The heart and other organs
Cardiovascular complications of radiation
therapy for thoracic malignancies: the role
for non-invasive imaging for detection
of cardiovascular disease
John D. Groarke1, Paul L. Nguyen2, Anju Nohria1,3, Roberto Ferrari4, Susan Cheng1*,
and Javid Moslehi1,3,5,6
1Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA;2Department of Radiation Oncology, Dana-Farber Cancer
Institute and Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA;3Adult Survivorship Clinic, Dana-Farber Cancer Institute, Harvard Medical School, Boston,
MA 02115, USA;4Department of Cardiology and LTTA Centre, University Hospital of Ferrara and Salvatore Maugeri Foundation IRCCS, Lumezzane, Italy;5Division of Medical
Oncology, Harvard Medical School, Boston, MA 02115, USA; and6Early Drug Development Center, Harvard Medical School, Boston, MA 02115, USA
Received 4 December 2012; revised 12 February 2013; accepted 12 March 2013; online publish-ahead-of-print 10 May 2013
Radiation exposure to the thorax is associated with substantial risk for the subsequent development of cardiovascular disease. Thus, the
increasing role of radiation therapy in the contemporary treatment of cancer, combined with improving survival rates of patients undergoing
this therapy, contributes to a growing population at risk of cardiovascular morbidity and mortality. Associated cardiovascular injuries include
pericardial disease, coronary artery disease, valvular disease, conduction disease, cardiomyopathy, and medium and large vessel vasculopa-
thy—any of which can occur at varying intervals following irradiation. Higher radiation doses, younger age at the time of irradiation, longer
intervals from the time of radiation, and coexisting cardiovascular risk factors all predispose to these injuries. The true incidence of radiation-
related cardiovascular disease remains uncertain due to lack of large multicentre studies with a sufficient duration of cardiovascular follow-
up. There are currently no consensus guidelines available to inform the optimal approach to cardiovascular surveillance of recipients of thor-
acic radiation. Therefore, we review the cardiovascular consequences of radiation therapy and focus on the potential role of non-invasive
cardiovascular imaging in the assessment and management of radiation-related cardiovascular disease. In doing so, we highlight characteristics
that can be used to identify individuals at risk for developing post-radiation cardiovascular disease and propose an imaging-based algorithm
for their clinical surveillance.
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Radiation therapy † Non-invasive imaging
Radiation therapy is established as an effective adjuvant therapy in
many malignancies, and is used in the management of more than
50% of cancer patients.1Significant improvements in disease-
specific and overall survival accompany the increasing use of radi-
ation therapy. For example, radiation following breast conserving
surgery for patients with breast cancer is associated with a 50% re-
duction in disease recurrence and a 17% reduction in breast cancer
death2; following chemoradiotherapy for Hodgkin’s lymphoma,
5-year survival rates exceed 85%.3However, radiation exposure
to the thoracic region is associated with clinically significant
cardiac disease that may not manifest until years after treatment.
Cardiovascular complications of thoracic radiation were origin-
ally described in the 1960s.4These complications include pericar-
dial disease, cardiomyopathy, coronary artery disease (CAD),
valvular disease, and conduction system disease in addition to
medium and large vessel vasculopathy (Figure 1). Compared with
contemporary regimens, traditional regimens involved larger total
radiation doses delivered over relatively wide target fields, with
* Corresponding author. Tel: +1 807 307 1964, Fax: +1 807 307 1955, Email: firstname.lastname@example.org (S.C.); email@example.com (J.M.)
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European Heart Journal (2014) 35, 612–623
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anterior mediastinal approaches. While avoiding toxicity to the
oesophagus and spinal cord, these earlier regimens predisposed
to cardiovascular toxicity.5Recent modifications in radiation
dose and delivery have reduced the incidence of cardiac complica-
tions, but the exact cardiac risks of contemporary regimens
remain unknown, largely given the delayed manifestation of
Herein, we provide an overview of the cardiovascular risks asso-
ciated with radiotherapy and discuss the role of non-invasive
imaging in screening for and diagnosing radiation-induced cardio-
Basics of radiotherapy
Radiation therapy uses high energy radiation from X-rays, gamma
rays, or charged particles to induce double-stranded DNA breaks
in malignant cells, thereby causing apoptosis or preventing cellular
division. The total dose of radiation delivered is determined by the
are less damaging to surrounding cells than a single fraction of an
equivalent total dose, since small repeated doses permit normal
tissue cells to repair damaged DNA and survive. Radiotherapy can
be used as monotherapy or adjuvant therapy, and may be delivered
with either palliative or curative intent.
Radiation dose is measured in Gray units; 1 gray (Gy) is the
absorption of 1 J of ionizing radiation energy by 1 kg of tissue.
Developments such as the use of CT planning systems, gating,
intensity-modulated radiotherapy, and helical tomotherapy now
serve to minimize cardiac dosing in modern-day regimens for
mediastinal and thoracic irradiation.6–8For example, cardiac
doses in irradiated breast cancer patients in Sweden increased
from the 1950s to the 1970s, and reduced significantly in the
following two decades.9Following breast conservation surgery
for breast cancer, currently a typical dose of 45–50 Gy is delivered
in 25–28 fractions (1.8–2 Gy per fraction) to the whole affected
breast over a 5–7 week period,10and a boost of approximately
10–16 Gy in 5–8 fractions is commonly added to the lumpectomy
cavity. In the treatment of Hodgkin’s lymphoma, 35 Gy involved
field radiation therapy (IFRT) has largely replaced traditional
35 Gy extended mantle radiation therapy since the mid-1990s,
reducing the median value of the mean dose to the whole heart
by 29%.11Contemporary IFRT regimens for Hodgkin’s lymphoma
involve total doses of approximately 35 Gy delivered in 20 daily
whereas a lower total dose of 20 Gy for earlier stages has been
advocated.13For any cancer type, it has long been known that ra-
diation doses above 30 Gy are associated with cardiac damage. A
recent, large population-based case–control study of 2168
women treated with radiation therapy for breast cancer over 5
decades reported an increase in rate of major coronary events
of 7.4% per Gy [95% confidence interval (CI) 2.9–14.5; P ,
0.001], with no apparent threshold below which there was no
increased risk.14Similarly, a retrospective analysis of patients
with breast cancer suggests an increased relative risk (RR) of
cardiac death of 3.1% per Gy of thoracic radiation exposure, com-
pared with radiotherapy naı ¨ve breast cancer patients.1
Basic pathophysiology of
radiation-induced heart disease
Radiation therapy causes damage to both the heart and the vascu-
lature. With respect to the heart, histological examination of the
myocardium after radiation treatment reveals diffuse fibrosis of
the interstitium and narrowing of both the arterial lumen and ca-
pillaries. Fibrosis occurs both in the myocardium and pericardium
with collagen deposition replacing myocytes and parietal pericar-
dium, respectively. Fibrosis of the myocardium can lead to a re-
strictive cardiomyopathy and diastolic heart failure. Similarly,
collagen deposition in the parietal pericardium can lead to a rigid
pericardial sac resulting in increased thickness and cardiac constric-
tion. With respect to the vasculature, radiation-induced coronary
and peripheral vascular disease results from intimal proliferation
Figure 1 Classification of cardiovascular injury following radiation therapy.
Imaging of cardiovascular complications following radiation therapy
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Imaging of cardiovascular complications following radiation therapy
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