Worldwide efforts during the past several years have improved
cancer-related survival, such that cancer survivorship has tripled from 1970 to
2000. Today, there are more than 12 million cancer survivors in the United
As cancer-related survival has improved, an unexpected increase in
premature cardiovascular events, including myocardial ischemia and myocardial
infarction, stroke, and the development of congestive heart failure, has
occurred. Associations have been identified between medications used to treat
cancer and CV events. Long-term cancer survivors now represent one of the
largest and fastest-growing patient populations at risk for premature CV
disease. In fact, increases in CV-related morbidity and mortality now threaten
to offset some of the advancements in cancer-related survival.
Currently, however, research initiatives, clinical management and
guidelines are lacking, regarding addressing the needs of cancer survivors. In
this article, we review the current knowledge related to the etiology,
diagnosis, treatment and management of CV disease in cancer survivors and
present concepts by which the CV and oncology communities can work together to
address the CV needs of cancer survivors.
As shown in Table 1, multiple agents are linked with CV injury after
treatment for cancer. The agents most commonly associated with injury include
the anthracyclines such as doxorubicin and alkylating agents such as
cyclophosphamide. Recently released agents such as the tyrosine kinase
inhibitors have also been associated with CV complications. TKIs regulate
multiple cellular functions (including cellular proliferation, differentiation
and survival) and are overexpressed in certain malignancies. TKIs include a
diverse group of therapies that “down-regulate” malignant cell
Trastuzumab (Herceptin, Genentech) is one of the more frequently
described TKIs associated with decrements in left ventricular function. This
agent is a monoclonal antibody that targets extracellular HER-2 that can be
overexpressed in breast cancer tumors. Interestingly, this receptor is also
expressed on developing cardiomyocytes. The association of trastuzumab with CV
injury is thought to be related to the drug’s affinity with the HER-2
receptors on cardiomyocytes.
Sunitinib (Sutent, CPPI CV) is another TKI that has recently been
associated with hypertension. Sunitinib inhibits angiogenesis by blocking the
activity of VEGF. Although the association of sunitinib with hypertension is
not fully understood, it may be related to the reduction in production of
vasodilators such as nitrous oxide and prostacyclin, resulting in
vasoconstriction and decreased renal excretion of sodium.
Androgen deprivation therapy (ADT) represents another class of cancer
treatments that is associated with CV events. Androgen suppression accelerates
atherosclerosis and is associated with insulin resistance, obesity, metabolic
syndrome, MI and cardiac death. Among 37,443 veterans with prostate cancer,
treatment with ADT was associated with diabetes (adjusted HR=1.28); coronary
artery disease (adjusted HR=1.19); MI (adjusted HR=1.28); and sudden cardiac
death (adjusted HR=1.35). These adverse associations are noteworthy and have
prompted initiation of primary CV prevention in many older men scheduled to
receive these agents.
Much of the data relating to susceptibilities to CV injury emanates from
the study of children or adults on protocols in which they received
anthracycline-based chemotherapeutic agents for the treatment of hematologic
malignancies, lymphoma, breast cancer or soft tissue sarcomas. Those more
likely to experience anthracycline-related injury are women, those aged older
than 65 years or younger than 15 years, and those with pre-existing CV disease
or CV risk factors. When compared with their siblings, 14,358 survivors of
pediatric cancer followed up to 30 years after their cancer diagnosis were
three times more likely to develop a chronic CV event. To date, however, there
are relatively few data regarding the factors that increase the risk for a CV
event in patients receiving other chemotherapeutic agents.
Currently, intramyocardial biopsies remain the gold standard methodology
for identifying myocyte injury as a result of chemotherapy administration.
Importantly, however, this technique requires an interventional procedure and
is not well-suited for repetitive examinations. For this reason, both
radionuclide ventriculography and transthoracic echocardiography (TTE) are
widely used to identify marked deteriorations in left ventricular systolic
performance when patients receiving chemotherapy or those surviving
chemotherapy experience symptoms suggestive of congestive heart failure.
Importantly, these radionuclide ventriculography or traditional 2-D
echocardiography methods only identify relatively large deteriorations in left
ventricular performance that are most often only associated with clinically
overt heart failure. Several recent small studies suggest that quantitative
applications regarding MRI or speckle tracking TTE identify the possibility
that subclinical markers of CV injury may be identified before more clinically
evident overt congestive heart failure ensues. With MRI or TTE, this is
achieved through identification of abnormal myocardial tissue characteristics
or quantitative assessments of myocardial strain or vascular function.
Currently, larger studies are necessary to determine the potential efficacy of
these noninvasive modalities for identifying early evidence of myocardial
injury that may forecast future CV events.
For those at risk for CV injury before receipt of potentially
cardiotoxic chemotherapy, dosing changes either through dose reduction, an
alteration of dosing schedules, or a change in the mode of administration of a
chemotherapeutic agent have been shown to reduce the risk for CV injury after
chemotherapy. Regarding anthracycline toxicity, the cardioprotective agent
dexrazoxane (Zinecard, Pfizer) is known to reduce early myocardial injury
during anthracycline treatment; however, it remains controversial as to whether
this class of agents may reduce the efficacy of cancer treatment.
For those who have experienced CV injury upon receipt of chemotherapy,
several small studies have demonstrated potential benefits of angiotensin
converting enzyme inhibition or beta-blockade with carvedilol (Coreg,
GlaxoSmithKline) to help avert left ventricular remodeling and further
deterioration of left ventricular ejection fraction.
To date, there are no widespread structured protocols, guidelines or
programs that focus on CV care and survivorship-related issues. In 2006, a
report from the Institute of Medicine, titled From Cancer Patient to
Cancer Survivor: Lost in Transition, sought to raise awareness of the
needs of cancer survivors through a series of recommendations. One of the
strongest recommendations was to provide comprehensive summary of treatment
delivered and detailed plans for undergoing care to patients at the completion
of their cancer treatment. Currently, however, there are few organized groups
of physicians that are assimilated who can deliver CV care to cancer survivors.
This lack of focus has several major implications. First, although there
are specific CV conditions associated with the administration of cancer
therapy, there are no standardized definitions for CV disease associated with
cancer therapy. Second, most protocols implementing current surveillance
measures for cardiac injuries are not coordinated through a central effort;
therefore, the selection of outcomes (eg, biomarkers, imaging results) is
inconsistent across studies. Third, because CV surveillance is not the primary
outcome measure for most of the protocols implemented to test the efficacy of
new cancer therapies, there has been inadequate data to provide phenotypic or
genotypic characteristics of patients who may be at risk for developing CV
disease. Finally, medical societies and health care delivery systems have not
determined the optimal pattern for physician surveillance of CV disease in
cancer survivors. Thus, although the Institute of Medicine suggests that
greater needs and resources should be dedicated toward patient care for most
survivors in the US, assessment and treatment of concerns related to CV care
are often incomplete.
To address these concerns, Albini and colleagues, in an article from the
Journal of the National Cancer Institute, have advocated the
creation of interdisciplinary “cardio-oncology” teams. The charge of
these interdisciplinary teams is to work together to develop research and
clinical programs for the purpose of managing CV risk and preventing CV events
in both cancer patients and survivors.
The precedence for oncologists and cardiologists to work together exists
from the early treatment of CV injury that occurred in the 1960s and 1970s. In
these previous decades, those treated with anthracyclines were discovered to
have a high risk for clinical CV injury, causing premature CV death and
irreversible congestive heart failure. Cardiologists and oncologists at this
time worked together to utilize radionuclide ventriculography to identify
deteriorations in left ventricular ejection fraction and then develop treatment
regimens that would dramatically reduce congestive heart failure and CV death.
Today, a somewhat similar intersocietal focus must occur that pulls together
the efforts of cardiologists and oncologists for the purpose of assessing CV
risk and preventing CV events among cancer survivors.
In summary, advances in treatment have reduced cancer-related mortality;
however, during the past 10 to 15 years, several investigations have identified
an increased incidence of premature CV events in populations of cancer
survivors. This increase in CV events threatens to offset some of the gains
realized in cancer-related treatments. Today, most of the information related
to CV events in survivors is obtained from cancer-directed trials with
inconsistent collection of CV-related outcomes. With an increasing number of
cancer survivors experiencing an increasing number of CV events, an important
opportunity exists to develop research studies focused on cancer survivors to
prevent and treat CV events. To address this need, unified efforts are needed
between both oncologists and cardiologists working to develop strategies,
programs and guidelines to prevent CV events after cancer treatment.
Albini W. Gregory Hundley, MD, is the director of the Cardiovascular
Magnetic Resonance Program, and professor, Internal Medicine (Cardiology) and
Radiology at Wake Forest School of Medicine in Winston-Salem, N.C. Disclosure:
Dr. Hundley reports having received research grants and funding from Bracco
Diagnostics and Siemens.
For more information:
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- Hewitt M. From Cancer Patient to Cancer Survivor: Lost in
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