2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Recent Advances in Cardiotoxicity of
Anticancer Therapies
Overview: The treatment of two major diseases in the Western
world, cancer and heart disease, has improved significantly
in recent years. Today, many more cancers are curable
than in previous years. Cancer treatment often consists of
chemotherapy, radiation therapy, and now also targeted therapy.
All three types of treatment can lead to an increased risk
of developing or of worsening a pre-existent cardiovascular
disease either during the treatment, immediately afterward,
or several years after cessation of therapy. Anthracyclines, a
class of drugs that are also known as anthracycline antibiotics,
and the drug cisplatin have contributed to the success
of cancer treatment. However, these agents can cause cardiovascular
disease during treatment, and studies have shown
CYTOTOXIC DRUGS, targeted therapy, and radiation
therapy have changed the final outcome for many
patients with cancer, many of whom are now cured of
cancers there were considered fatal just a few years ago.
Instead of a death sentence, their diagnosis is comparable to
that of a chronic disease with periods of remission, exacerbation,
and re-treatment. This means that treating patients
with cancer involves new challenges because modern cancer
treatments can have severe side effects, not only during
treatment but also in the long run. One side effect is the
increased risk of cardiovascular disease, either transient or
permanent depending on the nature of the injury to the
cardiovascular system. 1-3 Some of the types of cardiovascular
disease that presumably result from cancer treatment
are heart failure, ischemia, hypertension, hypotension, arrhythmias,
conductive disorder, thromboembolic events, and
QTc prolongation. The risk of developing cardiovascular
disease from cancer treatment may be underestimated because
of the process drugs undergo to be approved for
general use. To be approved for general use, positive phase
I through phase III trials must be conducted. Patients
participating in these trials are not always representative
of the average patient with cancer because patients with
significant comorbidity—including cardiovascular disease,
children, and the elderly—are excluded from the trials. This
means that the risk of cardiac disease is apparently greater
than shown in the trials. In recognition of these issues,
cooperation between oncologists and cardiologists is crucial.
Anthracyclines
Some of the classic cytostatic drugs, such as anthracyclines,
cyclophosphamid, 5-fluorouracil, and cisplatin, are
known to cause cardiovascular disease. Anthracyclines are
one of the most feared of these treatments because of their
ability to cause heart failure, not only in connection with the
treatment but also in the long term. Because they are also
highly active, widely used drugs, many long-term survivors
of cancer treatment (including children) have been successfully
treated with anthracycline-based chemotherapy. Anthracylines
remain an indispensable option in treating
cancer today, both for children and adults. Doxorubicin, an
anthracycline and one of the most active anticancer drugs
used today, was quickly recognized as having serious side
effects, including heart failure. In a retrospective study of
By Marianne Ryberg, MD
that the risk of disease persists for many years after treatment
stops. Irradiation contributes significantly to this risk when
the cardiovascular system is part of the radiation field. If
the targeted therapy also inhibits the genes responsible for
maintaining the function of the cardiovascular system, development
of cardiovascular symptoms is inevitable. Therefore, it
is essential to have a cardiovascular endpoint in trials with
targeted therapy. When treatment stops, however, the effect
on the cardiovascular system appears to cease, but it is not
known whether the long-term risk of developing cardiovascular
disease increases. Combined, these factors indicate that
close cooperation between oncologists and cardiologists is
essential to optimally benefit patients with cancer.
cardiotoxicity, Van Hoff 4 showed that the risk of developing
cardiac failure increased exponentially when the doxorubicin
dose was increased. Another anthracycline, epirubicin,
apparently has a linearly increased risk of approximately
40% for each 100 mg/m 2 . 5 This indicates that the cardiac
myocytes will be affected as of the very first treatment with
epirubicin. However, several studies show that risk increased
with serious comorbidity, the various ages of the
different patients, previous irradiation (including of the
heart), and concomitant antitumor therapy. 4-6 Furthermore
the upper limit of dose for doxorubicin and epirubicin is
based on retrospective studies in patients with metastatic
diseases. The problem with using this subset of patients to
establish upper limits of dose is that some of these patients
will die from cancer before they develop symptoms of heart
failure. Furthermore, a predisposing genetic variant involved
in the oxidative stress or metabolism and transport of
anthracycline can contribute to heart failure. 7 One paradox
is that an increase of the dose of the anthracycline appears
to improve the survival rate for those with metastatic
diseases. 5 This calls for a more personalized approach for
treatment of patients with metastatic disease using an
anthracycline. Furthermore, the risk of developing cardiotoxicity
in the long term after an anthracyline-based adjuvant
treatment is not addressed by the aforementioned
studies.
A prominent feature of the risk of developing cardiotoxicity
is subcellular damage or even necrosis in the heart
muscle cells during treatment, which seems to continue even
after treatment has stopped. 8 This is believed to be caused
by an increase in oxidative stress in cells. Reactive oxygen
species (ROS) are formed when the quinine moiety of anthracyclines
is reduced to semiquinone, thus initiating a
cascade of free-radical formation. Furthermore a highly
reactive ROS is created when an anthracycline uncouples
From the Department of Oncology, Herlev Hospital, University of Copenhagen, Denmark.
Author’s disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests to Marianne Ryberg MD, Department of Oncology, Herlev
Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2730 Herlev, Denmark; email:
mary@heh.regionh.dk.
© 2012 by American Society of Clinical Oncology.
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