Hazardous to Your Heart
Protecting
the heart from toxic side effects of cancer therapy.
By Jamie Spencer
At the dizzying moment when a patient
first receives a diagnosis of cancer, the side effects
of treatment to fight the disease may seem insignificant.
That was certainly true for Adriana Jenkins, who
found out in 2001 at age 31 that she had inflammatory
breast cancer and the disease had already spread
to her lymph nodes and chest wall.
“Quite honestly, my situation was so
dire,” she says now, “if they had said
hydrochloric acid would help, I’d have spread
it all over my body.” Instead, she entered a
trial for Herceptin® (trastuzumab). But after
12 weeks of treatment, despite her cancer responding
well, she had to withdraw from the trial because
of potentially dangerous changes in her heart rhythm.
While many side effects of traditional
chemotherapy are well-known, such as nausea, hair loss
and fatigue, other problems associated with targeted
cancer agents, including those affecting the heart,
may be much more serious. Drugs can prevent or reduce
the severity of cardiac toxicity, and advancements
in anticancer therapy are attempting to lower the
risk even more.
A Critical Organ
The heart is the body’s workhorse,
pumping blood throughout the circulatory system to
bring oxygen and other nutrients to tissues and organs.
When the heart is healthy, its four chambers coordinate
to keep blood flowing through the valves into the
blood vessels, all while its electrical system keeps
the heart pumping in a steady rhythm.
But when the heart is damaged
by certain types of cancer treatment, disturbances
can occur (see
illustration). The
effects can be acute, occurring shortly after the
start of treatment or months after the last dose,
or late, occurring years after treatment is over.
And unlike the more visible side effects of treatment,
such as hair loss, heart side effects are often silent,
though symptoms can include shortness of breath, dizziness,
irregular heartbeat or swollen feet or ankles.
“The old adage ‘do no harm’ doesn’t
always work in the treatment of cancer,” says
Michael Ewer, MD, a cardiologist at M.D. Anderson
Cancer Center in Houston. “Some cancers have
to be treated aggressively, and the price we pay
sometimes is a cardiac effect.”
Rare But Serious
Only a small percentage of patients who undergo
drug therapy or radiation experience cardiac toxicity,
and the percentage and severity can vary with different
drugs. When discussing cardiac toxicity, doctors say
it’s important for patients to understand the
difference between a cardiac event, which can be
a minor degree of injury that produces no symptoms,
versus serious heart damage that can lead to congestive
heart failure or other dangerous heart conditions.
Cardiac toxicity was recognized as early as
1967, when reports surfaced of heart failure in children
who received Adriamycin® (doxorubicin) to treat
leukemia. Since then, other cancer therapies have
been recognized as potentially harmful to the heart.
Drugs known as anthracyclines, which include
Adriamycin as well as Cerubidine® (daunorubicin),
Idamycin® (idarubicin) and Ellence® (epirubicin),
are known for their potential cardiac toxicity. Anthracyclines
treat a variety of cancers, including breast cancer,
sarcoma, lymphoma and leukemia. While serious heart
damage is rare in patients receiving anthracyclines—ranging
from 2 to 7 percent—the risk increases with
each dose, so oncologists carefully monitor a patient’s
total anthracycline dose received over a lifetime
to minimize the risk of permanent heart damage. Other
heart-toxic drugs often used in combination with other
cancer drugs are
5-fluorouracil, or 5-FU, and
cisplatin.
"The old adage ‘do no harm’ doesn’t
always work in the treatment of cancer. Some cancers
have to be treated aggressively, and the price we pay
sometimes is a cardiac effect.’’ —Michael
Ewer, MD
And then there is Herceptin, a targeted drug
used to treat the 25 to 30 percent of breast cancer
patients with HER2-positive breast cancer. While
Herceptin works well to reduce breast cancer recurrence
and risk of death, studies have shown anywhere from
1 to 11 percent of women who take the drug experience
symptomatic congestive heart failure. Investigators
who reported the 11 percent statistic clarified in
their study, published in late 2006 in the Journal
of Clinical Oncology, that the elevated percentage
wasn’t surprising since a significant number
of patients had a history of heart disease, prior
anthracycline exposure and prolonged exposure to
Herceptin (an average of 21 months).
“There is a concern that if patients
develop heart trouble [on Herceptin], they might need
to limit something that can help them,” says
Charles Geyer, MD, director of Breast Medical Oncology
at Allegheny General Hospital in Pittsburgh who investigated
the cardiac toxicity of Herceptin. But there are ways
to optimize its benefits, he says, and although some
therapies carry heart-toxic risks, their cancer-fighting
benefits may tip the scales. “We don’t
want people to be afraid of Herceptin.”
In addition to drug therapy, radiation
directed at the chest, spine or upper abdomen may cause
cardiac injury. But changes to methods of delivering
radiation in recent years, such as using lower doses
and reducing exposure to heart tissue, have reduced
the risk.
Certain pre-existing health problems
can increase the risk of heart damage. People with
heart disease, high blood pressure, diabetes or who
are either very young or elderly are at increased
risk. All of these factors must be weighed when making
decisions about treatment.
Preventing Heart Complications
With so many cancer patients surviving long
after treatment, the enduring consequences of therapy
have become more of a concern (see sidebar). “We
didn’t used to have long-term cancer survivors,” says
Carolyn Runowicz, MD, chair of the National Cancer
Advisory Board and director of the Neag Comprehensive
Cancer Center at the University of Connecticut Health
Center in Farmington. “It’s been an evolution.”
In addition to strategies to reduce
the dose of radiation to heart tissue, reducing the
overall dose of medication or administering the drug
differently can cut the risk of heart problems. With
Adriamycin, giving the drug by a continuous infusion
rather than in a large single dose can reduce its toxic
effects.
When Dr. Runowicz faced decisions about her
own breast cancer treatment in 1992 when she was in
her early 40s, she questioned whether she should take
Adriamycin. “There were not a lot of data yet
about the benefits of Adriamycin on survival, so we
didn’t know the effect,” she says. “But
I decided I’d rather have heart disease at 60
than be dead at 45 or 50. In my mind, it was worth
it.”
Fifteen years later, new drug formulations
can lower the risk of complications. A form of Adriamycin
called liposome-encapsulated doxorubicin, or Doxil®,
appears to reduce cardiac toxicity by enveloping
the drug within a bubble of fat, allowing it to be
slowly released. This allows a higher dose to be
given with less severe side effects.
Heart-protective drugs have been developed
to reduce the harmful effects of therapy. Zinecard® (dexrazoxane)
has been shown to lower iron levels in the blood,
reducing the level of free radicals that can damage
heart tissue. Zinecard also allows more patients
to be treated with extended doses of Adriamycin.
Another approach to protect the
heart from therapy involves ACE inhibitor medications,
such as enalapril, typically given to people with high
blood pressure or heart failure. These drugs slow the
progression of left ventricular dysfunction that results
from some chemotherapies.
Monitoring the Heart
Patients receiving potentially
cardiotoxic cancer therapy should be carefully monitored
both during and after treatment. An echocardiogram
(heart ultrasound) is the primary tool used to monitor
heart health, but other tests may also be done, including
blood tests, electrocardiograms or multiple-gated
acquisition (MUGA) scans, which produce a moving
image of the heart muscle.
M.D. Anderson Cancer Center’s department
of cardiology recently sponsored a panel discussion
of oncologists and cardiologists to discuss how to
best monitor a patient’s heart function. Concerning
the issue of whether to use non-invasive echocardiogram
or time-consuming yet generally more precise MUGA,
the panel determined either imaging method was acceptable
depending on the expertise of the radiologists and
cardiologists at a particular cancer center.
Following treatment, survivors
should have a yearly checkup to identify any long-term
consequences of cancer therapy. Those at higher risk
for heart complications may need more frequent monitoring.
An early and often missed warning sign of
heart damage, says Dr. Ewer, is a pulse rate that
goes up and stays up after minor exertion, such as
climbing stairs. “By the time patients are short
of breath, there may be more serious cardiac effects,” he
says.
If heart problems occur, stopping
the drug may reverse the effect. Treating the heart
problem can also help the heart to heal. The previously
mentioned Journal of Clinical Oncology study found
that most of the metastatic breast cancer patients
who suffered some degree of heart damage while taking
Herceptin saw an improvement in heart function after
stopping the drug and receiving cardiac treatments,
such as beta-blockers and ACE inhibitors. These patients
were then able to resume Herceptin therapy.
In Adriana Jenkins’ case, after being
pulled from the Herceptin trial, she was eventually
able to go back on the drug after having a mastectomy. “I
was devastated when I was pulled from the trial,” she
says. But now, almost six years later, her heart
is healthy and she’s cancer-free.
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