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Cardiovascular Complications of Cancer Therapy.
Yeh ETH et al. Circulation. 2004; 109:3122-3131.
Click
on text to access the topic:
1.
Cardiotoxicity Profiles Of
Chemotherapeutic Agents
2.
Cardiotoxic Syndromes Associated With
Chemotherapeutic Agents
3.
Cardiotoxicity Associated With
Radiation Therapy
4.
Monitoring
Cardiovascular Toxicity
5.
Strategies to Reduce Cardiovascular
Toxicity and Manage Complications
6.
Rules for Suspension of Herceptin
(Trastuzumab) Therapy |
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Radiation therapy is used in the treatment of many types
of cancer. Radiation to the thorax can damage the
pericardium, myocardium, valves, and coronary vessels,
with the pericardium being the most commonly involved.83
The incidence of radiation-induced heart disease is
higher in patients given high doses of radiation or
radiation therapy concurrent with doxorubicin.84
Patients with preexisting CAD are especially vulnerable.
Endothelial cell involvement is an early sign of
radiation-induced vascular damage.85 The precise
incidence of radiation-induced accelerated
atherosclerosis is difficult to confirm, but it has been
reported in patients who did not have the traditional
risk factors for CAD.86
Vascular injury from radiation therapy can be silent;
approximately 50% of asymptomatic patients develop new
myocardial perfusion defects.87 Clinically, most
patients present with angina, dyspnea, or heart
failure,86 although sudden death has been reported.88
Sudden death in patients given radiation therapy is
thought to result from diffuse intimal hyperplasia of
all coronary arteries or from significant left main
stenosis.86 The mean interval for developing CAD after
radiation therapy is approximately 82 months.83
Management of radiation-induced CAD is similar to that
of atherosclerotic disease. Both percutaneous
intervention and coronary artery bypass grafting have
been used.86 Surgical bypass grafting may be more
difficult in patients with radiation-induced
atherosclerosis because of mediastinal fibrosis, which
is associated with a high incidence of complications.86
Radiation-induced carotid disease produces carotid
lesions that are more extensive than the traditional
bifurcation stenosis and often involves atypical areas
such as long segments of carotid artery.89
Radiation therapy also causes fibrous thickening of the
pericardium,88 with the right ventricle more often and
more extensively involved. Pericardial disease after
radiation therapy most commonly presents as pericardial
effusion or pericarditis.83 The interval between
radiation therapy and symptom development in patients
with radiation-induced pericardial disease is variable,
ranging from 2 to 145 months. Pericardial effusion is
typically an early presentation, whereas pericardial
constriction is a late manifestation, usually appearing
after 18 months. |
Myocardial fibrosis is also a side effect of radiation therapy.83
Fibrosis is characterized by marked alterations in collagen
synthesis.90 Valvular heart disease is also common after radiation
because radiation causes fibrous thickening of cardiac valves.88
Left-sided valves are more often involved than right valves,83 and
only a minority of patients with radiation-induced valvular disease
have clinically moderate or severe dysfunction.88 The mean time from
radiation to onset of symptoms is approximately 98 months.83
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Monitoring
Cardiovascular Toxicity
The
experience with anthracycline cardiotoxicity proved that the
early detection and treatment of cardiotoxicity could
significantly reduce the development of clinical manifestations.
Endomyocardial biopsy is the most sensitive and specific way to
diagnose and monitor anthracycline cardiotoxicity, 91 but the
invasive nature of this procedure limits its use. Although
guidelines have been developed for children receiving
anthracyclines,92 no definite guidelines have been adopted for
adults.
The most
common noninvasive method of monitoring myocardial toxicity from
anthracyclines and other chemotherapeutic agents has been the
assessment of LV systolic function, with either radionuclide
ventriculography or echocardiography. Fractional shortening and
LV ejection fraction are the most commonly used measurements,93
but both depend on preload and afterload. LV ejection fraction
measurements also are not sensitive for the early detection of
preclinical cardiac disease.
Several
studies have suggested that diastolic dysfunction is an early
sign of anthracycline-induced cardiac dysfunction.94 Thus,
measurements of diastolic function by Doppler echocardiography
may be a sensitive method for early detection of toxicity.94,95
Provocative testing with exercise96 or dobutamine
echocardiography97 has also been used to assess early
anthracycline cardiotoxicity. Thus, these provocative-testing
modalities may be sensitive for the early detection of
subclinical cardiomyopathy and may provide an opportunity for
therapeutic intervention before the development of overt LV
dysfunction.
Biomarkers
such as troponin I and T98 may be useful in early detection of
doxorubicin cardiotoxicity before the appearance of changes in
LV ejection fraction, especially in children. During the past 10
years, several studies have confirmed the usefulness of B-type
natriuretic peptide (BNP), a neurohormone elevated in response
to volume overload, in the diagnosis and treatment of CHF.99
Recent studies in patients with cancer have shown that high
levels of BNP correlated with impairment of LV function during
anthracycline therapy.100,101 BNP has also been shown to be
elevated before the development of LV dysfunction in patients
undergoing high-dose therapy and hematopoietic stem cell
transplantation.102
Monitoring
for other anticancer drug–related cardiotoxic effects such as
arrhythmias, ischemic cardiac events, and pericardial disease
should be planned and specially tailored for each therapeutic
protocol according to which anticancer agents are prescribed.
Cardiac tests such as electrocardiography, rest and stress
myocardial perfusion imaging, and troponin levels can be used to
monitor ischemic cardiac complications. Twenty-four–hour Holter
monitoring can be very helpful in detecting and evaluating
suspected arrhythmias. Echocardiography has emerged as the test
of choice for the noninvasive evaluation of cardiac disease as
related to cancer therapy. This tool is essential in the
evaluation of LV systolic and diastolic function, pericardial
disease, and detailed evaluation of valvular heart disease.
Doppler echocardiography can also be used to assess hemodynamic
status, including the presence of pulmonary hypertension.
In patients
with chemotherapy-induced cardiomyopathy, a decrease in BNP
levels after dobutamine stress echocardiography correlated with
the presence of contractile reserve. This finding also
correlated with long-term improvement in LV systolic function
and New York Heart Association class rating when patients were
given _-blockers and angiotensin converting enzyme (ACE)
inhibitors.103
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Strategies to Reduce Cardiovascular
Toxicity and Manage Complications
Once cardiac
toxicity is anticipated, strategies to control these adverse events
can be developed, as evidenced by the changing patterns of
anthracycline administration over time. Anthracycline toxicity can
be minimized by reducing the total dose to <400 mg/m2 and changing
the administration from a rapid infusion to a continuous
infusion.104 Newer liposomal formulations also may reduce
cardiotoxicity.105,106 Dexrazoxane, a derivative of EDTA, can reduce
the amount of free iron in myocytes by producing free radicals that
decrease oxidized iron levels during anthracycline infusion.107
Generally, dexrazoxane has been recommended for patients with
metastatic breast cancer who have received cumulative anthracycline
doses of >300 mg/m2; dexrazoxane is not recommended at the beginning
of therapy because of the possibility of reducing the anticancer
effect of the anthracyclines.108 Dexrazoxane has led to improved
survival in some studies, but whether this improvement was due to
improved cardiac status is unclear. What is known, however, is that
dexrazoxane can worsen thrombocytopenia and granulocytopenia.
The evolution of
management strategies for trastuzumab-related cardiac toxicity is
following a progression similar to that of the anthracyclines. After
initial reports that the combination of trastuzumab, anthracyclines,
and cyclophosphamide led to severe heart failure in up to 16% of
patients with breast cancer undergoing this treatment, the
administration strategy was changed to avoid giving these drugs
simultaneously, and more stringent cardiac monitoring was
instituted. These modifications have considerably reduced toxicity
rates.48 Current studies of trastuzumab for a variety of breast
cancer populations will further define the risk of LV dysfunction
from such treatment. Trastuzumab-related cardiomyopathy seems to be
largely reversible with appropriate therapy. Such therapy would
include ceasing the drug, treating cardiac risk factors, and
administering appropriate therapy for LV dysfunction.109 These
principles apply to any cardiac toxicity discussed in this review
but especially to the management of LV dysfunction. ACE inhibitors
and beta-blockers are the cornerstones of therapy for LV dysfunction
and should be administered to patients with cancer as aggressively
as to any other patient population. Interestingly, rechallenge with
trastuzumab does not necessarily lead to redevelopment of LV
dysfunction or CHF,109 thus allowing important anticancer therapy to
be continued without compromising the patient’s cardiac status.
Much cardiac toxicity can be managed best by removing the offending
agent. Unfortunately, in the case of newly developed LV dysfunction,
chemotherapy may not be the only explanation for the reduced
function, and thus all possible reversible causes should be
investigated. In patients with cancer, ischemia is still a
reversible cause of LV dysfunction. Cardiac reserve and subsequent
improvement after aggressive CHF-based therapy can be predicted by
results from dobutamine stress echocardiography.103 More
importantly, once therapy is established, it may need to be
continued because withdrawal of therapy in some patients has been
associated with serious adverse events.110 |
Priya
Rastogi et al. J
Clin Oncol 23:7811-7819. |
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