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Review
10.1586/14737140.6.9.1229 © 2006 Future Drugs Ltd ISSN 1473-7140
1229
www.future-drugs.com
Cardiac and cardiovascular
toxicity of nonanthracycline
anticancer drugs
Robin L Jones
†
and Michael S Ewer
†
Author for correspondence
Royal Marsden Hospital,
Department of Medicine, Fulham
Road, London SW3 6JJ, UK
Tel.: +44 207 808 2883
Fax: +44 207 376 3918
robin.jones@icr.ac.uk
K
EYWORDS:
anticancer drugs, cardiotoxicity,
cardiovascular toxicity,
chemotherapy, nonanthracycline
Anthracyclines are a well-known cause of cardiotoxicity, but a number of other drugs used
to treat cancer can also result in cardiac and cardiovascular adverse effects.
Cardiotoxicity can result in the alteration of cardiac rhythm, changes in blood pressure
and ischemia, and can also alter the ability of the heart to contract and/or relax. The
clinical spectrum of these toxicities can range from subclinical abnormalities to
catastrophic life-threatening, and sometimes fatal, sequelae. These events may occur
acutely or may only become apparent months or years following completion of
oncological treatment. Ischemia and rhythm abnormalities are treated symptomatically in
most cases. Knowledge of these toxicities can aid clinicians to choose the optimal and
least toxic regimen suitable for an individual patient.
Expert Rev. Anticancer Ther. 6(9), 1229–1249 (2006)
A number of agents used in oncology can
result in cardiac and cardiovascular toxicity;
the most well known and extensively investi-
gated are the anthracyclines. Although less fre-
quent, a number of other agents can also result
in cardiovascular adverse effects.
Patients treated with anticancer drugs may
present with asymptomatic electrocardio-
graphic (ECG) changes or decreases in left
ventricular ejection fraction (LVEF) on
echocardiography
[1,2]. 5-fluorouracil (5-FU)
can cause ischemic chest pain requiring
prompt diagnosis and treatment
[3–5]. Brady-
cardia, conduction block, ischemia, blood
pressure (BP) changes and ventricular arrhyth-
mias have all been associated with paclitaxel
and are usually self-limiting or resolve soon
after administration of the culprit agent
[6].
Trastuzumab and interferon can result in con-
gestive heart failure (CHF)
[7,8], whereas
arsenic trioxide can cause prolongation of the
QT interval
[9]. Novel agents, such as bevaci-
zumab and sorafenib, have been reported to
cause changes in BP
[10–13]. In certain cases,
cardiac and cardiovascular toxicity manifests
as a self-limiting event that responds to drug
withdrawal or medical therapy
[2,14]. Other
chemotherapeutic combinations, such as
cisplatin-based regimens, can potentially
result in long-term cardiovascular
morbidity
[15–19].
Risk factors for cardiac and cardiovascular
toxicity are not known for many of these
agents. Pre-existing cardiac disease has been
postulated as a risk factor for 5-FU-induced
cardiotoxicity
[4,5], as have administration
schedule and renal disease
[20–22]. Patients
treated with trastuzumab and an anthracycline
are at greater risk of developing cardiotoxicity
[23]. The risk for QT-interval prolongation
secondary to arsenic trioxide increases with
low serum potassium and magnesium
concentrations
[24].
Despite clear recognition of the clinical fea-
tures of this toxicity, the pathogenesis is not
fully understood for most of the drugs dis-
cussed. Various hypotheses have been pro-
posed. For 5-FU these include vasospasm,
direct myocardial toxicity, coronary artery
thrombus, autoimmunity and activation of the
coagulation system
[3]. Cisplatin is known to
cause an autonomic neuropathy
[25] and has
been implicated in the development of long-
term cardiovascular toxicity, possibly second-
ary to metabolic abnormalities or endothelial
damage
[17]. Trastuzumab may have a direct
C
ONTENTS
5-Fluorouracil
Taxanes
Alkylating agents
Antimetabolites
(excluding 5-FU)
Antimicrotubule agents
(excluding taxanes)
Targeted therapy
Vascular-disrupting agents
Other agents
Expert commentary
Five-year view
Key issues
References
Affiliations
Jones & Ewer
1230
Expert Rev. Anticancer Ther. 6(9), (2006)
cardiotoxic effect via the cardiac human epidermal growth
factor receptor (HER)2 receptor
[26].
Arrhythmias, ischemic chest pain and CHF are treated symp-
tomatically, along with prompt discontinuation or alteration of
chemotherapy schedule. Correction of known risk factors, such
as hypokalemia and hypomagnesemia should be undertaken
prior to commencing treatment with drugs such as arsenic tri-
oxide
[9]. There is limited evidence regarding the role of rechal-
lenge, but there have been reports of rechallenge (with dose
reduction or prophylaxis) with 5-FU, interleukin (IL)-2, inter-
feron and trastuzumab
[2,3,5,8,20,27–29]. Conduction disturbances
secondary to paclitaxel do not always recur with repeated
courses and thus therapy with this agent may be continued
[6].
This article will review the cardiac and cardiovascular toxicity
of nonanthracycline drugs used in oncology (excluding
endocrine agents).
5-Fluorouracil
The ischemic syndrome associated with this agent can vary
from chest pain to acute myocardial infarction (MI); manifesta-
tions may include ECG changes, arrhythmia, hypotension,
pulmonary edema and cardiogenic shock
[3,30].
Incidence
Reports of the occurrence of 5-FU cardiotoxicity have ranged
from 1.2–1.6% in two large retrospective studies
[4,31], to up to
10% in patients treated with doses more
than 800 mg/m
2
/day [3]. The reported incidence of cardiotox-
icity in 367 patients receiving a first cycle of infusional 5-FU
was 7.6%, with a mortality rate of 2.2%
[3]. In a series of
231 patients treated with de Gramont infusional 5-FU, nine
(3.9%) developed cardiotoxicity, at a median onset of 2 days
(six developed an acute coronary syndrome, two CHF and one
atrial fibrillation (AF))
[22].
Clinical features
5-FU-related cardiotoxicity has a mean onset of 72 h following
administration, with some experiencing ischemic symptoms
within hours of the infusion. Ischemia occurs frequently during
the first course and symptoms often resolve on discontinuation
of the infusion. It has also been reported that patients are at
increased risk of recurrent and more severe symptoms if
retreated with the drug
[27].
Risk factors
There is no apparent relationship with cumulative dose, but pre-
existing coronary artery disease (CAD) has been documented as a
risk factor
[4,5]. The incidence of ischemic toxicity has been
reported as 1.1% in those with no history of CAD and 4.5% in
patients with known CAD
[4]. Schöber and colleagues retrospec-
tively analyzed 390 patients treated with intermediate-dose foli-
nic acid and 5-FU for advanced gastrointestinal cancer
[5]. In this
series, the overall risk of cardiotoxicity was 3%. However, eight
out of 53 patients with a history of cardiac disease developed car-
diac symptoms (15.1%). By contrast, five out of 337 patients
(1.5%) with no history of cardiac disease developed cardiotoxic-
ity. Symptoms developed at a median of 3 days (range: 2–6).
Angina resembling myocardial ischemia was the most common
symptom, occurring in eight out of 13 patients (61%), four
developed supraventricular arrhythmias and one experienced
reversible cardiac dysfunction. One patient died on day 6 of the
second cycle of chemotherapy, with symptoms suggestive of MI.
In addition, pre-existing renal disease and administration sched-
ule have also been suggested as risk factors
[20–22]. The possibility
of concurrent cytotoxic therapy having a contributory effect to 5-
FU cardiotoxicity has been discussed
[3]. However, Labianca and
colleagues demonstrated no significant difference in the incidence
of cardiotoxicity secondary to 5-FU between patients treated with
monotherapy (1.4%) and polychemotherapy (1.6%)
[4].
Echocardiographic & ECG studies
A prospective study using continuous ambulatory ECG moni-
toring during infusional 5-FU therapy reported a low incidence
of angina (one out of 25 patients), but a high incidence of
asymptomatic ECG changes during 5-FU infusion
[1]. Ischemic
ECG changes were present in 6 patients (24%) before 5-FU
infusion compared with 17 (68%) during 5-FU infusion
(p < 0.002). No change in overall incidence of ventricular ect-
opy during 5-FU therapy was demonstrated.
Grandi and colleagues have performed serial evaluation of sev-
eral cardiovascular factors in 16 colorectal carcinoma patients
treated with 5-FU and low-dose folinic acid
[32]. BP, heart rate
and segmental left ventricular (LV) wall motion remained nor-
mal in all patients throughout the 6-month treatment period.
However, LV diameter peak shortening rate and indexes of
diastolic function decreased progressively in all patients. All
patients displayed increased indexes of LV systolic and diastolic
function 6 months following completion of chemotherapy.
Etiology
The underlying pathophysiological mechanisms are poorly
understood. Various models have been proposed, including
vasospasm, direct toxicity on the myocardium, coronary artery
thrombus, an autoimmune response and activation of the coagu-
lation system
[3]. Mosseri and colleagues have suggested that 5-
FU myocardial ischemia is a result of protein kinase C-mediated
vasoconstriction of vascular smooth muscle
[33]. Data from ani-
mal studies have suggested that probucol may prevent endothe-
lial damage induced by 5-FU
[34]. Südhoff and colleagues have
evaluated the effect of intravenous 5-FU chemotherapy on bra-
chial artery diameter using high-resolution ultrasound
[35]. A
total of 15 out of 30 patients showed a contraction of the bra-
chial artery following 5-FU administration. By contrast, none of
the 30 patients treated with non-5-FU based chemotherapy
demonstrated brachial artery contraction.
Treatment
Screening and diligent clinical monitoring of patients with pre-
existing cardiac disease should be performed. 5-FU should be
stopped immediately in any patients who develop cardiac
Nonanthracycline cardiotoxicity
www.future-drugs.com
1231
symptoms, and the potential for rechallenge with this agent is
controversial
[27]. A recently reported study of 668 patients
treated with 5-FU or capecitabine demonstrated chemotherapy
dose reduction either alone or in combination with anti-anginal
medication prevented cardiotoxicity during subsequent cycles
of 5-FU in 9 (60%) and 3 (20%) of 15 assessable patients
[20].
In total, four patients experienced a relapse of cardiac symp-
toms on reinstitution of chemotherapy in the series reported by
Schöber and colleagues, including one patient who died
[5].
Dose reduction decreased anginal symptoms in one patient and
prevented them in another, but prophylactic nitrates proved
ineffective in this study. Cianci and colleagues have reported on
three patients who developed 5-FU-associated cardiotoxicity
and were rechallenged with dose reduction and prophylactic
transepidermal nitrate, with no recurrent anginal symptoms
[28]. In one patient, the administration schedule of 5-FU was
changed and no nitrate prophylaxis given.
Treatment of ischemia
Those experiencing anginal symptoms should be evaluated and,
if confirmed, treated for an acute MI in a coronary care unit.
Patients in cardiogenic shock may require inotropic and venti-
latory support. In most patients with ischemic symptoms,
standard antianginal treatment (
β-adrenergic blockers and/or a
long-acting nitrate) should be instigated along with supportive
care. Calcium channel-blocking agents may also help prevent
recurrences of ischemia.
Treatment of CHF
Angiotensin-converting enzyme inhibitors (ACEIs), angi-
otensin receptor blockers (ARBs),
β-adrenergic blockers, diu-
retics and digoxin may be used in the treatment of CHF.
Hypertension should be controlled and appropriate lifestyle
changes instigated.
In conclusion, the cardiotoxicity associated with 5-FU is rare,
but clinicians should be aware of this potential toxicity, particu-
larly in patients with concurrent cardiac disease. Prompt treat-
ment of anginal symptoms is mandatory. The role of rechal-
lenge with dose reduction and prophylactic nitrates and/or
calcium channel blockers remains to be elucidated definitively.
Further work assessing predisposing factors and causative
mechanisms is required.
Capecitabine
Capecitabine, the oral prodrug of 5-FU, has been reported to
have similar cardiotoxicity
[36–39]. A retrospective analysis of 1189
patients documented an overall cardiotoxicity incidence of 3% in
those treated with capecitabine monotherapy and 0.8% of grade
3/4 toxicity
[37]. A similar incidence was observed in the group
treated with bolus 5-FU. Ng and colleagues analyzed 153 patients
treated with capecitabine and oxaliplatin in two prospective
colorectal trials
[40]. A total of 6.5% of patients developed cardio-
toxicity, 4.6% experiencing angina. This suggests that a history of
cardiotoxicity associated with 5-FU should be considered a risk
factor for similar toxicity with capecitabine. In addition, there
have been two reported cases of severe hypertrigyceridemia
[41].
The etiology of capecitabine-induced cardiotoxicity is unknown.
Treatment is the same as with 5-FU-induced angina.
Uracil & tegafur
There have been rare reports of clinical cardiotoxicity associated
with the use of UFT
[42,43]. Kikuchi and colleagues conducted a
retrospective analysis of 223 patients treated with tegafur. In
this series, 11 out of 108 patients treated with intravenous
tegafur developed ECG changes and four out of 115 treated
with the oral preparation
[44]. In a study by Meydan and col-
leagues, a patient who developed CHF secondary to
de Gramont 5-FU subsequently died following re-challenge
with UFT
[22].
Taxanes
The most common cardiac effect of the taxanes is bradycardia;
however, other rhythm disturbances have also been reported
[6].
Myocardial depression, especially when the taxanes are used in
conjunction with an anthracycline, has received considerable
attention in the literature
[45–47]. Serious hypersensitivity reactions
were documented during early Phase I trials of paclitaxel and, as a
result, routine continuous cardiac monitoring was performed
during subsequent trials, to better manage such reactions
[6].
Incidence
Arbuck and colleagues have assessed cardiac adverse events in
over 3400 patients treated with paclitaxel
[48]. The incidence of
all grade 4 and 5 cardiac events reported to the Cancer Therapy
Evaluation Program (CTEP) was 0.5%
[48]. Asymptomatic
bradycardia is the most frequent cardiac event associated with
paclitaxel and the incidence of other cardiac adverse events is
low in the absence of cardiac risk factors
[48]. More significant
arrhythmias have been documented, but a large proportion had
either no symptoms or symptoms that could not be directly
attributed to paclitaxel
[48].
Clinical features
Rowinsky and colleagues catalogued cardiotoxicity experienced
by patients treated within the context of one Phase II and three
Phase I studies
[6]. A diverse range of cardiotoxicity was
observed, including ventricular arrhythmias, bradycardia, vary-
ing degrees of atrioventricular (A-V) conduction block, bundle
branch block, ventricular tachycardia and cardiac ischemia.
Many of these effects developed late during the paclitaxel infu-
sion and were usually self-limiting or resolved soon after dis-
continuation of the infusion. All patients were of good per-
formance status at the onset of drug administration and had no
relevant cardiac risk factors.
Risk factors
Paclitaxel can be administered with an acceptable safety profile
to patients with no concurrent cardiac history
[48]. Patients with
cardiac risk factors were excluded from study protocols
following the reports of cardiotoxicity and, as a result, it is
Jones & Ewer
1232
Expert Rev. Anticancer Ther. 6(9), (2006)
difficult to identify factors that may exacerbate paclitaxel cardi-
otoxicity. Data on the administration of paclitaxel to patients
with a history of ischemic heart disease, MI, altered cardiac
conduction (i.e., first-degree atrioventricular block and bundle
branch block) and patients on drugs that alter cardiac conduc-
tion (i.e., digoxin,
β-adrenergic blockers and calcium channel
blockers) are limited and vigilance is essential while such
patients receive therapy
[49–51].
Etiology
These cardiac disturbances have been attributed to a number of
causes, including the Cremophor EL formulation vehicle
[52],
premedications administered prior to the infusion
[48] and,
related to its antimicrotubule action, paclitaxel could mediate
cardiac damage by affecting other subcellular organelles
[6].
Treatment
In the presence of asymptomatic sinus bradycardia, paclitaxel
may be continued without dose modification. Those who
develop symptomatic bradycardia or heart block should be
monitored closely. In certain instances, the need for temporary
or permanent pacemaker insertion will need to be considered.
Markman and colleagues have reported a series of 15 patients
with gynecological malignancies, to investigate the safety of
administering paclitaxel to patients with major cardiac risk fac-
tors
[49]. All women received paclitaxel as single agent or in
combination with cisplatin or carboplatin. One of these
patients developed a severe hypersensitivity reaction to paclit-
axel, but no cardiac events. Another woman had a severe con-
duction defect and in such patients, cardiac monitoring would
be recommended with the first cycle of therapy. The number of
patients in this report was small, but it does suggest that paclit-
axel may be administered to some patients with concurrent car-
diac disease
[49,50], a finding supported by another small
retrospective study
[51].
Interaction
Several groups have investigated the efficacy and toxicity of
combining taxanes with anthracycline-based therapy.
Paclitaxel & doxorubicin
In the mid-1990s, trials conducted in women with metastatic
breast cancer reported that CHF may occur at lower cumula-
tivee doses of doxorubicin than the recommended limit of
500–550 mg/m
2
, when used in combination with
paclitaxel
[45–47]. An increased risk of cardiotoxicity in those
treated with paclitaxel by 3-h infusion and cumulative doses of
doxorubicin more than 360 mg/m
2
was observed [45]. Pharma-
cological studies demonstrated an interaction between doxoru-
bicin and paclitaxel, resulting in increased plasma and tissue
concentrations of doxorubicin and its toxic secondary alcohol
metabolite, doxorubicinol. The interaction between these two
drugs was enhanced by shorter intervals between doxorubicin
and paclitaxel administration and more rapid paclitaxel
infusions, possibly resulting in greater cardiotoxicity. Gianni
and colleagues performed a retrospective analysis of different
doses and schedules of paclitaxel and doxorubicin administered
in ten studies
[45]. They demonstrated that the incidence of
CHF was independent of the duration of paclitaxel administra-
tion and the interval between doxorubicin and paclitaxel, up to
a cumulative dose of 380 mg/m
2
doxorubicin [45]. The risk of
developing CHF was less than or equal to 5% at a total doxoru-
bicin dose of 380 mg/m
2
, but in patients who had received a
total doxorubicin dose of more than 440 mg/m
2
, the incidence
of CHF was more than 25%, but similar to doxorubicin mono-
therapy. Decreases in LVEF were more frequent in patients who
later developed CHF, but most of CHF patients did not have a
decrease in LVEF. In the 67 cases that developed LVEF
decreases to less than 50%, 25 recovered.
Further pharmacological studies by this group have suggested
that paclitaxel, as clinically formulated in Cremophor EL, may
lead to slower elimination of doxorubicin and doxorubicinol,
thus resulting in prolonged exposure
[53]. Experimental work
has proposed that both paclitaxel and docetaxel, but not the
tubulin-active alkaloid vinorelbine, enhance the metabolism of
doxorubicin to toxic species in human myocardium
[54].
However, Sparano and colleagues recorded a 6% rate of CHF
in 52 patients with metastatic breast cancer treated with
60 mg/m
2
doxorubicin followed 15 min later by 200 mg/m
2
paclitaxel as first-line chemotherapy [55]. The median
cumulative dose of doxorubicin was 240 mg/m
2
.
It is of note that these two studies are limited, the former due
to its retrospective nature and the latter by the small number of
patients. A Phase III trial randomized women with anthracy-
cline naive metastatic breast cancer to receive either 60 mg/m
2
doxorubicin followed 30 min later by a 3-h infusion of
175 mg/m
2
paclitaxel (AT) or doxorubicin 60 mg/m
2
and
cyclophosphamide 600 mg/m
2
(AC) [56]. Both regimens were
administered once every 3 weeks for a total of 6 cycles. There
was no significant difference in the incidence of CHF in the
two treatment groups; three women in the AT arm and one in
the AC arm (p = 0.62). Decreases in LVEF below the lower
limit of normal were observed in 33% of the AT arm and 19%
in the AC arm, and none of these patients developed CHF.
As a consequence of this trial, it is apparent that the combi-
nation of doxorubicin and paclitaxel is devoid of excessive risk
of CHF when a maximum cumulative doxorubicin dose of
360 mg/m
2
is administered.
Paclitaxel & epirubicin
Paclitaxel appears to play a minor role in the metabolism of epi-
rubicin when both drugs are used in combination
[57]. Gennari
and colleagues assessed cardiotoxicity in 105 patients treated
with epirubicin and paclitaxel as first-line therapy for advanced
breast cancer
[58]. A total of 76 of these women were treated
with 90 mg/m
2
epirubicin and paclitaxel doses ranging from
135 to 225 mg/m
2
. A total of 29 women were treated with
gemcitabine, epirubicin and paclitaxel within the context of a
Phase II trial. No patient developed cardiotoxicity while
receiving therapy, but nine women eventually developed
Nonanthracycline cardiotoxicity
www.future-drugs.com
1233
symptomatic CHF, seven of whom had received prior chest
wall radiotherapy. Cumulative doses of epirubicin in these cases
were; 1080 mg/m
2
in four women, 720 mg/m
2
and 540 mg/m
2
in two patients each and 630 mg/m
2
in one woman. None of
the women who received gemcitabine in combination with
paclitaxel and epirubicin developed CHF.
A multicenter Phase III trial randomized women with
advanced breast cancer to receive 90 mg/m
2
epirubicin and a
3-h infusion of 200 mg/m
2
paclitaxel for eight cycles or
120 mg/m
2
epirubicin for four cycles followed by four courses
of 250 mg/m
2
paclitaxel [59]. Patients treated in the combina-
tion arm demonstrated a gradual rise in cardiotoxicity during
chemotherapy. However, those in the sequential arm displayed
a modest increase in cardiotoxicity during the first four cycles
of therapy (epirubicin), but the risk stabilised and no additional
event was reported during or after four cycles of paclitaxel.
These data strongly suggest that paclitaxel, in both arms, had
no impact on cardiotoxicity.
Docetaxel & doxorubicin
There is no observed increase in cardiotoxicity when these two
agents are used in combination
[60].
Alkylating agents
Cyclophosphamide
Cardiotoxicity associated with cyclophosphamide ranges from
asymptomatic pericardial effusions to pericarditis, myocarditis
and CHF. In many cases, CHF associated with cyclophospha-
mide is mild and resolves on discontinuation of the drug
[61].
Symptoms develop acutely, usually within 1–10 days of the first
course and may persist for 1–6 days
[61]. The total dose of
cyclophosphamide administered with each cycle is associated
with the likelihood of developing cardiotoxicity, rather than the
cumulative dose
[62]. Although doses of cyclophosphamide as
low as 120 mg/kg have been reported to cause this adverse
effect, typically total doses of 180–200 mg/kg over 2–4 days
have caused symptomatic cardiomyopathy
[62]. The incidence
for patients receiving greater than 1.55 g/m
2
/day was 25%,
which compared with 3% in patients being treated with lower
doses
[62]. Steinherz and colleagues performed serial echocardio-
grams in 40 pediatric patients treated with
cyclophosphamide
[63]. A total of 21 of these 40 children
(52.5%) developed one or more echocardiographic changes and
seven (17.5%) experienced clinical symptoms of cardiotoxicity.
The clinical and echocardiographic toxicities were distributed
equally between patients treated with 170 mg/kg or more sin-
gle-agent cyclophosphamide and those treated with
120–160 mg/kg cyclophosphamide in combination
with 100 mg/m
2
or more anthracycline.
Others have reported an acute and frequently fatal myopericar-
ditis, usually associated with intravenous bolus administration of
cyclophosphamide
[64–67].
Various risk factors for cyclophosphamide-induced cardio-
toxicity have been proposed, including previous anthracycline
treatment and mediastinal radiotherapy
[62]. Older age was
reported as a risk factor in a series of 61 women with metastatic
breast cancer treated with high-dose cyclophosphamide as part
of a triple sequential high-dose regimen
[68]. Six (10%) of these
women developed clinically reversible grade 3 CHF following
administration of cyclophosphamide.
The exact underlying mechanism is unknown and various
hypotheses have been suggested. Postmortem findings have
included increased cardiac weight, cellular hypertrophy, mild-
to-moderate myocardial edema and fibrosis, and in some cases
hemorrhagic multifocal necrosis, leading to the suggestion that
a toxic metabolite may be responsible for myocyte and
endothelial injury
[69,70].
CHF should be treated as described previously and myoperi-
carditis may be symptomatically treated with anti-inflamma-
tory drugs. Cyclophosphamide is known to affect glutathione
levels and an animal study has suggested that glutathione plays
an important role in protecting cardiac tissue against cyclo-
phosphamide under normal and glutathione-depleted
conditions
[71].
Ifosfamide
Cardiovascular toxicity, although rare, has been reported with
ifosfamide therapy. Cardiac arrhythmias were observed in five
out of 33 patients (15.2%) receiving 6.5–10 g/m
2
ifosfamide
over 3–5 days with mesna
[72]. All arrhythmias were reversible
on discontinuation of the drug and in one patient, readminis-
tration led to an arrhythmia that was refractory to therapy. No
predisposing factors were identified in this series. Another study
reported two patients, who had previously been treated with
doxorubicin (cumulative doses 344 mg/m
2
and 550 mg/m
2
),
developing CHF following high-dose ifosfamide 18 g/m
2
[73].
No acute ECG changes were recorded and both improved with
standard medical therapy. A retrospective study of 52 patients
with advanced lymphoma and carcinoma, treated with high-
dose ifosfamide (escalating from 10–18 g/m
2
), followed by
autologous bone marrow transplantation within two Phase I tri-
als, demonstrated nine cases of dose-dependent CHF (17%)
[74]. Ifosfamide was administered in combination with either
carboplatin and etoposide or lomustine and vinblastine. Eight
of the nine patients developed severe CHF necessitating admis-
sion to an intensive care unit, and all eight had received previ-
ous doxorubicin (mean cumulative dose: 340 mg/m
2
; range:
190–550 mg/m
2
). Three had received prior mediastinal radio-
therapy. Symptoms developed a mean of 12 days (range: 6–23
days) following chemotherapy and all patients with severe CHF
had accompanying ECG changes, but none displayed ischemic
changes or cardiac enzyme elevation. One patient died of cardi-
otoxicity and another five died of noncardiac causes. The car-
diac symptoms stopped on discontinuation of ifosfamide and
no subsequent symptoms were reported following initiation of
supportive therapy.
In the series reported by Quezado and colleagues, development
of CHF was significantly correlated with doubling of serum cre-
atinine from preifosfamide therapy values
[74]. The reversal of
CHF with time suggests that ifosfamide-associated cardiotoxicity
Jones & Ewer
1234
Expert Rev. Anticancer Ther. 6(9), (2006)
may be related to delayed elimination of cardiotoxic metabolites.
In addition, fluid retention or electrolyte disturbances related to
ifosfamide may contribute to cardiotoxicity.
The etiology of ifosfamide-induced cardiotoxicity is poorly
characterized. Ifosfamide is structurally similar to cyclophospha-
mide and it is possible that cardiotoxicity secondary to both
drugs has a similar underlying mechanism
[74]. Animal studies
have revealed that high-dose ifosfamide can cause severe myocar-
dial damage with loss of striation and sometimes fragmentation
of ventricular muscle fibers
[64].
No prophylactic therapy is available, but careful attention
should be given to fluid balance during drug
administration
[74]. Once cardiotoxicity is established, ifosfa-
mide should be discontinued and standard treatment for CHF
commenced.
Platinum compounds
Acute cardiac symptoms reported with cisplatin-based chemo-
therapy have included arrhythmias, chest pain and infrequently
elevated cardiac enzymes suggestive of MI
[75–83], as well as
acute cerebrovascular accidents
[80,84,85]. However, acute cardio-
toxicity associated with cisplatin-based therapy is rare and plati-
num analogs are often administered in combination with other
chemotherapeutic agents. In contrast, Nichols and colleagues
conducted a questionnaire-based assessment of patients treated
with cisplatin-based treatment in the Testicular Cancer Inter-
group study, and found no evidence of acute cardiovascular
toxicity following cisplatin-based chemotherapy
[86].
Nephrotoxicity, experienced by 35% of those treated with
cisplatin, can result in significant hypomagnesemia and
hypokalemia, which in turn can exacerbate cardiac
arrhythmias
[83].
The underlying etiology is not known, although autonomic
neuropathy and hypomagnesemia could potentiate arterial
vasospasm
[87].
Chest pain and arrhythmias should be treated using standard
protocols. Further studies are required to confirm and define
the relationship between platinum analogs and acute
cardiovascular toxicity.
Recently, an increase in the intima-media thickness of the
carotid artery and plasma von Willebrand factor has been dem-
onstrated in 65 testicular cancer patients treated with cisplatin-
based chemotherapy (bleomycin, etoposide and cisplatin
[BEP])
[88]. Nuver and colleagues have suggested that changes
in these parameters during treatment may be of prognostic
significance for cardiovascular complications in the long term.
A number of studies have investigated the long-term effects
of cisplatin-based regimens for testicular cancer in terms of
cardiovascular morbidity.
Nuver and colleagues have suggested that decreased testoster-
one levels and increased urinary cortisol metabolite excretion
through an association with body mass index may play a role in
the development of the metabolic syndrome (which is associ-
ated with an increased risk of cardiovascular disease) in
chemotherapy-treated testicular cancer survivors
[89].
Meinardi and colleagues have reported that cisplatin-based
chemotherapy can cause cardiovascular effects 10–20 years fol-
lowing curative treatment of metastatic testicular
carcinoma
[17]. In their study, 87 patients treated with chemo-
therapy, who were in remission for 10 years and less than 50
years of age at the time of analysis were evaluated for cardiovas-
cular events and their risk profile compared with 40 patients
with comparable age and follow-up duration treated with
orchidectomy for stage I disease. In five out of the 87 patients
(6%), major cardiac events were documented, including two
with MI and three with angina and proven myocardial
ischemia. One patient experienced a cerebrovascular accident.
The chemotherapy patients had higher BP, total cholesterol,
triglyceride and were more insulin resistant. Echocardiographic
evaluation revealed normal systolic function in most cases, but
diastolic LV function was abnormal in 33% of cases.
There have been a number of other reports documenting
long-term cardiovascular morbidity following cisplatin-based
chemotherapy for testicular cancer
[15,16,18,19,90–96]. Huddart
and colleagues assessed the cardiovascular morbidity in 992 tes-
ticular cancer patients with a median follow-up of 10.2 years
[18]. In this study, 6.7% of patients treated with chemotherapy
had experienced cardiotoxicity compared with 3.7% treated
with orchidectomy alone.
A comparison of cardiovascular disease in 2512 5-year testicu-
lar cancer survivors with the general population rate has been
published recently
[19]. Cisplatin, vinblastine and bleomycin
(PVB) was associated with a 1.9-fold (95% confidence interval
[CI]: 1.7–2.0-fold) increased risk of MI. BEP was associated with
a 1.5-fold (95%CI: 1.0–2.2) increased risk of cardiovascular
disease, but no increased risk of MI.
The exact mechanism for acute cardiac symptoms is
unknown
[83]. Several factors may be involved in the develop-
ment of long-term cardiovascular toxicity, including sex-hor-
mone imbalance, endothelial damage and insulin resistance
[17].
Arrhythmias and chest pain should be treated using standard
protocols.
In conclusion, it should be noted that cisplatin generally has
a low cardiotoxicity profile. Chemotherapy schedules for testic-
ular cancer contain drugs other than cisplatin, thus it is diffi-
cult to attribute the observed acute cardiotoxicity solely to plat-
inum analogs. Further work is required to assess the causative
mechanisms of long-term cardiovascular complications in
patients treated with cisplatin-based regimens for germ cell
tumors.
Mitomycin
There have been a number of reports of CHF secondary to
mitomycin, especially in combination with doxorubicin, with
reported incidences of 2–15%
[97–102].
Cardiotoxicity due to mitomycin in combination with doxo-
rubicin, or mitomycin alone after doxorubicin, may become
evident even at low cumulative doses of the anthracycline. Ver-
weij and colleagues conducted a prospective study to assess the
dose dependency of mitomycin cardiotoxicity
[102]. Of 37
Nonanthracycline cardiotoxicity
www.future-drugs.com
1235
evaluable patients, one developed CHF following 30 mg/m
2
mitomycin and only 150 mg/m
2
doxorubicin. Reviewing the
previous literature, the authors concluded that mitomycin car-
diotoxicity is dose dependent occurring at cumulative doses
of 30 mg/m
2
or more, usually in patients treated simultane-
ously or previously with doxorubicin. The underlying
mechanism is not known.
CHF should be treated with ACEIs,
β-adrenergic blockers
and diuretics; digoxin may be used to improve symptoms.
Bleomycin
As well as pulmonary fibrosis, there have been reports of an
acute chest pain syndrome during bleomycin infusions,
suggestive of pleuritis and/or pericarditis
[103].
A series of 287 patients treated with bleomycin were moni-
tored prospectively for pulmonary toxicity
[103]. In total, 2.8%
of patients developed acute chest pain, often occurring during
the first course of treatment. Pericarditis has been documented
with bleomycin
[104], as has CAD, myocardial ischemia and inf-
arction in patients treated with bleomycin in combination with
other chemotherapeutic agents
[105–107].
Analgesics and reducing the infusion rate are recommended
in patients experiencing acute chest pain associated with bleo-
mycin. In the series reported by White and colleagues, all
symptoms improved on discontinuation of bleomycin
[103]. In
most cases, retreatment with bleomycin did not lead to recur-
rent episodes and no long-term sequelae were noted. In those
with intractable pain or ECG changes, the drug should be
stopped
[103].
Carmustine (BCNU)
Kanj and colleagues reported a case series of three young
patients with no cardiac risk factors who developed chest pain,
hypotension and sinus tachycardia during infusion of carmus-
tine
[108]. The fact that carmustine is given in combination with
other agents raises the question as to whether these effects are
due solely to carmustine and makes it difficult to quantify its
incidence.
Similar mechanisms to those of 5-FU-induced ischemia may
be responsible for carmustine cardiotoxcitity owing to the
similarity of the two syndromes
[108].
Hypotension should be treated with intravenous fluid resus-
citation and chest pain and symptomatic sinus tachycardia
should be treated with standard protocols.
Busulfan & chlormethine
There have been rare reports of endocardial fibrosis with busul-
phan
[109] and cardiotoxicity with high-dose chlormethine [110].
Antimetabolites (excluding 5-fluorouracil)
Cytarabine (Ara-C, cytosine arabinoside)
Cardiac complications associated with this agent are rare and
include both supraventricular and ventricular arrhythmias,
pericarditis and recurrent CHF
[111,112]. Castleberry and
colleagues have described a syndrome associated with
cytarabine administration in children, consisting of high fever,
rash, joint pain, malaise and chest pain, typically occurring
6–12 h following infusion of the drug
[113].
The pathophysiology of this syndrome is unknown and all
patients responded to cessation of the drug.
Gemcitabine
There have been reports of atrial flutter and fibrillation in
patients treated with gemcitabine
[114–117]. An active metabolite
of gemcitabine, 2´,2´-difluorodeoxyuridine, could be responsi-
ble for this toxicity
[117]. In most cases, the arrhythmia resolves
spontaneously or responds to medical therapy.
Fludarabine & melphalan
There have been reports of cardiotoxicity (LV failure) in
patients treated with fludarabine and melphalan conditioning
regimens prior to transplantation
[118,119]. In addition, paroxys-
mal AF has been observed in patients treated with high-dose
melphalan
[120].
Pentostatin
A retrospective analysis of more than 1100 patients treated with
pentostatin identified 11 patients, all of whom were over the
age of 60 years, who developed clinical cardiotoxicity
[121]. Five
of these had a cardiac history, one had long-standing hyperten-
sion and three pulmonary metastases. Three categories of
events were observed: angina/MI, CHF and acute arrhythmias.
From this series, acute cardiac events can occur following
pentostatin in those with pre-existing cardiac disease and
possibly pulmonary metastases
[121].
From preclinical and clinical data it is unlikely that pentosta-
tin is directly cardiotoxic, although indirect effects of this drug
might affect cardiac function
[122–124].
As this drug is commonly used in patients who frequently
have concurrent cardiac disease, careful attention should be
given to drug administration and management of any associated
toxicity. In order to avoid acute renal failure and aid renal clear-
ance of pentostatin, adequate hydration should be given
[121]. In
those with known impaired LVEF, fluid balance should be mon-
itored diligently. Dose reduction in those with impaired renal
function is mandatory and the correction of hypercalcemia and
anemia will enable the drug to be administered more safely. The
optimization of cardiac medication and control of nausea and
vomiting are important considerations
[121].
Antimicrotubule agents (excluding taxanes)
Vinca alkaloids
These agents can cause cardiovascular autonomic neuropathy,
changes in BP, angina with ECG changes, myocardial ischemia
and infarction
[125–135]. A meta-analysis of 19 trials, involving
2441 patients treated with vinorelbine and 2050 control
patients revealed the incidence of cardiotoxicity associated with
vinorelbine to be 1.19%
[135]. No difference in the risk of
cardiotoxicity between vinorelbine and other drugs was
observed, but the overall risk of cardiac events was significantly
Jones & Ewer
1236
Expert Rev. Anticancer Ther. 6(9), (2006)
higher in women, regardless of the drug combination used.
Those who had a pre-existing cardiac history were more likely
to experience cardiotoxicity.
The pathophysiological process responsible for the cardiotox-
icity of vinca alkaloids remains unknown, proposed mecha-
nisms have included a direct effect on cellular microtubuli and
the impairment of myocardial cell metabolism
[131].
Patients with a past medical history of MI and ischemia
should be maintained on appropriate anti-anginal therapy.
Chest pain should be treated as described previously. Further
work is required to conclusively link vinca alkaloids with MI
and clearly identify risk factors.
Etoposide
There have been reports of myocardial ischemia and infarction
in patients treated with etoposide in combination with various
other chemotherapeutic agents
[136]. Many of these episodes
occurred in patients with no cardiac risk factors.
Several mechanisms have been proposed, including coronary
artery vasospasm mediated through the release of vasoactive
substances, direct injury on vasculature or the induction of an
immune response
[136].
Targeted therapy
Trastuzumab
Trast u zum a b (Hercep t i n
®
) is a humanized monoclonal anti-
body to the HER2 protein, a transmembrane receptor tyrosine
kinase, overexpressed in approximately 25–30% of breast
cancers and associated with a poor prognosis
[23].
Incidence
A pivotal Phase III trial randomized 469 women with metastatic
breast cancer to receive either chemotherapy alone or combined
with trastuzumab. Symptomatic and asymptomatic cardiotoxicity
was observed in 27% of patients treated with trastuzumab in com-
bination with an anthracycline and cyclophosphamide (AC), com-
pared with 8% in those treated with AC chemotherapy alone. Car-
diotoxicity was reported in 13% of those treated with trastuzumab
in combination with paclitaxel, compared with 1% in patients
administered paclitaxel alone
[23]. In other single-agent trials, cardi-
otoxicity was observed in 3 and 5% of patients in the first- and sec-
ond/third-line setting, respectively (within the H0650g and
H049g trials)
[7]. These reports prompted a retrospective review of
cardiotoxicity in seven Phase II and III trials by an independent,
blinded Cardiac Review and Evaluation Committee (CREC)
[7].
In total, 1219 patient records were screened and 202 analyzed
more closely. Cardiotoxicity was identified as an adverse event in
112 women. Of the 1219 women assessed by the CREC, ten car-
diac-related deaths were identified. Nine of these were in patients
treated with trastuzumab within a clinical trial setting.
Clinical features
Cardiotoxicity due to trastuzumab presents as LV dysfunction
that may be transient and asymptomatic or, especially in
patients exposed to anthracyclines, as more serious cardiac
dysfunction or CHF
[23]. In contrast to pure anthracycline
cardiotoxicity, trastuzumab cardiac dysfunction appears to have
a much greater potential to be reversible
[137].
Risk factors
The CREC identified increasing age as a risk factor for trastu-
zumab-associated cardiotoxicity, but only in the AC-treated
subgroup
[7]. There is currently insufficient information to con-
firm or refute the role played by other suspected risk factors,
such as pre-existing ischemic heart disease, cumulative dose of
previous anthracyclines and chest wall radiotherapy.
Etiology
HER2 plays a critical role in embryonic cardiogenesis and car-
diac hypertrophy and it is possible that trastuzumab has a direct
cardiotoxic effect via the cardiac HER2 receptor
[26]. Others
have suggested that trastuzumab may have inherent cardiotox-
icity or may have additive effect when given with or following
an anthracycline
[138]. HER2 receptors appear to be cardiopro-
tective as they mediate the activation of important cardiac sur-
vival pathways
[7]. Thus it is possible that trastuzumab may
interfere with growth and repair following anthracycline-
induced toxicity
[139,140].
Treatment
In the analysis performed by the CREC, 83 out of 110 patients
(who had their symptoms noted) presented with symptoms of
cardiotoxicity and 82 of these 83 women received treatment for
CHF. Therapy included diuretics, ACEIs, cardiac glycosides
and other inotropic agents. Most patients responded to therapy
(79%). Notably, treatment outcome differed between patients
treated with trastuzumab plus AC compared with trastuzumab
plus paclitaxel in the trial reported by Slamon and colleagues.
Eight out of 39 women in the trastuzumab in combination
with AC subgroup continued to display significant functional
impairment (NYHA class III) following medical therapy. In
contrast, none of the 12 patients treated with paclitaxel and
trastuzumab displayed functional impairment following medi-
cal therapy. In heavily pretreated patients treated with single-
agent trastuzuamb (within the H0650g and H049g trials), less
impressive improvement in functional status was observed.
The reversibility of trastuzumab-related cardiotoxicity has
been illustrated in a study of 38 women treated previously with
anthracycline-based therapy who developed cardiac dysfunc-
tion
[2]. In this series of patients, the mean LVEF decreased sig-
nificantly following trastuzumab. LVEF recovery occurred in
32 (84%) patients with medical therapy and six (16%) with no
treatment, mean time to LVEF recovery was 1.5 months. Of
note, 25 women were retreated with trastuzumab; three
patients had recurrent LV dysfunction but 22 (88%) did not.
Nine of these women underwent endomyocardial biopsy and
none displayed pathological features of cardiotoxicity. In total,
20 (52%) of these patients had symptomatic CHF and 15 were
treated with standard medical therapy for CHF, which included
ACEIs and beta-blockers. Two of the five patients who did not
Nonanthracycline cardiotoxicity
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1237
receive CHF therapy had persistent LV dysfunction on reassess-
ment 6 months afterwards. In addition, 16 of those with no
symptoms, but who experienced LVEF decreases, were treated
with medical therapy.
Trastuzumab in the adjuvant setting
The HERA trial randomized patients to receive adjuvant chem-
otherapy alone or followed by trastuzumab
[141]. There was one
cardiac death in the chemotherapy-alone arm. Nine patients
(0.54%) in the trastuzumab arm developed severe CHF. Symp-
tomatic CHF occurred in 1.7% of patients in the trastuzumab
arm and 0.06% in the chemotherapy alone arm. A decrease of
LVEF 10% or more from baseline to an LVEF of less than 50%
at any time was observed in 7.1% of those in the trastuzumab
arm and 2.2% in the observation arm.
Tan-Chiu and colleagues assessed the frequencies of cardiac
events between the treatment arms of the NSABP B-31
trial
[14,142]. Of the 814 patients treated with chemotherapy
alone, five met the criteria for a cardiac event (defined as
class III / IV CHF); four developed CHF and one died proba-
bly secondary to a cardiac cause. In the trastuzumab treated
arm, 31 developed a cardiac event, all CHF. For patients treated
with trastuzumab evaluable for analysis, the cumulative inci-
dence of cardiac events 3 years following day 1 of cycle five was
4.1% (95% CI, 2.9–5.8%). The difference between the arms
was 3.3% (95% CI, 1.7%–4.9%). The overall incidence of car-
diac dysfunction associated with trastuzumab was 19%. Trastu-
zumab-associated CHF generally responded to drug with-
drawal and standard medical therapy. In most cases, the
decrease in LVEF recovered to or close to pretreatment values.
In conclusion, these preliminary reports suggest that
trastuzumab adds to toxicity of anthracyclines and,
additionally, has toxicity of its own. The toxicity appears to be
less than was suggested in the original trials, but is nevertheless
not trivial. As trastuzumab toxicity is, to a large degree, reversi-
ble, it is difficult to compare the relative components with car-
diotoxicity of the anthracycline and the monoclonal antibody.
Although one of the four adjuvant trials was closed temporarily
owing to toxicity concerns, all ultimately proceeded: the thresh-
old for closure because of increased cardiotoxicity in the trastu-
zumab arm was not achieved. The clinical and mechanistic dif-
ferences between the cardiac effects of trastuzumab and those of
the anthracyclines has lead to the suggestion that myocardial
dysfunction secondary to trastuzumab could be classified as
type II cancer therapy-related cardiac dysfunction
(TABLE 1) [137].
Alemtuzumab
Cardiac adverse effects are infrequent with this humanized mon-
oclonal antibody to the CD52 antigen. There may be an associa-
tion with cardiotoxicity in patients with T-cell malignancies
treated with alemtuzumab. Lenihan and colleagues retrospec-
tively reviewed the occurrence of cardiotoxicity in eight patients
with mycosis fungoides and Sezary syndrome
[143]. Of these, four
with no history of cardiac disease developed significant cardio-
toxicity. Three of these experienced CHF, which improved on
discontinuing the drug in two cases. One patient developed AF
and this improved on stopping the drug. A cytokine-release
syndrome was proposed as a cause of these adverse effects.
In contrast, Lundin and colleagues reviewed 22 mycosis fun-
goides/Sezary syndrome patients treated with alemtuzumab
within European trials and eight patients in similar trials con-
ducted in the UK
[144]. Seven of the 22 had pre-existing cardiac
risk factors and five had been treated with prior anthracycline
chemotherapy. None of the total of 30 cases reviewed developed
Table 1. Type I and II cancer therapy-related cardiac dysfunction.
Type I: myocardial damage Type II: myocardial dysfunction
Drug class Anthracycline Trastuzumab
Clinical course and response to therapy May stabilize.
Underlying damage appears to be permanent
and irreversible.
Recurrence in months or years may be related
to sequential stress.
High likelihood of recovery to or near baseline
cardiac status within 2–4 months (reversible).
Dose effect Cumulative dose related. Not dose related.
Noninvasive assessment Decreased LVEF.
Global decrease in wall motion.
Decreased LVEF.
Global decrease in wall motion.
Ultrastructure Vacuoles, myofibrillar disarray and
dropout, necrosis.
No apparent ultrastructural changes.
Effect of rechallenge High probability of recurrent dysfunction that
is progressive and may result in intractable
CHF and death.
Increasing evidence for the relative safety of
rechallenge. Further data required.
Effect of late sequential stress High likelihood of sequential stress-
related dysfunction.
Low likelihood of sequential stress-related
cardiac dysfunction.
Reproduced from [137]. CHF: Congestive heart failure; LVEF: Left ventricular ejection fraction.
Jones & Ewer
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Expert Rev. Anticancer Ther. 6(9), (2006)
clinical cardiotoxicity. In addition, therapy with this agent for
peripheral T-cell lymphoma and T-cell prolymphocytic leukae-
mia has not been associated with cardiotoxicity
[145–147] and Lun-
din and colleagues suggest, as a consequence, it is unlikely that
T-cell cytokines are a cause of significant cardiotoxicity
[144].
In a multivariate analysis, Oshima and colleagues have
reported cumulative dose of anthracycline (p = 0.0016) and use
of alemtuzumab (p = 0.0001) as independent significant risk
factors of grade II–IV cardiac complications in 142 patients
treated with in vivo alemtuzumab as part of the conditioning
regimen in adult patients undergoing allogeneic hematopoietic
stem cell transplantation
[148]. All of the cardiac complications
in patients treated with alemtuzumab were successfully treated
with diuretics and/or catecholamines.
From the previously mentioned studies, it is apparent that
cardiac complications are uncommon following alemtuzumab
and are generally manageable with early detection and
employment of medical therapy.
Bevacizumab
Bevacizumab is a recombinant humanized monoclonal anti-
body that blocks the activity of vascular endothelial growth fac-
tor (VEGF). Hypertension and proteinuria have been docu-
mented in patients treated with this agent
[10–12]. In a Phase III
trial of 462 metastatic breast cancer patients treated with
capecitabine, either alone or in combination with bevacizumab,
two women in the capecitabine-alone arm developed grade 3 or
4 CHF compared with seven in the combination arm
[12].
Mean pretreatment LVEF and the number of women with
baseline LVEF less than 50% was similar in both arms. In all
but one patient, cardiac symptoms improved with medical
therapy and two out of seven affected patients continued beva-
cizumab. Greater than expected cardiotoxicity was documented
in a Phase II study of bevacizumab combined with doxorubicin
in soft-tissue sarcoma patients
[149]. LVEF declined significantly
(grade 2 or worse) in six of the 17 patients. However, with
follow-up LVEF improved in five of the six patients.
Sorafenib
In a series of 20 patients treated with this tyrosine kinase inhibi-
tor, a significant and sustained increase in BP was documented,
as well as an increase in vascular stiffness
[13]. Only two of these
patients required the addition of, or an increase in, the dose of
antihypertensive medication. The circulating concentration of
various humoral factors was also assessed, but no significant
change in these was observed. However, a significant inverse rela-
tionship between decrease in catecholamine levels and increase in
systolic BP was documented, pointing towards a secondary
response to BP elevation. The mechanisms responsible for these
changes require further evaluation.
Imatinib
Recent clinical and laboratory data suggest that imatinib can
cause cardiotoxicity
[150]. This report describes ten cases of
clinical CHF in patients with chronic myelogenous leukemia
treated with imatinib. Before treatment LVEF was normal in all
of these patients.
Vascular-disrupting agents
Cardiotoxicity has been observed in Phase I trials of other novel
agents such as combretastatin A4 phosphate
[151] and
ZD6126
[152]. In the Phase I study reported by Cooney and
colleagues, two out of 25 patients had ECG changes consistent
with the acute coronary syndrome, occurring within 24 h of
combretastatin A4 phosphate infusion
[151]. Both patients
recovered and had no further cardiac sequelae. In contrast, in a
Phase I trial, Bilenker and colleagues observed no cardiotoxicity
among 16 patients treated with a combination of combretasta-
tin A4 phosphate and carboplatin
[153]. In another Phase I trial
incorporating weekly ZD6126, four patients experienced chest
pressure and a further four developed elevated creatine phos-
phokinase levels
[152]. Decreases in LVEF were observed in three
patients, but none had clinical symptoms of CHF.
Other agents
Interleukin-2
IL-2 exhibits well-recognised toxicity that may manifest as
tachycardia, decrease systemic vascular resistance, increased car-
diac output and capillary leak syndrome with pulmonary dys-
function
[154]. Cardiotoxicity can be expressed as sinus tachy-
cardia, arrhythmias, ischemia or even fatal MI
[154,155]. The
most common cardiovascular toxicity secondary to IL-2 is
hypotension, due to increased vascular permeability and a
decrease in systemic vascular resistance
[154,29]. This results in
an increase in cardiac output and tachycardia, which can be
associated with atrial arrhythmias
[154]. In a study of 93 patients
(treated with high dose IL-2 10
5
IU/kg and lymphokine-acti-
vated killer cell), 21% developed arrhythmias, mainly
supraventricular tachycardias and AF. Five patients experienced
significant ventricular ectopy requiring anti-arrhythmic therapy
and temporary cessation of IL-2
[155]. One patient developed
ventricular tachycardia and another died of myocardial infarc-
tion while on treatment. In a series of 199 patients treated with
high dose IL-2 reported by White and colleagues, arrhythmias
occurred in 6% of courses and 2.5% of patients had elevated
creatine phosphokinase levels, with elevated MB isoenzyme
[29].
The incidence of ischemic chest pain varies from 2.6 to 4.3%,
and MI between 1.2–4.3%
[154,155].
A randomized comparison of low- and high-dose IL-2 for renal
cell cancer, demonstrated a significantly higher incidence of
hypotension in the high- compared with low-dose arm, (3 vs 55
courses, respectively; p < 0.001)
[156]. However, this was reversi-
ble with supportive care and cessation of IL-2 and no treatment-
related mortality was documented in either arm. Further data
reported by Yang and colleagues suggest markedly reduced toxic-
ity with low- compared with high-dose IL-2
[157], with hypoten-
sion occurring in 36.4, 2.9 and 0% of courses in high-, low- and
subcutaneous arms of a randomized trial in renal cell carcinoma,
respectively. In addition, atrial arrhythmias were observed in 4.2,
1.5 and 0% in the high-, low- and subcutaneous arms,
Nonanthracycline cardiotoxicity
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1239
respectively. Analysis of toxicity data from a Phase III rand-
omized trial of high-dose IL-2 compared with subcutaneous IL-2
and interferon in patients with metastatic renal cell carcinoma,
revealed a higher incidence of grade 3 and 4 cardiac toxicities in
the high-dose IL-2 arm (8.4 vs 0%, respectively)
[158].
The exact mechanism underlying IL-2 cardiotoxicity is
unknown. An animal study has suggested that the cardiotoxic-
ity associated with Il-2 is triggered by IL-2-activated lym-
phocytes, which exert cytolytic effects first on endothelial cells
and subsequently on cardiac myocytes. As a consequence,
lesions are produced that involve both the cardiac microcircula-
tion and muscle cells, resulting in myocarditis and myocardial
necrosis
[159].
Hypotension is reversible with cessation of IL-2 along with
intravenous fluid resuscitation and, if required, vassopressor sup-
port
[154]. Supraventricular tachycardias usually respond to
standard anti-arrhythmic therapy, and ischemic symptoms
should be treated using standard protocols
[154]. A total of 11 out
of 14 patients who developed atrial arrhythmias in the series
reported by White and colleagues subsequently received further
Il-2; six were on no anti-arrhythmic therapy, four were on
digoxin and one was receiving verapamil for hypertension
[29].
IL-2 is administered in wide dose ranges
(72,000 IU/kg–720,000 IU/kg), and toxicity appears to be less
severe with low dose regimens. For example the reported inci-
dence of hypotension changes from 36–69% with high-dose
regimens to 2.9% with low-dose regimens
[156,160].
Interferon
The possibility of interferon-induced cardiotoxicity was first
raised following four deaths, secondary to MI, in patients
treated with this agent
[161]. The incidence of arrhythmia with
this agent is uncommon
[8] and there have been case reports of
reversible cardiomyopathy
[8,162–165] and one report of
irreversible cardiomyopathy
[166].
In a study of 15 non-small cell lung cancer patients treated
with interferon, three were withdrawn owing to cardiovascular
events
[166]: one patient with a past history of ischemic heart
disease developed a complete A-V block requiring pacemaker
implantation; a second developed intermittent AF; and the
third experienced ventricular premature beats. A retrospective
analysis of 44 patients with cardiotoxicity secondary to inter-
feron reviewed eight cases of MI, six of whom died
[8]. Another
patient had ischemic chest pain with ST elevation on ECG,
which was complicated by pulmonary edema. A past medical
history was available for five patients, and all five had underly-
ing CAD. Interferon was restarted at a reduced dose in one
patient, with no further cardiotoxicity
[8].
LVEF was evaluated in 11 patients with chronic viral hepati-
tis treated with interferon
[168]. Prior to commencing inter-
feron, all patients had normal LVEF, but a significant decrease
was observed following 1 month of therapy. A reduction of
greater than 10% was observed in five patients. LVEF returned
to near pretreatment values in nine of the 11 patients 3 months
following cessation of interferon.
Risk factors for interferon-induced cardiotoxicity are not
clear
[8]. In most cases, toxicity is not necessarily related to
extensive interferon therapy and can occur in patients treated
with both low and high daily doses
[8]. There appears to be no
relationship between cardiotoxicity and age, but it has been
suggested that a past history of cardiac disease is a risk factor for
interferon-induced arrhythmia and ischemia
[8].
The mechanism of this toxicity is not known. Various in vitro
studies have reported conflicting results
[8]. A mouse model has
demonstrated a statistically significant increase in the thickness
of the endothelial structure of myocardial capillary walls in
mice treated with interferon, with accompanying decrease in
size of the capillary lumen
[169].
Interferon should be stopped if myocardial ischemia develops
and standard therapy initiated
[8]. In some cases, interferon has
been recommenced at a lower dose, with no further cardiotox-
icity
[8]. Myocardial dysfunction secondary to interferon gener-
ally improves on stopping the drug and again, in some cases,
rechallenge may prove feasible with stable cardiac function
[8].
All-trans retinoic acid
A syndrome characterized by fever, dyspnea, hypotension, peri-
cardial and pleural effusions develops in 5–27% of patients,
and usually within the first 21 days of therapy. The mortality
rate ranges from 5 to 29%
[170]. A series reported by Tallman
and colleagues recorded an incidence of 26% of this syndrome
in 167 patients with newly diagnosed acute promyelocytic
leukemia
[170]. The overall mortality rate in this series was two
patients (5%).
It is still uncertain what the best approach to predict, prevent
or treat this syndrome should be. No risk factors for this syn-
drome have been identified and the pathogenesis is not fully
understood
[170]. Postmortem histological findings suggest
microvasculature damage
[170].
Symptoms usually resolve rapidly with prompt administra-
tion of dexamethasone, even among patients who continue all-
trans retinoic acid (ATRA). Concurrent administration of
chemotherapy with ATRA may decrease the incidence,
although this has not been clearly established
[170]. ATRA can
be reintroduced following resolution of symptoms, without the
need for concurrent prophylactic steroid therapy and there
appears to be no risk of the syndrome developing in patients
given maintenance ATRA
[170].
Arsenic trioxide
Barbey and colleagues assessed the effects of QT-interval pro-
longation in 99 patients with advanced malignancies treated
within two Phase I and two Phase II trials
[9]. Among the cases
assessed, 170 individual courses of arsenic trioxide therapy were
evaluated. Baseline ECG abnormalities were observed in
36 patients, despite this, in 80% of the ECGs the RR and QT
interval could be determined. A total of 52% of patients in this
study had received anthracycline-based therapy previously and
22 patients were treated with concomitant drugs known to pro-
long the QT interval. Prolonged QT interval developed in
Jones & Ewer
1240
Expert Rev. Anticancer Ther. 6(9), (2006)
38 patients, with the degree of prolongation being higher in
men than women during the first course of therapy, as well as in
patients with hypokalemia. The QT changes observed in this
analysis revealed a cumulative but reversible effect
[9]. There
have also been reports of atrioventricular block, torsade de
pointes, ventricular tachycardia and sudden cardiac
death
[171–175].
Two recent trials assessing the efficacy and safety of arsenic
trioxide in patients with myelodysplastic syndrome have been
published
[176,177]. Of 115 patients in the trial reported by Vey
and colleagues, three (3%) developed QT/QTc-interval pro-
longation
[176]. Severe or life-threatening cardiotoxicity was
observed in six patients, and in only one of these was the toxic-
ity deemed to be related to therapy (grade 3 pulmonary
edema). In the trial conducted by Schiller and colleagues of 70
patients, 17 (24%) developed QT/QTc prolongation
[177].
None of these patients developed clinical symptoms and the
events were easily rectified with correction of electrolyte abnor-
malities and withholding arsenic therapy until normalization of
QT intervals.
Recently, Siu and colleagues assessed the effects of oral
arsenic trioxide on QT intervals in 16 patients by performing
ECG and 24-h Holter monitoring at baseline, during and after
therapy with this agent
[178]. Oral arsenic trioxide gives a similar
bioavailability, but lower peak plasma arsenic concentrations, as
compared with intravenous arsenic trioxide. Long-term oral
arsenic trioxide increased the mean heart rate and corrected QT
interval (QTc). However, QT interval, QT and QTc disper-
sions were not changed. No ventricular proarrhythmias were
observed in this group of patients. These data suggest that oral
arsenic trioxide may be the preferred formulation for prolonged
therapy with this drug.
The mechanism of QT prolongation is unknown, although
various hypotheses have been proposed, including neuropathy
of the cardiac sympathetic system, direct myocardial effects and
interactions of arsenic with magnesium
[172]. Ficker and col-
leagues have published evidence that arsenic trioxide prolongs
the action potential of guinea pig ventricular myocytes via two
independent molecular mechanisms
[179]. Arsenic trioxide
increases calcium currents, which regulate the plateau phase of
the cardiac action potential. Additionally, arsenic trioxide
reduces surface expression of the cardiac potassium current
hERG/I
Kr
, which plays a crucial role in the later stages of car-
diac repolarization. Preclinical work by Drolet and colleagues
suggests that the variability in the extent of QT-interval prolon-
gation and onset of ventricular arrhythmias during arsenic tri-
oxide treatment represent competing effects, both blocking and
activating multiple repolarizing potassium channels
[180].
Prior to commencing arsenic trioxide, baseline electrolytes
and ECG should be performed and any pre-existing electrolyte
abnormality should be corrected
[9]. If the QT interval is more
than 500 ms then corrective measures should be initiated and
QT interval again assessed prior to commencing therapy
[9].
Any possible concomitant agents known to prolong the QT
interval should be withheld
[24]. A list of drugs known to
prolong the QT interval is available at
[301]. QT changes during
arsenic trioxide therapy develop gradually over a period of more
than 6 days
[24]. Therefore, ECGs can be performed once a
week or more regularly if increases are greater than normal
[24].
Provided the QT interval remains normal, the frequency of
ECG monitoring can be decreased to once every 2 weeks, as the
risk of prolongation reduces with time
[24]. Serum potassium
and magnesium should be recorded at least once a week and, if
low, should be corrected immediately, as this will reduce the
risk of QT prolongation developing
[24]. If the QT interval rises
above normal (460 ms), then serum potassium and magnesium
concentrations should be increased to higher than the recom-
mended lower limit of normal, this usually decreases the inter-
val
[24]. If the absolute QT interval is more than 500 ms the
drug should be discontinued
[24].
Asparaginase
There have been case reports of MI in patients with recent
exposure to asparaginase, vincristine and daunorubicin
[181,182].
One patient subsequently received chemotherapy with no
asparaginase and did not experience further cardiac
symptoms
[181]. Asparaginase has also been reported to cause
disturbances in lipid metabolism, varying from decreases in
cholesterol and triglyceride levels
[183] to hypercholesterolemia
and hypertriglyceridemia during therapy
[183–187]. Parsons and
colleagues obtained serial fasting and lipid and lipoprotein
specimens in 38 out of 43 consecutively diagnosed children
with ALL before, during and after asparaginase therapy
[188].
Triglyceride levels were significantly higher during asparaginase
therapy compared with pre- and postasparaginase treatment.
During asparaginase therapy, hypertriglyceridemia was reported
in 67% of patients. A fasting lipid and lipoprotein profile was
recorded in 30 long-term survivors and triglyceride levels in
these patients did not exceed the normal range.
Thalidomide
Thalidomide is generally well tolerated and many of the com-
mon adverse effects can be managed with dose adjustment
[189].
Mild sinus bradycardia can occur in up to 25% of patients, and
in 1–3% this can be severe, necessitating discontinuation of the
drug. The mechanism of this toxicity is not known
[189]. Mild
peripheral edema occurs in approximately 15% of cases and in
3% of patients, severe edema that limits function may become
apparent. In those with severe edema, thalidomide should be
stopped and diuretics commenced. Thalidomide may be re-
started with a 50% dose reduction on resolution of edema
[189].
Orthostatic hypotension has been reported and may be a mani-
festation of autonomic neuropathy. Again, in severe cases, tha-
lidomide should be withheld until the symptoms resolve and
then restarted at 50% dose
[189]. Venous thromboembolism has
also been associated with thalidomide therapy
[190] and, rarely,
pulmonary embolism
[191]. Cerebrovascular accidents have also
been reported rarely in patients treated with thalidomide
[191].
Interestingly, two studies have suggested a potential role for
thalidomide in the management of patients with CHF
[192,193].
Nonanthracycline cardiotoxicity
www.future-drugs.com
1241
Table 2. Summary of cardiac & cardiovascular toxicity associated with anticancer agents. Toxicity Incidence Other information
5-FU Ischemia
MI
ECG changes
Arrhythmia
Overall incidence clinical
cardiotoxicity 1.6%
[4].
Of the order of 10% with higher
doses
[3]
ECG changes 68% [1]
Ischemia most common manifestation. Higher
incidence in patients with history of coronary artery
disease
[4]
Capecitabine can also cause ischemic pain [36–40]
Taxanes Bradycardia
AV conduction +
bundle branch block
Ventricular tachycardia
Ischemia
Incidence grade 4–5 cardiotoxicity
0.5%
[48].
Combination of doxorubicin + paclitaxel devoid of
excessive risk of CHF, doxorubicin maximum
cumulative dose ≤ 360 mg/m
2
[56]
Cyclophosphamide Pericardial effusions
Pericarditis
Myocarditis
CHF
3–34% with high-dose schedules
[68]
Pathological findings include increased cardiac
weight, cellular hypertrophy and myocardial
oedema
[70]
Ifosfamide CHF
Arrhythmias
Rare Monitor fluid balance + renal function [74]
Platinum compounds Long-term cardiovascular
morbidity
Acute cardiotoxicity
BEP 1.5 fold increased risk of
cardiovascular compared with
general population. PVB 1.9 fold
increased risk MI
[19].
Case reports of acute toxicity
[75–83]
Acute toxicity reported in combination with other
chemotherapeutic agents
[75–83]
Mitomycin CHF 2-15% [97–102] Usually observed in patients treated with
simultaneous or previous anthracyclines
[97–102]
Bleomycin Pericarditis
Ischemia and infarction
2.8% in one series [103]
Carmustine Hypotension
Sinus tachycardia
Chest pain
Rare [108] Given in combination with other agents, raising the
possibility that effects may not be solely due to
carmustine
[108]
Busulfan
Chlormethine
Endocardial fibrosis
Cardiotoxicity with high
doses
Very rare
[109]
Very rare [110]
Cytarabine Arrhythmias
Pericarditis
CHF
Rare [ 111 ,112] Syndrome of fever, rash, joint pain, malaise + chest
pain described in children
[113]
Gemcitabine Atrial fibrillation and flutter Rare [114–117] Responds to drug cessation ± medical therapy
[114–117]
Fludarabine +
melphalan
LV failure Rare [118,119] Conditioning regimen prior to transplantation
[118,119]
Pentostatin Arrhythmias
CHF
Ischemia/MI
1% [121] More likely in patients with concurrent cardiac
disease and pulmonary metastases
[121]
Vinca alkaloids Autonomic neuropathy
Blood pressure changes
Ischemia/MI
Incidence of cardiotoxicity with
vinorelbine 1.19%
[135]
In a meta analysis no difference in the risk of
cardiotoxicity between vinorelbine and other drugs
was observed
[135]
Etoposide Ischemia/MI Rare [136] Case reports of cardiotoxicity in combination with
other agents
[136]
ATRA: All-trans retinoic acid; AV: Atrioventricular; BEP: Bleomycin–etoposide–cisplatin; ECG: Electrocardiogram; FU: Fluorouracil; LV: Left ventricular; MI: Myocardial
infarction; PVB: Cisplatin–vinblastine–bleomycin.
Jones & Ewer
1242
Expert Rev. Anticancer Ther. 6(9), (2006)
Hamlin and colleagues have demonstrated in an animal model
that thalidomide has potential to lengthen QTc and has both
positive inotropic and lusitropic properties
[194].
Expert commentary
A wide variety of cardiotoxicity has been reported in patients
treated with nonanthracycline oncological drugs
(TABLES 2 & 3).
Although these adverse events are rare, it is important that cli-
nicians are aware of them, so that appropriate measures may be
taken to prevent the occurrence of these toxicities (correction of
electrolyte imbalance in patients receiving arsenic trioxide), or
treat the sequelae (or supportive therapy instigated as in the
case of 5-FU-induced ischemia). In certain cases, the cardiotox-
icity is reversible and the oncological agent can be continued.
Work is ongoing to elucidate the mechanism of cardiotoxicity
of some of these agents; in the case of myocardial depression
induced by trastuzumab, it is now apparent that the myocardial
dysfunction is different to that of anthracyclines and it has been
designated as type II cardiac dysfunction. In the case of agents
such as cisplatin, the secondary cardiovascular toxicities may
become apparent years after the completion of therapy. With
the growing number of survivors of cancer, the issue of long-
term cardiotoxicity is of increasing importance. Optimizing
present treatment regimens in order to ensure the best chance
of cure, but avoiding potential long-term sequalae of therapy
must be a prime consideration for oncologists.
Five-year view
With the development and application of novel agents in oncol-
ogy there will be a continued need for surveillance for
Trastuzumab Transient LV dysfunction
CHF
Single agent 3–5%
27% in combination with
anthracyline for metastatic breast
cancer
[7]
Cardiotoxicity reversible and certain patients may be
rechallenged
[2]
Interleukin-2 Hypotension
Arrhythmias
Ischemia
MI
Very common
6 – 21%
2.6 – 4%
1 – 4%
[154,155]
Wide dose range, toxicity less severe with low dose
regimens
[156–158]
Interferon Arrhythmia
Ischemia
Cardiomyopathy
Uncommon Rechallenge in cases of ischemia + cardiac
dysfunction may be possible
[8]
ATRA Fever, dyspnoea,
hypotension, pericardial +
pleural effusions
5–27% [170] Treat with dexamethasone [170]
Arsenic trioxide QT prolongation
Atrio-ventricular block
Torsade de pointes
Ventricular tachycardia
3–24% [176,177] Close monitoring of serum electrolytes [9]
Asparaginase MI
Lipid abnormalities
Rare [181,182]
During asparaginase therapy, 67%
developed hypertriglyceridemia in
one series [188]
Effects vary from decreases in cholesterol and
triglcerides to hypercholesterolaemia +
hypertriglyceridemia [183–188]
Thalidomide Sinus bradycardia
Peripheral oedema
Orthostatic hypotension
Venous thromboembolism
Severe 1–3%
Severe 3%
[189]
Rare [190]
Withhold thalidomide until resolution of symptoms
and then recommence at reduced dose
[189]
Table 2. Summary of cardiac & cardiovascular toxicity associated with anticancer agents (cont.).
Drug Toxicity Incidence Other information
ATRA: All-trans retinoic acid; AV: Atrioventricular; BEP: Bleomycin–etoposide–cisplatin; ECG: Electrocardiogram; FU: Fluorouracil; LV: Left ventricular; MI: Myocardial
infarction; PVB: Cisplatin–vinblastine–bleomycin.
Table 3. Cardiac and cardiovascular toxicity of novel
anticancer agents.
Drug Cardiac & cardiovascular effects Ref.
Alemtuzumab CHF; AF [143,148]
Bevacizumab Hypertension; proteinuria; CHF [10–12]
Sorafenib BP changes [13]
Combretastatin
A4 phosphate
ECG changes consistent with the
acute coronary syndrome
[151]
ZD6126 Chest pressure; elevated creatine
phosphokinase levels
[152]
AF: Atrial fibrillation; BP: Blood pressure; CHF: Congestive heart failure; ECG:
Electrocardiogram.
Nonanthracycline cardiotoxicity
www.future-drugs.com
1243
cardiovascular toxicity. This will require co-operation between
oncologists and cardiologists. Ongoing studies will give greater
insight into the cause and risk factors for a number of these
agents. Longer follow-up of patients treated with trastuzumab,
particularly in the adjuvant setting, is required before the full
nature of the risks and benefits can be determined, and the
impact of treatment interventions placed in perspective. Balanc-
ing the benefits of effective curative therapy against the
possibility of chronic toxicity will continue to be of prime con-
cern to those treating cancer patients, as treatments and outcome
improve. However, continued awareness and investigation of
patients treated with known potentially cardiotoxic agents is
required. Advances in genomics and proteomics could lead to the
selection of patients most likely to benefit from particular drugs
and the identification of those likely to develop cardiovascular
toxicity. It remains to be seen whether newer imaging and bio-
chemical tests will be improve detection of toxicity compared
with conventional tests such as ECG, echocardiography and
multigated radionuclide angiography. Although some of these
sequelae are rare, efforts to minimize their incidence, expression
and long-term effects will remain an important consideration for
physicians treating cardiac disease in cancer patients.
Key issues
• Cardiotoxicity secondary to anticancer drugs is rare.
• Manifestations of this adverse effect can include changes in cardiac rhythm, alteration in blood pressure, myocardial ischemia and
impairment of the ability of the heart to contract and/or relax.
• Some agents can also result in biochemical disturbances, which can result in cardiovascular morbidity.
• The monoclonal antibody to human epidermal growth factor receptor (HER)-2, trastuzumab, appears to cause reversible cardiac
dysfunction.
• 5-fluorouracil can rarely cause an ischemic syndrome.
• Cyclophosphamide and ifosfamide have been associated with congestive heart failure and myopericarditis.
• Both acute and long-term cardiovascular complications have been attributed to cisplatin-based chemotherapy.
• Hypersensitivity reactions and arrhythmias have been recorded in patients treated with taxanes.
• Vinca alkaloids can result in cardiovascular autonomic neuropathy, angina with electrocardiogram changes, myocardial ischemia
and infarction.
• A syndrome characterised by fever, dyspnoea, hypotension, pericardial and pleural effusions can develop in approximately 26% of
those treated with all-trans retinoic acid.
• Arsenic trioxide can cause prolonged QT interval.
• Thalidomide is generally well tolerated and many of the common adverse effects can be managed with dose adjustment.
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Websites
201 University of Arizona Center for Education
and Research on Therapeutics
www.qtdrugs.org
Affiliations
• Robin L Jones, BSc, MB BS, MRCP
Specialist Registrar Medical Oncology, Royal
Marsden Hospital, Department of Medicine,
Fulham Road, London SW3 6JJ, UK
Tel.: +44 207 808 2883
Fax: +44 207 376 3918
robin.jones@icr.ac.uk
•Michael S Ewer
, MPH, MD, JD
Professor of Cardiology, The University of Texas,
Department of Cardiology, MD Anderson
Cancer Center, Houston, Texas 77030, USA
Tel.: +1 713 745 2216
Fax: +1 713 792 8427
mewer@mdanderson.org
