1982)
Pottage
et al.31
(1978)
Retrospective
231
NR
Retrospective
390
Retrospective
Symptomatic VT, a history CVD or previous
AMI within 12 months of study entry: 0%
5-FU mono. (593)
BI
CAP mono.(832)
PO
Colorectal
5-FU comb. (25)
BI
Colon, rectum, gastric, pancreas,
breast
5-FU comb.
BI
Gastrointestinal, head and neck,
esophageal, breast, lung, prostate
5-FU mono
CI
NR
CVD: 15%
Diabetes mellitus: 12%
Previous XRT: 8%
Cardiac medications: 15%
NR
NR
5-FU comb
5-FU
Ratio 1/3
53 (27–75)
IHD or risk factors for IHD: 14%
Gastrointestinal
5-FU comb.
CI
CI
910
NR
NR
NR
5-FU
NR
Prospective
100
38/62
Prospective
367
137/230
Mean 50 (30–
70)
NR
CVD: 0,0%
ECG abnormalities: 0.0%
NR
Gastrointestinal, head and neck,
bladder, biliary
Esophageal, gastrointestinal,
nasopharyngeal, salivary gland
Esophageal, head and neck,
colorectal, breast, cervix
mono. (1)
combb (99)
mono. (39)
comb. (326)
CI
CI
CI
CI
Retrospective
244
NR
NR
NR
Head and neck, gastrointestinal
5-FU comb. (244)
CI
Prospective
80
15/65
Mean 63 (40–
72)
CVD or pre-treatment ECG abnormalities:
39%
Esophageal, head and neck, gastric
5-FU combb (80)
II
Prospective
25
7/18
Mean 60 (41–
79)
Head and neck
5-FU mono (7)
5-FU combb (18)
CI
CI
Prospective
76
9/67
Mean 64 (28–
80)
IHD: 28%
Riskfactors for IHD: P 68%
ECG abnormalities: 24%
CVD or abnormal ECG: 43%
Cardiac medications: 18%
Head and neck, esophageal
5-FU combb (76)
CI
Mostly
retrospective
1083
NR
420 < 55 years
663 > 55 years
IHD: 12%
Gastrointestinal, breast, pancreas
5-FU mono. (480)
5-FU comb. (603)
BI
NR
Retrospective
140
NR
NR
Previous AMI or IHD: 0%
Hypertension: 0%
XRT: 100%
Breast, gastricc
5-FU
NR
ECG abnormalities: 0.0%
Exclusion: > NYHA II, severe hypertension,
pericarditis, valvular heart disease,
diabetes mellitus
CVD: 0.0%
ECG abnormalities: 0.0%
Colorectal, breast
5-FU
5-FU
5-FU
5-FU
BI (201) CI
(30)
A. Polk et al. / Cancer Treatment Reviews xxx (2013) xxx–xxx
CAP = capecitabine, 5-FU = 5-fluorouracil, NR = not reported, mono. = monotherapy, comb. = combination therapy, CI = continuous infusion including De Gramont based regimens, BI = bolus infusion, II = intermediate infusion (2 h4 h), PO = peroral, NS = No significant difference, MCRC = metastatic colorectal cancer, MBC = metastatic breast cancer.
a
Proportion of patients with previous acute myocardial infarction (AMI), pre-existing cardiovascular disease (CVD), ischemic heart disease (IHD), risk factors for IHD, baseline ECG abnormalities, previous cardiotoxic treatment
and thoracic radiotherapy (XRT).
b
A significant part of the patients received cisplatin.
c
Only reported for cases.
5
Please cite this article in press as: Polk A et al. Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: A systematic review of incidence, manifestations and predisposing factors. Cancer Treat Rev (2013), http://dx.doi.org/10.1016/j.ctrv.2013.03.005
Van Cutsem
et al.7
(2002)
Reference
6
No. of
participants
Overall incidence of symptomatic
cardiotoxicity, n (%)
Chest pain
AMIa, n
(%)
non-AMI, n
(%)
Dyspnoea, n
(%)
Palpitations,
n (%)
Hypotension,
n (%)
Other cardiovascular symptoms or
events, n (%)
Sudden death,
n (%)
Khan et al.28 (2012)
301
60 (19.9)
–
10 (3.3)b
–
–
18 (6.0)
9 (3.0)
0
5 (9.6)
4 (7.6)
12 (23.1)
2 (3.8)
9 (8.5)
0
9 (8.5)
3 (2.8)
–
–
Hypertension: 7 (2.3)
Cardiac arrest: 1 (0.3)
Bradycardia: 36 (12)
Ventricular tachycardia: 11 (3.7)
AV block: 2 (0.7)
Tachycardia: 3 (5.8)
Hypertension: 1 (1.9)
–
Koca et al.16 (2011)
52
18 (34.6)
Jensen et al.
(2010,
2012)
Kosmas et al.17 (2008)
106
644
26 (4.0)
7 (1.1)
10 (1.6)
–
8 (1.2)
–
Tsibiribi et al.33 (2006)
Jensen et al.26 (2006)
Ng M et al.19 (2005)
1350
668
153
16 (1.2)
29 (4.3)
10 (6.5)
2 (0.1)
2 (0.3)
3 (2.0)
12 (0.9)
26 (3.9)
4 (2.6)
–
2 (0.3)
–
–
–
–
–
–
–
Meydan et al.3 (2005)
Wacker et al.23 (2003)
Van Cutsem et al.c7
(2002)
Balloni et al. 11 (2000)
231
102
1425
9 (3.9)
19 (18.6)
46 (3.2)
1 (0.4)
0
3 (0.2)
6 (2.6)
19 (18.6)
5 (0.4)
6 (2.6)
–
–
5 (2.2)
–
–
2 (0.9)
–
–
25
2 (8.0)
0
0
–
–
–
Meyer et al.18 (1997)
483
9 (1.9)
–
5 (1.0)
3 (0.6)
–
2 (0.4)
Weidmann et al.34
(1995)
Schöber et al.32 (1993)
Keefe et al.d27 (1993)
Akhtar et al.8 (1993)
231
6 (2.6)
0
6 (2.6)
2 (1.2)
–
3 (1.2)
390
910
100
13 (3.3)
5 (0.55)
8 (8.0)
3 (0.7)
4 (0.4)
0
5 (1.3)
1 (0.1)
5 (5.0)
–
–
–
4 (1.0)
–
3 (3.0)
–
–
–
De Forni et al.10 (1992)
367
28 (7.6)
–
18 (4.9)
(0.5)
–
6 (1.6)
Gradishar et al.25
(1991)
244
22 (9.0)
–
4 (1.6)
–
–
–
Jeremic et al.15 (1990)
Rezkalla et al.20 (1989)
Eskilsson et al.12
(1988)
Labianca et al.29 (1982)
Pottage et al.31 (1978)
80
25
76
12 (15.0)
1 (4.0)
14 (18.4)
–
–
–
5 (6.3)
1 (4.0)
6 (7.9)
–
–
–
–
–
–
1083
140
17 (1.6)
4 (2.9)
1 (0.1)
1 (0.7)
15 (1.5)
3 (2.1)
–
1 (0.7)
1 (0.1)
–
13,14
Individual patients may have presented P 1 clinical manifestation.
a
Acute myocardial infarctions.
b
Unclear whether these patients had elevated coronary enzymes.
c
Reported as CTC-grades, only grade 3–4 cardiotoxic events are outlined in the study.
d
Only serious adverse events are reported.
Malaise: 4 (0.6)
Diaphoresis: 2 (0.3)
Syncope: 1 (0.2)
Collapse: 1 (0.2)
Heart failure: 1 (0.07)
Heart failure: 2 (0.3)
Heart failure: 1 (0.7)
Collapse: 1 (0.7)
–
–
Heart failure: 1 (0.07)
Tachycardia: 1 (0.07)
Tachycardia: 2 (8.0)
Hypertension: 1 (4.0)
Hypertension: 1 (0.2)
Tachycardia: 1 (0.2)
Tachycardia: 4 (1.7)
0
0
1 (0.16)
2 (0.15)
NR
1 (0.65)
0
NR
2 (0.14)
0
2 (0.41)
NR
–
–
–
–
Cardiac arrest: 2 (0.2)
Sweating: 2 (2.0)
Cardiogenic shock: 1 (1.0)
Hypertension: 5 (1.4)
Malaise: 4 (1.1)
Cardiac arrest: 1 (0.4)
Cerebrovascular accidents: 3 (1.2)
Pulmonary embolism: 3 (1.2)
Venous thrombosis: 1 (0.4)
–
–
–
1 (0.26)
(0.11)
0
0
2 (8.0)
1 (1.3)
1 (0.1)
–
–
–
NR
NR
8 (2.2)
11 (4.5)
A. Polk et al. / Cancer Treatment Reviews xxx (2013) xxx–xxx
Please cite this article in press as: Polk A et al. Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: A systematic review of incidence, manifestations and predisposing factors. Cancer Treat Rev (2013), http://dx.doi.org/10.1016/j.ctrv.2013.03.005
Table 2
Incidence and clinical manifestations of 5-FU and capecitabine cardiotoxicity.
7
A. Polk et al. / Cancer Treatment Reviews xxx (2013) xxx–xxx
Table 3
Electrocardiographic manifestations of 5-FU or capecitabine cardiotoxicity (10 studies).
Reference
Electrocardiographic monitoring
Percentage of
patients with new
onset ECG-findings
Arrhythmias
ST-segment
deviations
De- and repolarisation changes
Koca
et al.16
(2011)
12-lead ECG between 1–4 h after
treatment start, on day 4, 21 and 24
32.6%
25.0%
Prolonged QTc interval: 19.2%
Yilmaz
et al.24
(2007)
Continuous ECG for 24 h before and the
first 24 h during first cycle of
chemotherapy
Ceyhan
et al.4
(2004)
Oztop
et al.6
(2004)
Wacker
et al.23
(2003)
12-lead ECG at 0 h and 48 h of first cycle
–
Sinus tachycardia:
21.1%
VPC: 3.8%
APC: 3.8%
Sinus bradycardia:
1.9%
VPC: 19 (70.3%)
Complex
ventricular
arrhythmia: 22.2%
VT: 2 (7.4%)
APC and VPC pr
hour or pr 1000
beats increased: S
Mean HR
decreased: S
–
12-lead ECG before, 24 h after first cycle
and before consecutive cycles
–
Continuous ECG during infusion, 12-lead
ECG prior to, during and 3 months from
baseline
–
Orditura
et al.30
(1998)
Akhtar
et al.8
(1993)
Jeremic
et al.15
1990)
Rezkalla
et al.20
(1989)
12-lead ECG before treatment and shortly
after beginning of chemotherapy
–
12-lead ECG baseline, on day 1, 2, 3 and 4
Eskilsson
et al.12
(1988)
Prolonged PR interval: 5.8%
0
–
8.0%
Prolonged mean Pmax and higher mean
Pdispersion: S
0
0
Significantly higher
frequency of
bradycardia and
VPC
–
–
Mean QTmax and mean QTd increased
from baseline to 24 h and in subsequent
cycles: S
PQ intervals, QRS complexes and QT
intervals on 12-lead ECG: NS QTc
prolongation 3 months from baseline: S
–
Mean PR, RR, QRS, QT and QTc: NS
6.0%
3.0% (VPC and
tachycardia)
3.0%
–
12-lead ECG at baseline, on day 3 and 5
10.0%
6.3% (atria
fibrillation or APC)
7.5%
–
Continuous ECG 23 +/ 4 h before
infusion + 98 +/ 9 h during infusion,
daily 12-lead ECG during chemotherapy
44.0%
Ventricular ectopy:
NS
–
12-lead ECG at baseline, on day 3 and 5
11.8%
7.9%
In 24% before
treatment and
68.0% after
treatment: S
9.2%
–
VPC = ventricular premature complexes, APC = atrial premature complexes, HR = heart rate, NS = No statistically significant changes, S = statistically significant changes.
values during treatment, whilst Holubec et al.9 reported TnI values
higher than 0.04 lg/L (the pathologic cut-off level for the assay) in
57% of the patients and higher than 0.3 lg/L in 14%. Holubec et al.9
measured TnI before and after 2., 3. and 4. cycle of chemotherapy
and increased TnI values were found in more patients before the
2. cycle than in the remaining measurements. Two studies13,20
measured CK-MB fraction levels. Mean CK-MB rose during therapy
but CK-MB levels did not exceed diagnostic cut-off levels for myocardial infarction in any patients. NT-proBNP or BNP levels were
measured in two studies9,13 and exceeded the corresponding reference interval in 29% and 48% of the patients, respectively. Jensen
et al.13 showed that NT-proBNP rose during therapy and reverted
at follow-up. The increase in NT-proBNP was significantly higher
in patients with symptoms of cardiotoxicity.13 In same study14 levels of lactic acid, von Willebrand factor and fibrin D-dimer in blood
samples and urine albumin-to-creatinin-ratio increased during
treatment with 5-FU, while coagulation factors II + VII + X decreased. These changes were transient and did not differ between
patients with clinical signs of cardiotoxicity or not. In a study by
Salepci et al.21 angiotensin II levels remained unchanged during
and up to 72 h after bolus 5-FU-infusion and did not differ between
study and control group. Südhoff et al.22 measured big endothelin
levels in relation to 5-FU-induced vasoconstriction of the brachial
artery. Big endothelin levels tended to rise after 5-FU application
but independently of whether patients developed 5-FU-induced
vasoconstriction.
5-FU and capecitabine cardiotoxicity and vascular influence detected
by imaging techniques
Systematically assessment of left ventricular function was performed by echocardiography in three studies5,6,11 and by radionuclide ventriculography in one study.13 Conventional 2D
echocardiography, M-mode- and Doppler echocardiography and
radionuclide ventriculography revealed no significant changes in
systolic or diastolic ventricular function between baseline, treatment and post-treatment recordings. The subset of patients experiencing symptoms of cardiotoxicity did not differ from other
patients with respect to parameters for ventricular function. Determination of changes in ultrasonic cyclic variation of integrated
backscatter (CVIBS) in one study5 revealed a decline in CVIBS values measured at the interventricularseptum and posterior wall
areas 48 h after treatment start. These changes were seen in 95%
of the patients and CVIBS values were returned to baseline levels
at day 15.
Please cite this article in press as: Polk A et al. Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: A systematic review of incidence, manifestations and predisposing factors. Cancer Treat Rev (2013), http://dx.doi.org/10.1016/j.ctrv.2013.03.005
8
A. Polk et al. / Cancer Treatment Reviews xxx (2013) xxx–xxx
Measurements of the brachial artery diameter with high resolution ultrasound were performed in two studies.21,22 Contraction of
the brachial artery was observed after 5-FU-infusion while no
vasoconstriction was observed in controls.21,22 The 5-FU-induced
vasoconstrictions were transient and reoccurred when 5-FU was
re-administered.22 Glyceryltrinitrate prevented the vascular contractions.22 In the study by Wacker et al., coronary angiography
performed in a subset of symptomatic patients showed no significant obstruction of the coronary arteries.23
Predisposing factors
Potential predisposing factors were analyzed mostly by univariate analyzes; only in two studies were multivariate analyzes
applied.13,18 Ischemic heart disease was a predisposing factor in
three studies16,18,29 but failed to be so in two studies.3,19 Known
risk factors for ischemic heart disease (e.g. hypertension, hyperlipidemia, diabetes mellitus, obesity (body mass index), smoking and
family history of cardiac disease or stroke) were not associated
with development of cardiotoxicity.17–19 Abnormal baseline echocardiography was a predisposing factors in one study,16 whilst
abnormal pre-treatment ECG were of no significance in another
study.19 Preexisting cardiac disease of any type remained a significant risk factor in multivariate analyses in the study by Meyer
et al.18 but were not a significant factor when tested in univariate
analyses in three studies3,19,28 and in multivariate analysis in the
study by Jensen et al.13
Female gender were slightly predictive of increases in NT-proBNP levels in the study by Jensen et al.13, but gender was not related
to symptomatic cardiotoxicity in two other studies.18,29 Other patient-related factors like age, body surface area, alcohol intake, thyroid-, renal- and pulmonary disease were of no significance.17,18,29
According to Meyer et al.18 patients with gastrointestinal cancers
were at lower relative risk for cardiotoxicity compared to patients
with other cancers. Patients with metastatic disease were not at increased risk compared to patients with localised disease.19
Continuous 5-FU-infusion was associated with a higher incidence of cardiotoxicity compared to bolus infusion in three studies17,26,28 but not in the study by Wacker et al.23 Meyer et al.18
found that the amount of 5-FU administered were not predictive
of cardiotoxicity neither was the cycle of infusion. Combination
regimens in general were not associated with a higher risk of cardiotoxicity compared to 5-FU alone3,18,29, but a higher rate of cardiotoxicity was observed in patients who received cisplatin in
combination with 5-FU.28 Additionally, Kosmas et al.17 reported increased rates of cardiotoxicity with leucovorin plus continuous 5FU-infusion compared to continuous 5-FU infusion alone. Previous
chest radiotherapy was a risk factor in the study by Koca et al.16,
but were of no significance in the study by Meyer et al.18 Concurrent radiotherapy resulted in higher rates of cardiotoxicity in the
study by Khan et al.28
Risk of bias across studies
Fig. 2A shows that smaller studies reported a higher incidence
of cardiotoxicity compared to larger studies which could not be
fully explained by the greater imprecision in results from smaller
studies. Differences in mortality related to study size (Fig. 2B) were
less pronounced. However, treatment related death was overrepresented in smaller studies compared to larger studies.
Possible explanations can be publication bias or selection of patients at increased risk for cardiotoxicity, but the higher rates of
cardiovascular toxicity in smaller studies can also result from the
use of more sensitive techniques of cardiovascular monitoring
(ECG, Holter monitoring, CVIBS etc.) in these studies. Additionally,
larger studies may be retrospective or may not have evaluation of
cardiotoxicity as the primary objective which may lead to underreporting of fluorouracil induced cardiac symptoms. Hence, sensitivity for cardiovascular toxicity is higher in smaller studies and
might account for some of the differences seen in Fig. 2A and B.
Discussion
The frequency of fluorouracil induced cardiotoxicity was addressed in 30 studies with different design, patient selection criteria and treatment schedules. Most studies evaluated cardiac
symptoms with subsequent evaluation of symptomatic patients
with ECG and cardiac biomarkers. The reported frequency of symptomatic cardiotoxicity varied between 0% and 35%, with the highest incidences found in smaller studies (Fig. 2). Considering
studies with >400 patients results in estimates of symptomatic cardiotoxicity of 1.2–4.3%. The frequency of treatment-related sudden
death varied from 0% to 8% but clustered around 0–0.5% in larger
studies with >400 patients.
Clinical manifestations of cardiotoxicity were similar for 5-FU
and capecitabine. The cardinal symptom was chest pain but many
patients presented with palpitations, dyspnoea or hypotension.
Tachycardia, bradycardia, hypertension and heart failure occurred
less frequently. The electrocardiogram could show signs of myocardial ischemia or arrhythmias. Although symptoms and electrocardiographic changes could mimic acute myocardial infarction
most patients had CK-MB and troponin levels below the cut-off
points for myocardial infarction.
Electrocardiographic studies revealed silent myocardial ischemia and asymptomatic arrhythmias in some patients. Such asymptomatic electrocardiographic abnormalities were present on single
ECG acquisition in 5% and 5.2%, respectively, in the studies by Jeremic et al.15 and Eskilsson et al.12 The use of continuous electrocardiographic monitoring in the study by Rezkalla et al.20
demonstrated asymptomatic ST-deviations in 64% of the patients
in a study population with a high prevalence of cardiac co-morbidities. This finding was not reproduced by Yilmaz et al.24 in a study
population free of a history of cardiac disease; in contrast supraventricular and ventricular ectopy were common. Complex forms
of ventricular premature beats may accompany myocardial ischemia and ventricular fibrillation may be of ischemic origin. Likely,
the substrate for arrhythmias during fluorouracil treatment might
be an underlying ischemic myocardium. Prolonged QTc and QTdispersion were demonstrated during fluorouracil-treatment6,23
reflecting abnormal repolarization of the myocardium. Specifically,
increased QTdispersion indicates inter-lead variances in myocardial repolarization. Such heterogenity in recovery of excitability
provides a basis for development of malignant ventricular arrhythmias. The increased p-wave duration and p-wave dispersion demonstrated by Ceyhan et al.4 reflect intra- and inter-atrial
conduction delays and may predispose to atrial fibrillation.35–37
Serial assessment of troponin levels (markers of myocyte injury) early in treatment seemed not to be a sensitive marker for
fluorouracil cardiotoxicity according to Oztop et al.6 and Salepci
et al.21 Holubec et al.9 reported raised troponin and BNP values
during therapy, but no baseline values were provided neither
was the cardiovascular status of the patients before treatment
start. Hence, the interpretation of the results from this study is difficult. Monitoring NT-proBNP levels in the study by Jensen et al.13
indicated subclinical cardiac influence in most patients with higher
levels in symptomatic patients. The elevated NT-proBNP levels
were not related to dysfunction of the left ventricle as measured
by ventriculography.13 NT-proBNP is a peptide that is released
from ventricular cardiomyocytes in response to stretch and elevated plasma levels of angiotensin II and endothelin-1.38 It has
prognostic value in patients with non-ST acute coronary syndrome
Please cite this article in press as: Polk A et al. Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: A systematic review of incidence, manifestations and predisposing factors. Cancer Treat Rev (2013), http://dx.doi.org/10.1016/j.ctrv.2013.03.005
A. Polk et al. / Cancer Treatment Reviews xxx (2013) xxx–xxx
9
Fig. 2. Aand B. Patient number in relation to incidence of cardiotoxicity and mortality, respectively.
and patients with heart failure.39–41 The predictive value of natriuretic peptides including NT-proBNP and BNP for development of
fluorouracil cardiotoxicity should be validated in future studies.
Left ventricular ejection fraction and regional and global systolic function was preserved in the majority of patients treated
with 5-FU.5,6,11,13 This is compatible with the fact that fluorouracil
infrequently lead to symptoms of heart failure. In contrast, ultrasonic tissue characterization with integrated backscatter revealed
a transient decline in cyclic variation of integrated backscatter
(CVIBS) in 35 of 37 patients in the study by Ceyhan et al.5 This technique quantifies the acoustic properties of myocardial tissue and a
temporal profile of cyclic variation in integrated backscatter is normally observed throughout a cardiac cycle.42 A decline in cyclic
variation in integrated backscatter is demonstrated rapidly after
the onset of myocardial ischemia and in conditions with myocardial fibrosis and remodelling.43–45 Cyclic variation in integrated
backscatter reflects myocardial tissue viability and myocardial
contractility.42,44,46 Since most patients showed declined CVIBS
values 48 h after 5-FU administration regardless of clinical signs
of cardiotoxicity, it is uncertain whether this technique adds information on which patients will develop symptoms of cardiotoxicity
or merely reflect a transient influence of fluorouracil on the
myocardium.
The clinical picture of myocardial ischemia without obstruction
of the coronary arteries and the vasoconstrictive properties of 5-FU
demonstrated with ultrasound of the brachial artery indicate that
fluorouracil compounds may lead to vasospasm resulting in compromised myocardial blood flow. Although the results from experimental studies are ambiguous there is some support for this
mechanism, as Mosseri et al.47 demonstrated a dose-dependent
contraction of rabbit aorta rings after 5-FU exposure.
Predisposing factors
Differences in incidence of cardiotoxicity between studies could
be a reflection of different risk profiles in the study populations.
Such risk profiles could be composed of patient related factors
and factors related to previous and current therapy. Few patient related factors were associated with increased risk for cardiotoxicity.
Cardiovascular co-morbidities were a risk factor for cardiotoxicity
in 4 studies,16,18,20,29 but 4 studies3,13,19,28 found no influence. More
studies found ischemic heart disease to be a risk factor18,20,29 than
heart disease of any type18, suggesting that the type of cardiac disease might matter. However, some of the studies were small and
the number of patients presenting with cardiotoxicity were few.
Hence, some studies lacked the sufficient power to reach statistical
significance. A well-powered prospective study was performed by
Meyer et al.18 and in multivariate analysis they found patients with
preexisting cardiovascular disease to have a relative risk of 8 for
cardiotoxicity compared to patients without cardiac disease. More
well-powered studies are needed to clarify the influence of cardiovascular diseases. Among other patient-related factors female gender was associated with increased levels of NT-proBNP in
multivariate analysis, but other studies failed to show association
between age and cardiotoxicity.18,29
There were differences in cardiotoxicity pertaining to different
administration schedules. Continuous 5-FU infusion was a risk factor in 317,26,28 of 4 studies comparing continuous and bolus infusion schedules suggesting that prolonged exposure to fluorouracil
compounds are more cardiotoxic. According to Jensen et al.26 and
the meta-analyses by Van Cutsem et al.7 the incidence of cardiotoxicity from capecitabine (1250 mg m 2 day 1 and 2500 mg m 2
day 1, respectively) resembled that of 5-FU administered as the
Mayo regimen (daily bolus injection of 425 mg m 2 for 5 days
every 4 weeks). In contrast, Kosmas et al.17 reported a significant
difference in incidence of cardiotoxicity between capecitabine
and bolus 5-FU-infusion plus leucovorin. Capecitabine is activated
through a 3-step process with the final transformation catalysed by
thymidine phosphorylase, an enzyme with higher activity in tumours than in normal tissues.48 Higher levels of 5-FU is thus produced in tumours than in healthy tissues and the plasma levels
of 5-FU is low after capecitabine treatment.49,50 Therefore, in tissues with low thymidine phosphorylase activity capecitabine therapy mimic a continuous low dose 5-FU infusion.
Three studies3,18,29 found polychemotherapy to be of no significance for the risk of cardiotoxicity. However, they pooled the different combinations of chemotherapeutics in one analysis which
might obscure real differences. Khan et al.28 observed a much higher incidence of cardiotoxicity with the combination of 5-FU with
cisplatin. Similarly, in the 6 studies8,10,12,15,23,28 that reported the
Please cite this article in press as: Polk A et al. Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: A systematic review of incidence, manifestations and predisposing factors. Cancer Treat Rev (2013), http://dx.doi.org/10.1016/j.ctrv.2013.03.005
10
A. Polk et al. / Cancer Treatment Reviews xxx (2013) xxx–xxx
highest incidences of symptomatic cardiotoxicity (8.0–19.9%) cisplatin was administered concurrently with 5-FU in a high proportion of the patients (20–100%). There are evidence from case
reports and experimental studies that cisplatin can induce cardiac
side effects, notably arrhythmias.51–57 Thus, the cardiotoxic effects
observed in studies with concomitant cisplatin administration cannot be attributed solely to the administration of 5-FU.
Taken together, the evidence for predisposing factors is not
compelling. Many factors are analyzed in retrospective view or in
prospective studies with inadequate statistical power. Since most
factors were analyzed with univariate analyzes confounding might
be a problem. Further work is needed to clarify the significance of
these factors for the risk of cardiotoxicity.
Limitations
Most of the included studies are observational studies which
are more prone to bias and confounding inherent to the study design than RCTs. However, for the evidence of adverse events observational studies can be useful as study populations are more likely
to resemble real-life patient populations as regards patient characteristics and co-morbidities. Also, the inclusion of patients with comorbidities allow for the investigation of these factors as potential
risk factors for cardiotoxicity. Beside the inherent risk of bias related to study design, most included studies had other substantial
risks of bias. Attrition bias could not be ruled out in many studies
due to inadequate reporting. If follow-up is incomplete it may result in underestimation of the frequency of cardiotoxicity. Similarly, differences in duration of follow-up might lead to
differences in incidence between studies because a short follow
up period will miss patients that develop cardiotoxicity in subsequent treatment cycles. As few studies reported duration of follow-up it is likely that such differences together with the
heterogeneity in criteria for cardiotoxicity may account for some
of the variation in frequency.
Most studies had a high risk of detection bias and lacked a control group. In such circumstances the presence of presumed risk
factors can lead the clinician to classify symptoms as related to
therapy or to pre-existing disease. Additionally, possible confounding factors were inadequately adjusted for in several studies making it difficult to attribute the observed cardiac events to
fluorouracil-treatment alone. Possible confounders are previous
chemotherapeutic treatment and previous radiation therapy
involving the heart, which was poorly defined in most studies.
Also, reporting on cardiovascular status of patients was inadequate
in a number of publications, especially in older publications. The
consequence is limited external validity. We cannot rule out publication bias, as we observed a tendency to higher incidences of
cardiotoxicity in smaller studies. Finally, we restricted our literature search to articles in English which might have resulted in
missed studies.
place. Possible risk factors were cardiac co-morbidity, continuous
infusion schedules and concomitant cisplatin treatment, but definite conclusions could not be made mostly due to lack of statistical
power and lack of control for confounders in many studies.
Future research should focus on the effect of the relatively more
frequent asymtomatic events on the clinical outcome of the patients and the predictive value of patient-related factors for fluorouracil cardiotoxicity. Particularly, further understanding of the risk
related to different cardiac co-morbidities could potentially provide clinical oncologists with tools for risk stratification of the patients. However, it is unlikely that such anamnestic factors alone
can provide sufficient information for risk stratification; therefore
identification of complementary methods to identify patients at
high risk is high priority. Potential methods might be genetic analyses and biomarkers. Finally, the key to a better understanding and
improved treatment of fluorouracil-induced cardiotoxicity is enhanced insight into the pathophysiological mechanisms.
Conflicts of interest
All authors declare no conflicts of interest and no funding has
been received for the preparation of the manuscript.
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Most patients with fluorouracil induced cardiotoxicity suffer
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Please cite this article in press as: Polk A et al. Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: A systematic review of incidence, manifestations and predisposing factors. Cancer Treat Rev (2013), http://dx.doi.org/10.1016/j.ctrv.2013.03.005