2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

the electron transport chain in the mitochondria. ROS have
a deleterious effect on the cells, thus leading to cell death
and to organ damage. 9,10 A recent experimental study in
rats demonstrates that anthracycline-caused cardiomyopathy
can be mediated by depletion of the cardiac stem cell
pool. When exposed to an anthracycline, cardiac progenitor
cells (CPCs) appeared to be even more vulnerable to damaged
ROS. Additionally, CPC cells were arrested in the
G2/M cell cycle, resulting in a depletion of the CPC cell pool
in the myocardium. The final result is heart failure in the
animal. To establish whether the delivery of syngeneic
contaminating tumor cells (CTCs) could oppose the progression
of anthracycline cardiotoxicity, the syngeneic CTCs
were injected in the failing myocardium. This improved the
regeneration of cardiac myocytes and of vascular structure,
consequently improving ventricular performance and the
rate of animal survival. 11 These encouraging results can
perhaps lead to the possibility of implementation of stem cell
transplantation as part of treatment with anthracyclines.
Timing of Combination Chemotherapy
The story behind the introduction of taxanes in the treatment
of patients with breast cancer is a lesson in how
important timing is in order to avoid cardiotoxicity. 12 In an
early phase II study doxorubicin and paclitaxel were given
simultaneously for metastatic breast cancer, resulting in
an impressive response but with approximately one-fifth of
the patients experiencing cardiotoxicity. 12 Pharmacokinetics
studies show that the presence of paclitaxel increases the
plasma level area under the curve (AUC) of doxorubicin by
30%, compared with a 24-hour delay in administration of a
paclitaxel infusion. A later phase III study that separated
the administration of doxorubicin and paclitaxcel by 24
hours did not show an increase in cardiotoxicity. 13 These
important results have been translated to benefit the adjuvant
treatment of patients with breast cancer. Part of the
adjuvant anthracycline-based treatment has been replaced
with a taxane-based treatment so that the cumulative dose
of an anthracycline recommended in adjuvant treatment has
been reduced.
Cisplatin
During treatment, some chemotherapy agents can cause
ischemia syndrome (i.e., chest pains), palpitations, and in
rare cases a lethal myocardial infarction (MI). This can
happen with cisplatin, for example, where the syndrome can
KEY POINTS
● The risk for development of cardiac disease is substantial
after treatment with chemotherapy, radiation
therapy, or with targeted therapy.
● In order to avoid cardiotoxicity, timing of combination
therapies is essential.
● The cardiac risk in the long term for patients treated
with targeted therapy is not known.
● Preclinical and clinical trials must be designed to
evaluate a cardiac risk.
● Cooperation between oncologists and cardiologists is
crucial.
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occur not only during treatment but also subsequently. Our
knowledge about the risk of cardiac disease after cessation of
treatment is obtained by studies of testicular cancer survivors.
The treatment consisted of a cisplatin-based chemotherapy
for patients generally diagnosed between 20 to 40
years of age, and nearly all of them were cured. In all
likelihood, they will survive for years to come, but they will
have an increased risk of developing hypertension, hypercholesterolemia,
myocardial ischemia, and MI. 14 The increased
risk for MI was approximately 5.7% in a median
observation time of 19 years (13–19 years) for 990 long-term
survivors treated with cisplatin-based chemotherapy. One
reason for this delayed risk is that the patients had an
increased plasma level of endothelia and inflammatory
marker protein years later that might eventually progress to
more severe endothelia dysfunction and overt atherosclerosis.
15 This increase may be because cisplatin can still be
measured in the blood 20 years after treatment. 16
5-Fluorouracil/Capecitabine
5-Fluorouracil and its prodrug, capecitabine, can cause
ischemic syndrome during treatment, but the symptoms
disappear when treatment stops. The mechanism is not well
established, but may be a result of coronary vasospasm. It
has also been reported to cause Takotsubo cardiomyopathy.
17 These two drugs are the foundation of the adjuvant
treatment of colorectal cancer. When needed, the treatment
can be repeated despite the occurrence of previous cardiac
events. The treatment must be given in close cooperation
with cardiologists and at lower doses. Capecitabine is also
used in palliative setting for many types of cancer, including
breast cancer. The true incidence of cardiac events is not
known but is believed to be approximately 1% to 18%. 18,19
Compared with cisplatin, no increased risk of cardiotoxicity
has been reported subsequently.
Radiotherapy
MARIANNE RYBERG
Radiotherapy has been and is still an essential modality in
the curative treatment of many types of cancer. This applies
to both children and adults with cancer. Radiation therapy
can cause coronary artery disease (CAD), diffuse myocardial
fibrosis, and the more seldom-occurring pericarditis and
pericardial fibrosis. The most common side effect, however,
is CAD. A radiation dose of greater than 30 GY is definitively
known to cause damage to the heart. However, it is unknown
whether a threshold dose exists that does not incur
risk to the heart. 20 Because of a prolonged latency of 10 to 15
years before the occurrence of cardiac disease, it is difficult
to be certain as to whether the increased incidence is
because of the irradiation or whether it is caused by a
comorbidity due to aging. A study of 4,122 survivors treated
for cancer in their childhoods has increased understanding
of the extent of the risk. Compared with the general population,
patients in this study were generally shown to have 5
times greater risk of dying of cardiac disease. The authors
have retrospectively estimated that the mean radiation dose
delivered to the heart and the risk of dying of cardiac disease
increased linearly when the average radiation dose exceeded
5 Gy. 21
Patients with breast cancer (BC) who underwent irradiation
to the right breast had a lower risk for MI than those
patients treated for left-sided BC. 20 This was demonstrated