Radiol Oncol 2019; 53(1): 1-5. doi: 10.2478/raon-2018-0035
1
review
Pericardial disease after breast cancer 
radiotherapy
Tanja Marinko 
Institute of Oncology Ljubljana, Department of Radiotherapy, Ljubljana, Slovenia
Radiol Oncol 2019; 53(1): 1-5.
Received 5 May 2018
Accepted 12 May 2018
Correspondence to: Tanja Marinko, M.D., Ph.D., Institute of Oncology Ljubljana, Zaloška cesta 2, SI-1000 Ljubljana, Slovenia. 
Phone: +386 1 5879 515; Fax: +386 1 5879 400; E-mail: tmarinko@onko-i.si
Disclosure: No potential conflicts of interest were disclosed.
Background. Breast cancer is the second most common cancer worldwide. Thanks to the modern oncological treat-
ments, disease specific survival has improved throughout the last decades. The number of breast cancer survivors has 
been increasing, and more and more attention has been paid to the breast cancer treatment side effects. Whereas 
there are many data regarding ischemic heart disease after radiotherapy for breast cancer, there is not much data 
in the literature about the incidence and clinical meaning of pericardial disease after breast cancer radiotherapy. 
Conclusions. Although radiation-induced pericarditis is the earliest form of radiation-induced cardiovascular disease 
after irradiation of the heart, it seems that in clinical practice, especially by using modern radiotherapy treatment 
techniques, it is underdiagnosed because patients are mostly asymptomatic. In some cases, especially in its late form 
and after multimodal systemic oncological treatment in combination with radiotherapy, it could be presented in 
severe form and life threatening. Treatment modalities for radiation-induced pericardial diseases are the same as in 
the non-irradiated population, but in the irradiated patients, surgery may be difficult. 
Key words: pericardial disease; cardiotoxicity; cardio- oncology; breast cancer; radiotherapy
Introduction
Nowadays, breast cancer is a highly curable dis-
ease. Thanks to the modern oncological treatments, 
patients with early breast cancer live many years, 
decades after the treatment. For many of them life 
expectancy some years post treatment is the same 
as for the general population.1 Consequences of 
the oncological treatment may have a very impor-
tant influence on the quality of the subsequent life. 
Therefore, all the efforts must be oriented towards 
treatment benefits as well as in minimizing treat-
ment’s side effects.
Radiation therapy is an important part of treat-
ment for early breast cancer with a significant im-
pact on survival of breast cancer patients.2 Besides 
its treatment effect, it also has side effects. Among 
them, one of the most important is cardiotoxicity. 
This is of special concern, because in its severe form 
it is life-threatening, instead of breast cancer itself.
Radiotherapy of the breast cancer, especially 
of the left breast, almost always involves some in-
cidental irradiation of the heart. It can result in a 
range of cardiotoxic effects including coronary ar-
tery disease, cardiomyopathy, pericardial disease, 
valvular dysfunction and conduction abnormali-
ties.3 Radiation induced heart disease generally oc-
curs with a latent period of 10 to 15 or even more 
years.4 It can be intensified with chemotherapy and 
other systemic oncological treatments, but its occur-
rence also depends on patient’s habits (smoking, di-
et) and simultaneous, especially cardiovascular dis-
eases.3,5,6 In addition to radiotherapy, breast cancer 
therapy may include anthracyclines and therapies 
targeting human epidermal growth factor receptor 
2 (HER2) that may have important cardiotoxic ef-
fects (Khouri 2012, Taskforce).3,7 Radiation-induced 
heart disease is of special concern, especially in 
younger patients as they survive longer.8
Radiation-induced pericardial disease is one of 
the most common and also the earliest manifesta-
Radiol Oncol 2019; 53(1): 1-5.
Marinko T / Breast size and adjuvant radiotherapy2
tion of radiation-induced heart disease to occur fol-
lowing irradiation of the heart.9 It could be present-
ed as acute pericarditis, pericardial effusion, de-
layed thickening and constrictive pericarditis. It is 
classically associated with mediastinal irradiation.10
There is not much data in the literature about the 
incidence of pericardial disease after breast cancer 
radiotherapy. In 2011, McGale et al. published a 
large study about the incidence of heart disease 
in 35.000 women treated with radiotherapy for 
breast cancer between 1976 and 2006 in Denmark 
and Sweden.5 In this, clinical and national registers 
based study, they reported that incidence for peri-
carditis was 1.61 (95% CI 1.06–2.43) higher if the 
patient had been irradiated for left breast cancer 
compared to the patient irradiated for right breast 
cancer. Altogether, among 35.000 breast cancer 
patients, they found 96 patients with subsequent, 
clinically or on autopsy proven pericardial disease. 
Interestingly, the incidence of pericarditis for left 
breast cancer patients comparing to the right breast 
cancer patients was changing through the years 
passed from the treatment: in the first four years 
after the treatment it was 1.68 (0.96–2.96), from 5–9 
years 1.92 (0.89–4.13), and after 10 years it was 0.95 
(0.33–2.73). The weakness of these data is a small 
number of cases and a broad 95% confidence inter-
vals, but nevertheless, these data are in accordance 
with the fact that most radiation-induced pericar-
ditis resolve over the years post radiotherapy.
In a recently published study, analyzing early 
cardiotoxicity after adjuvant concomitant treat-
ment with radiotherapy and trastuzumab in breast 
cancer patients, treated between 2005 and 2010 and 
evaluated with transthoracic echocardiography, 10 
(5.7%) out of 175 patients had pericardial effusion 
after a median observation time of 4.7 years.11 In 
this study, left breast cancer patients had signifi-
cant more pericardial effusions than right breast 
cancer patients (9 [11%] vs. 1 [1%]; p = 0.007). The 
thickness of pericardial effusion, measured at tran-
sthoracic echocardiography, was > 1 cm in 1 patient 
with left breast cancer, all the rest were < 1cm wide.
The recently published study, with retrospective 
analysis of 63 patients who underwent pericardiec-
tomy for constrictive pericarditis, which is the most 
severe form of radiation induced pericardial dis-
ease, between 1997 and 2012, showed a significant 
decrease in overall survival associated with postra-
diation etiology (p  =  0.05). The number of irradi-
ated patients in this study was very small (n  =  3; 
8.3%), but also other studies report similar data.12
A golden standard in the evaluation of cardio-
toxicity in cancer patients is standard transthoracic 
two-dimensional echocardiography.13 It provides 
useful morphologic and hemodynamic informa-
tion. A standard part of the echocardiographic 
exam are measurements of heart chambers and 
great vessels dimensions, estimation of ventricular 
systolic and diastolic function, assessment of ven-
tricular wall contraction abnormalities, valvular 
anatomy and function and diagnosis of pericardial 
disease. In obese patients or in patients after chest 
irradiation, the quality of measurements can be 
poor due to suboptimal chest echotranslucency. In 
these settings tissue Doppler imaging (TDI) offers 
additional information.13 Computed tomography 
is particularly helpful in identifying calcification.3 
In the evaluation of constrictive pericarditis, also 
magnetic resonance imaging and right-sided cath-
eterization is used.14
Pathophysiology
The pathophysiologic pathway responsible for 
most manifestations of cardiotoxicity appears to 
involve damage to blood vessels. The generation 
of reactive oxygen species, caused by radiation, 
disrupt DNA strands. Secondary inflammatory 
changes then lead to fibrosis.15
Acute pericarditis is caused by radiation-induced 
inflammation of the pericard. Pericard becomes po-
rous, resulting in a neutrophilic infiltrate and col-
lection of a high-protein exudate (exudative peri-
carditis).16 Changes of pericard in acute stage may 
later lead to fibrosis of the pericard, impairing the 
venous drainage of extracellular fluid.17 Inefficient 
drainage results in the accumulation and formation 
of pericardial effusions, which are mostly fibrinous 
exudates.18 Pericardial fat is replacing by collagen. 
Early and acute or delayed and chronic pericarditis 
should be regarded from a histopathological stand-
point as two distinct disease entities.9
The histopathologic picture of the radiation-
induced pericardial disease, the dose-independent 
latency time, and the reversibility indicate that 
radiation-induced pericarditis is an acute radiation 
response of an actively proliferating cell popula-
tion. Mesothelial cells are the most likely candi-
dates for target cells, but systematic cell kinetic 
studies have not been performed.6
Clinical meaning and therapy
Acute pericarditis is a rare short-term complica-
tion of radiotherapy and develops during or days 
Radiol Oncol 2019; 53(1): 1-5.
Marinko T / Breast size and adjuvant radiotherapy 3
to weeks after irradiation.14,15 It can be revealed by 
asymptomatic pericardial effusion or symptomatic 
pericarditis. Patients may present with chest pain, 
they may have a fever, pericardial rub, electrocar-
diogram abnormalities (ST-T changes) and mild 
elevations in cardiac markers within days to weeks 
of therapy, near the timing of radiotherapy.18 Acute 
pericarditis usually resolves by itself, spontane-
ous clearance of effusion may occur. Half of the 
patients do not require any active intervention.15 
Nevertheless, if treatment of pericarditis is needed, 
it is usually supportive with non-steroidal anti-in-
flammatory drugs (NSAID) and colchicine.3,14,19 As 
a second-line agent, steroids may be prescribed. In 
resistant cases, interleukin 1β receptor antagonist 
is also an option.15,20,21 In the case of large pericar-
dial effusion, especially if the patient is hemody-
namically compromised, pericardiocentesis is indi-
cated. According to the literature, 20% of patients 
may proceed to have chronic pericarditis.15
Pericardial effusions may appear weeks, months 
or even years after irradiation with the mean laten-
cy for development of approximately one year.8,14 
Patients may be asymptomatic or develop progres-
sive shortness of breath. Effusions that are hemo-
dynamically insignificant require close monitor-
ing, but those, who are symptomatic or in the case 
of tamponade, require urgent drainage of fluid.20
Constrictive pericarditis is usually the most 
severe form of pericarditis and commonly occurs 
with a latent period of 10 or more years post-radi-
ation exposure as congestive heart failure.18 It can 
lead to disabling symptoms and severe heart fail-
ure with the poor quality of life. Surgical pericar-
diectomy is the cornerstone of management.12 In 
a recently published case report, in a 57-year-old 
breast cancer patient with late onset radiation-in-
duced constrictive pericarditis and cardiomyopa-
thy 22 years after radiotherapy for left breast can-
cer, even heart transplant operation was necessary 
and successfully done.22
Effect of radiation dose and 
techniques of treatment plan-
ning and delivery
Radiation-induced cardiotoxicity is related to both 
the irradiated volume of the heart and the radiation 
dose delivered to that volume. It seems that there 
is no safe dose that could be delivered to the heart 
with no increased risk of cardiovascular disease.23
The so-called »tolerance dose« of the pericard is 
described in the literature as a mean heart dose of 
greater than 36 or 40 Gy, or a > 50 Gy dose adminis-
tered to > 30% of the heart.6,8,24 The radiation effect 
on the pericard is highly dose-dependent, with the 
incidence of pericarditis increasing from < 5% to > 
50% as the total dose to the heart is increased from 
40 to 50 Gy.25 
According to the data from the Quantitative 
Analysis of Normal Tissue Effects in the Clinic 
(QUANTEC) review, published in 2010, which 
based on the previous report from Emami and col-
leagues published in 1991, the relations between 
the irradiated volume of the critical structure, 
threshold and outcome for pericarditis are as fol-
lows25,26:
•   Mean heart dose < 26 Gy  ....... < 15% probability 
for pericarditis
•   Heart V30 < 46%   ......... < 15% probability for 
pericarditis
Currently, all predictions for pericarditis prob-
ability are based on dose delivered to the heart. In 
the literature, there is no specific recommendations 
for dose restrictions that would base on the dose 
delivered to the pericard, as seems to be more ac-
curate. Namely, in classical left breast irradiation 
with tangential fields, the pericard is the closest 
cardiac substructure that lies behind the irradiat-
ed target and, because of the steep gradient fall of 
the dose behind the targets, it probably receives a 
higher dose that the rest of the heart. In the current 
breast contouring recommendations and atlases, 
the whole heart is included, but it is likely that also 
cardiac substructures are important as we begin to 
understand the impact of radiotherapy on cardiac 
function.27-29 At the moment, in the literature, there 
are at least two heart atlases, with instructions for 
countouring heart substructures. No one has de-
tailed instructions for contouring of the pericard, 
although the second one, published in 2017, ena-
bles contouring of 15 cardiac segments.29,30
However, do we need to pay special attention 
on the contouring of the pericard as a specific 
structure, similarly as we contour coronary ar-
tery? According to the incidence of the treatment 
required, radiation-induced pericardial disease, it 
seems, that there is maybe no reason for that. But 
for the definite answer, it needs to be evaluated in 
a clinical study.
Dose, delivered to the heart during radio-
therapy for breast cancer, largely depends on the 
treatment technique used. With the modern ra-
diotherapy techniques, it is possible to spare the 
heart much more from radiation, than it was pos-
sible in the past by using older techniques.31 Unlike 
2D radiotherapy, 3D radiotherapy allows defining 
Radiol Oncol 2019; 53(1): 1-5.
Marinko T / Breast size and adjuvant radiotherapy4
the dose delivered to any point to the heart. If ra-
diotherapy is delivered in a breath hold, which al-
lows the heart to move down and posterior to the 
treatment volume, the sparing effect to the heart is 
even greater.32 In a study comparing free breath-
ing (FB) with voluntary deep inspiration breath 
hold (V-DIBH) resulted in a significant reduction 
of mean cardiac dose from 6.1 +/- 2.5 to 3.2 +/- 1.4 
Gy (p < 0.001), maximum cardiac dose from 51.1 +/- 
1.4 to 48.5 +/- 6.8 Gy (p = 0.005) and cardiac V25Gy 
from 8.5 +/- 4.2 to 3.2 +/- 2.5% (p < 0.001). There is 
no specific data for the dose to the pericard.
With an increasing awareness of potential cardi-
otoxicity of radiotherapy, new studies with proton 
therapy have emerged. Stick et al. in their study did 
an estimation of cardiac toxicity after comprehen-
sive nodal photon versus proton therapy for breast 
cancer. In their report, they concluded that mod-
ern photon therapy yields a limited risk of cardiac 
toxicity in most patients, but proton therapy could 
reduce the predicted risk of cardiac toxicity by 
up to 2.9%.33 A systematic review of the literature 
with the aim to evaluate proton therapy in locally 
advanced breast cancer, done by Kammerer et al., 
showed that proton therapy often decreased mean 
heart dose by a factor of 2 or 3. As an example for 
mean heart dose, they listed 1 Gy with proton ther-
apy versus 3 Gy with conventional 3D, and 6 Gy for 
intensity-modulated radiotherapy (IMRT).34 There 
is again no specific data for pericard.
Future directions
Good news is that the very recently published, 
registry-based study, reporting long-term heart-
specific mortality among 347.476 breast cancer pa-
tients treated with radiotherapy or chemotherapy 
between 2000 and 2011, found that heart-specific 
mortality among breast cancer survivors was not 
increased compared with the general population.35 
According to the available literature, the absolute 
risk for pericardial disease associated with breast 
cancer radiotherapy is small and appears to be out-
weighed by the benefits of the treatment. 
Nowadays, awareness about potential harm to 
the heart during radiotherapy is much higher than 
in the past, and efforts to deliver the prescribed ra-
diation dose to the treatment target with the mini-
mum possible dose delivered to the heart, are a part 
of a daily treatment planning routine in the major-
ity of radiotherapy departments. But there is still a 
lot of room for improvement. The challenge for the 
future is in answering the question of the tolerance 
dose and the roll of each heart substructure in the 
etiology of radiation-induced heart disease.
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