DOSE-MODELING STUDY TO COMPARE EXTERNAL BEAM TECHNIQUES
FROM PROTOCOL NSABP B-39/RTOG 0413 FOR PATIENTS WITH HIGHLY
UNFAVORABLE CARDIAC ANATOMY
JESSICA R. HIATT, B.S.,* SUZANNE B. EVANS, M.D., M.P.H.,†LORI LYN PRICE, M.S.,†
GENE A. CARDARELLI, PH.D., M.P.H.,* THOMAS A. DIPETRILLO, M.D.,*†
AND DAVID E. WAZER, M.D.*†
*Department of Radiation Oncology, Rhode Island Hospital, Brown University School of Medicine, Providence, RI; and
†Department of Radiation Oncology, Tufts–New England Medical Center, Tufts University School of Medicine, Boston, MA
Purpose: The aim of this study was to select patients with heart anatomy that is specifically unfavorable for
tangential irradiation in whole-breast radiotherapy (WBRT), to be used as an experimental cohort to compare
cardiac dosimetric and radiobiological parameters of three-dimensional conformal external beam accelerated
partial breast irradiation (3D-CRT APBI) to WBRT with techniques as defined by the National Surgical
Adjuvant Breast and Bowel Project (NSABP) B-39/Radiation Therapy Oncology Group (RTOG) 0413 clinical
Methods and Materials: A dosimetric modeling study that compared WBRT and 3D-CRT APBI was performed
on CT planning data from 8 patients with left-sided breast cancer. Highly unfavorable cardiac anatomy was
defined by the measured contact of the myocardium with the anterior chest wall in the axial and para-sagittal
planes. Treatment plans of WBRT and 3D-CRT APBI were generated for each patient in accordance with
NSABP B-39/RTOG 0413 protocol. Dose–volume relationships of the heart, including the V5min (minimum dose
delivered to 5% of the cardiac volume), biological effective dose (BED) of the V5min, and normal tissue
complication probability (NTCP) were analyzed and compared.
Results: Despite expected anatomic variation, significantly large differences were found favoring 3D-CRT APBI
in cumulative dose–volume histograms (p < 0.01), dose to the entire heart (mean difference 3.85 Gy, p < 0.01),
NTCP (median difference, 1.00 Gy; p < 0.01), V5min (mean difference, 24.53 Gy; p < 0.01), and proportional
reduction in radiobiological effect on the V5min (85%, p < 0.01).
Conclusions: Use of 3D-CRT APBI can demonstrate improved sparing of the heart in select patients with highly
unfavorable cardiac anatomy for WBRT, and may result in reduced risk of cardiac morbidity and mortality.
© 2006 Elsevier Inc.
Partial breast irradiation, Cardiac toxicity.
Radiation therapy as a component of breast-conserving
treatment conventionally uses tangential beam arrange-
ments that include the entirety of the breast, a portion of the
chest wall, and some contents of the anterior thoracic cavity.
In the case of left-sided breast cancer, tangent fields can
include a substantial volume of the heart (1), leading to
profound and persistent myocardial perfusion defects (2).
Some clinical trials have shown that the consequence of
left-sided tangential breast irradiation can be an increase in
the risk of cardiovascular morbidity and mortality (3, 4).
However, other data suggest that modern treatment plan-
ning and delivery techniques have ameliorated the risk of
late cardiac injury associated with left breast tangential
Most clinicians would readily recognize that there is
considerable patient-to-patient variation in the volume of
heart that can be included within a left breast tangential
field. This fact is largely ignored in studies of cardiac
morbidity after breast irradiation. The relative curvature of
the anterior chest wall, the size of the breast, the position of
the breast on the chest wall, the size of the heart, and the
position of the heart relative to the anterior chest wall can all
be factors that lead to the inclusion of more cardiac volume
in some patients as compared with others. In some cases, the
anatomic relationship of the heart to the left anterior chest
wall can be so unfavorable as to raise serious doubt as to the
Reprint requests to: David E. Wazer, M.D., Department of
Radiation Oncology, Tufts–New England Medical Center, 750
Washington Street, Boston, MA 02111. Tel: (617) 636-7673; Fax:
(617) 636-9714; E-mail: email@example.com
Received Feb 15, 2006, and in revised form Mar 15, 2006.
Accepted for publication Mar 16, 2006.
Int. J. Radiation Oncology Biol. Phys., Vol. 65, No. 5, pp. 1368–1374, 2006
Copyright © 2006 Elsevier Inc.
Printed in the USA. All rights reserved
0360-3016/06/$–see front matter
safety of conventional whole-breast radiotherapy in the con-
text of long-term cardiovascular risk. Furthermore, in such
extreme cases where the heart is in direct apposition to the
anterior chest wall with its position minimally affected by
respiratory excursion, special planning maneuvers including
IMRT may result in inadequate sparing of dose to the
Accelerated partial breast irradiation (APBI) has not
yet been proved to be equivalent to whole-breast irradi-
ation in terms of disease control. Nonetheless, a putative
advantage ascribed to the use of APBI relates to the
reduction in volume of normal tissue exposed to high-
dose radiotherapy. However, there are no studies to either
quantify the potential normal tissue advantages inherent
in the use of APBI or normal tissue dose–volume infor-
mation to provide clinicians the context in which to
consider APBI as a noninvestigational alternative to
whole-breast irradiation. We postulate that the clinical
circumstance of highly unfavorable cardiac anatomy with
regard to tangential breast irradiation provides an appro-
priate experimental model with which to begin to explore
the possible normal tissue advantages of APBI. As such,
we have studied a specific group of patients with cardiac
anatomy that is markedly unfavorable for breast tangen-
tial irradiation. We follow with a dosimetric, radiobio-
logic, and normal tissue complication probability com-
parison of external beam techniques described in the
National Surgical Adjuvant Breast and Bowel Project
(NSABP) B-39/Radiation Therapy Oncology Group
(RTOG) 0413 protocol for whole-breast radiotherapy and
three-dimensional conformal external beam (3D-CRT)
METHODS AND MATERIALS
Eight patients were selected from a cohort previously treated
at our institution. The analysis performed for this study con-
sisted of purely dosimetric modeling and was fully independent
of care delivered to each patient. Cases with left-sided breast
cancer and a readily identifiable lumpectomy cavity were se-
lected for study. For dosimetric comparison, we purposely
selected patients with extremely unfavorable cardiac anatomy
as defined by direct apposition of the myocardium to the ante-
rior chest wall. Furthermore, we attempted to define in quanti-
tative terms the relative poor quality of cardiac anatomy with
the cardiac contact distance (CCD). The CCD was calculated in
both the axial (CCDax) and para-sagittal (CCDps) planes. In the
axial plane, the CCDaxwas defined by taking the measure of the
shortest linear distance between the medial point of contact of
the cardiac silhouette with the chest wall to the lateral point of
contact with chest wall at the level of the right hemi-diaphragm
Fig. 1. Demonstration of the measurement of cardiac contact distance (CCDaxand CCDps, represented by thick white
line). Midpoint of left hemithorax is demonstrated by thin vertical white line, and the horizontal thin white line
demonstrates the midpoint of the thorax. Coronal image confirms that this measurement was made at the apex of the
right hemidiaphragm. In this case, CCDaxmeasures 10.80 cm, and CCDpsmeasures 5.05 cm.
1369External beam techniques from NSABP B-39/RTOG 0413 ● J. R. HIATT et al.
(Fig. 1). The cardiac contact distance was also defined in a
para-sagittal plane that was measured at the midpoint of the left
hemithorax as determined in the transverse and coronal plane.
In the para-sagittal plane, CCDpswas defined as the linear
distance of direct contact by the heart with the chest wall (Fig.
1). For the specific purpose of this study, highly unfavorable
cardiac anatomy was defined as cases with a CCDaxof more
than 5 cm and a CCDpsof more than 2 cm.
We performed CT simulation with the patient supine on a
breast board. At simulation, radiopaque markers were placed at
midline, mid-axillary line, 1 cm below the infra-mammary fold,
and at the level of the head of the clavicle. The CT data were
transferred to the Pinnacle (Phillips Medical System, Madison,
Wisconsin) treatment planning workstation. The breast volume
and excision cavity were delineated per specifications of the
NSABP B-39/RTOG 0413 protocol (6), as previously detailed
(7). The heart volume included the entire myocardium and
blood volume from the apex to the infundibulum of the right
ventricle, the right atrium and auricle, the root of the ascending
aorta, and pulmonary trunk. As the planning study was obtained
with a Phillips AcQSim single-slice CT scanner without con-
trast, neither the left ventricular volume nor relative position of
the left anterior descending coronary artery could be delineated
with certainty. Treatment planning for both conventionally frac-
tionated whole-breast radiotherapy (WBRT) and 3D-CRT APBI
were in accordance with the methodology specified in the
NSABP B-39/RTOG 0413 trial (6).
For 3D-CRT APBI planning, the treatment isocenter was
placed in or near the excision cavity. Configurations consisting
of 4 to 5 convergent noncoplanar tangential beams were used,
with the goal of minimizing treatment to surrounding normal
tissues while achieving the dose requirements to the clinical
target volume (CTV). The prescription dose was 38.5 Gy in 10
fractions. Beam weighting, tissue heterogeneity corrections,
and appropriate tissue compensation wedges were used to meet
homogeneity (?10% above prescription dose) and normal tis-
sue dose constraints.
For conventional WBRT planning, two tangentially opposed
isocentrically positioned beams were used. The medial entry point
was defined at the mid-line of the sternum and the lateral entry
point was defined at the mid-axillary line. The whole-breast dose
was 46 Gy in 2 Gy daily fractions. All beam trajectories were
forward-planned with either 6 MV or a combination of 6 and 18
MV photons. Beam weighting, tissue heterogeneity corrections,
and appropriate tissue compensation wedges were used to meet
homogeneity (?15% above prescription dose), normal tissue dose
constraints, and to ensure that the lumpectomy cavity was encom-
passed by ?90% isodose shell.
The V5min was defined as the minimum dose delivered to the
5% of the cardiac volume receiving the highest dose which in
all cases included the most anterior portion if the heart in direct
apposition to the chest wall. The V5min was determined for
each case from the tabular dose–volume histogram. Normal
tissue complication probability (NTCP) calculations were per-
formed (8) for cardiac mortality (9) with the following param-
eters for the predictive model: ?/? ? 3, ? ? 1.28, D50 ? 52.3
Gy. Biological effective dose (BED) calculations for myocar-
dium (unadjusted for treatment time as a presumed late-re-
sponding normal tissue with no acute proliferative response)
were performed with an ?/ ? ? 3 (8, 9). Treatment fraction size
for the BED calculations was determined for each case based on
the mean total dose to the evaluated volume, divided by 23 for
WBRT and 10 for 3D-CRT APBI.
Because of the small sample size, the nonparametric signed rank
test was used for one-sample and paired data analyses. Repeated
measures analysis (10) was used to compare the dose–volume
curves of partial and whole-breast radiation.
Select clinical and volumetric characteristics of the
modeled patient cohort are presented in Table 1. Cases
were chosen for this study by virtue of a cardiac anatomy
deemed highly unfavorable for conventional tangential
whole-breast irradiation as reflected in the median CCDax
of 9.75 cm and CCDps of 4.94 cm (Fig. 1). A cumulative
dose–volume histogram for the heart compares the results
obtained with WBRT and 3D-CRT APBI (Fig. 2). For the
most anterior portion of the heart that constitutes ?5% of
Table 1. Clinical and volumetric characteristics of the patients included in the dosimetric modeling study
Age (y)Excision cavity volume (cc) Left breast volume (cc)Heart volume (cc)CCD (cm)
Abbreviation: CCD ? cardiac contact distance.
Fig. 2. Composite dose–volume histogram of the heart for all cases
comparing whole-breast radiotherapy (WBRT) to three-dimen-
sional conformal external beam accelerated partial breast irradia-
tion (3D-CRT APBI).
1370 I. J. Radiation Oncology ● Biology ● PhysicsVolume 65, Number 5, 2006
total cardiac volume, there is consistently less dose de-
livered with 3D-CRT APBI as compared with WBRT.
For the complete cohort of 8 modeled cases, the dose
delivered to the entire heart with conventional WBRT as
compared with 3D-CRT APBI is shown in Table 2. In
absolute terms, the mean total heart dose remained low
irrespective of treatment technique. The mean dose to the
entire heart was 4.60 Gy and 0.75 Gy with WBRT and
3D-CRT APBI, respectively, with a mean difference of
3.85 Gy (p ? 0.01). There was a proportional reduction
in the mean dose of 84% to the entire heart with 3D-CRT
APBI as compared with WBRT (p ? 0.01).
Despite highly unfavorable cardiac anatomy, most of
the heart (usually ?90% of volume) is excluded from
direct exposure to the treatment beam with either WBRT
or 3D-CRT APBI. This suggested that the mean dose to
the entire heart may be a dosimetric variable of limited
comparative or prognostic utility. Furthermore, it has
been shown that a small volume of the heart exposed to
large doses of radiation can have functional conse-
quences (11, 12). As such, a parameter was selected
(V5min; minimum dose to 5% of cardiac volume) that
may better reflect the potential for late injury and be more
sensitive to small but critical volumes of cardiac tissue.
Table 3 presents a comparison of the V5min values
obtained for WBRT as compared with 3D-CRT APBI.
The mean V5min with 3D-CRT APBI is 15.4% of that
seen with WBRT (absolute mean difference, 24.53 Gy, p
Inferences as to the potential clinical relevance of a
comparison of WBRT to 3D-CRT APBI based exclu-
sively on an analysis of absolute dose is limited by
marked differences in both the total prescribed dose and
treatment fraction size associated with each technique.
To address this issue in a manner that takes into account
the radiobiological implications of both dose and fraction
size, we performed BED calculations on the most anterior
regions of the heart as defined by the V5min (Table 3).
These data show that the mean proportional reduction in
radiobiological effect to the V5min region achieved with
3D-CRT APBI was 85% (p ? 0.01). To examine further
the potential radiobiological consequences of treatment
technique on these select patients with unfavorable car-
diac anatomy, an NTCP calculation was performed. This
resulted in a median value of predicted cardiac mortality
from WBRT of 1% (range, 0.2–4.1%) as compared with
0% (range, 0–0.7%) for 3D-CRT APBI, with a median
difference of 1.00 (p ? 0.01).
Despite the favorable dosimetric and radiobiological
parameters, defining an advantage with 3D-CRT APBI in
the setting of highly unfavorable cardiac anatomy is
complex and appears to be dependent on the location of
the excision cavity within the breast. This is both quan-
titatively and qualitatively apparent upon visual inspec-
tion of comparative plans and their associated DVH.
Figure 3 shows 2 different cases in which the CTV has
been defined in either a medial or lateral position in the
breast, with the associated dose volume histograms in
Fig. 4. As can be seen, if the excision cavity is in the
lateral aspect of the breast, the relative sparing of cardiac
tissue from high dose irradiation with 3D-CRT APBI is
essentially complete. In contrast, when the CTV is in the
medial portion of the breast, the overall volume of heart
exposed to radiation is markedly reduced though a small
volume remains within the boundaries of the 80% isodose
Table 2. Comparative dosimetry of the entire heart
dose WBRT (Gy)
Mean cardiac dose
3D-CRT APBI (Gy)
(WBRT versus 3D-CRT APBI)
reduction in cardiac
dose with 3D-CRT APBI
p ? 0.01
p ? 0.01
Data are mean, median, and ranges of heart dose between whole-breast radiotherapy (WBRT) and three-dimensional conformal external
beam accelerated partial breast irradiation (3D-CRT APBI), and the proportional reduction in mean dose to the entire heart.
Table 3. Comparison of the dose to V5min and biological effective dose (BED) at the V5min for whole breast radiotherapy (WBRT)
and three-dimensional conformal external beam accelerated partial breast irradiation (3D-CRT APBI)
in V5min dose
BED of V5min
in BED V5min
dose with 3D-CRT
29.00 (27.92)4.47 (1.88)24.53 (24.17)43.34 (39.55)6.32 (2.02)37.02 (34.89)
p ? 0.01
p ? 0.01
1371External beam techniques from NSABP B-39/RTOG 0413 ● J. R. HIATT et al.
There is evidence that progressive refinement of exter-
nal beam radiotherapy planning and delivery systems can
lead to reduced rates of cardiac mortality after left-sided
breast irradiation. For example, Giordano et al. (13)
compared 12-year rates of cardiovascular mortality after
left-sided vs. right-sided breast irradiation in the periods
1973 to 1979, 1980 to 1984, and 1985 to 1989. They
found that in each year after 1979, there was a 6%
decrease in cardiovascular mortality associated with left
breast irradiation, presumably because of the implemen-
tation of improved external beam radiotherapy tech-
niques. Another analysis in support of a link between the
evolution in the technical aspects of radiotherapy deliv-
ery to decreasing rates of cardiac morbidity has also been
provided from an examination of the data set from the
Surveillance, Epidemiology, and End Results study (14).
Despite these encouraging studies as to the safety of
modern whole-breast tangential irradiation, there are
nonetheless a series of sobering reports that suggest the
potential in some patients of severe cardiac injury. The
patients with highly unfavorable cardiac anatomy as ex-
emplified in the current study could constitute a popula-
tion at particular risk for clinically significant radiation-
Yu et al. (15) showed that left-sided tangential breast
irradiation can lead to quantifiable perfusion deficits and
that, in approximately one third of cases, these deficits
can be correlated with later development of ischemic
symptoms. Marks et al. (16) reported that perfusion de-
fects on single photon emission computed tomography
(SPECT) imaging can develop within 6 months of left-
sided whole-breast irradiation. These defects did not re-
solve with extended follow-up, and their physiologic
impact was underscored in that they were associated with
segmental wall motion abnormalities (16).
The dose–volume relationships associated with cardiac
injury after irradiation are still being defined. Lind et al.
(17) have found that myocardial perfusion defects were
highly correlated to left ventricular irradiated volume and
were seen in the context of a remarkably low threshold
(5% of left ventricle). Hardenbergh et al. (2) have re-
Fig. 3. Comparison of conventional whole-breast radiotherapy (WBRT) tangential fields (left) with a five-field
three-dimensional conformal external beam accelerated partial breast irradiation (3D-CRT APBI) plan (right) in a
patient with medial CTV (top) and lateral CTV (bottom). Isodose lines depicted are 102% (yellow), 98% (purple), and
1372I. J. Radiation Oncology ● Biology ● PhysicsVolume 65, Number 5, 2006
ported that as little as 25 Gy can result in an elevated risk
of compromised perfusion of the left anterior descending
coronary artery. In a study by Carr et al. (18), patients
treated for peptic ulcer disease with fractionated radio-
therapy (1.5 Gy/fx) resulted in a mean dose to the entire
heart of 1.6 to 3.9 Gy and subsequently experienced an
increase of 44% in the relative risk of acute myocardial
infarction. The increase in cardiovascular morbidity seen
in the patients described by Carr et al. was associated
with a low dose to a small volume of the heart as the
primary incident beam included only 5% of the cardiac
volume and delivered a total of 7.6 to 18.4 Gy (18).
The current study has quantified the relative advantages in
dosimetric and radiobiological parameters with 3D-CRT APBI
in patients specifically selected for cardiac anatomy that was
highly unfavorable for conventional tangential WBRT. The
mean dose to the entire heart, the V5min, the BED V5min, and
NTCP were all markedly reduced with 3D-CRT APBI. Of
particular note, the V5min observed with 3D-CRT APBI was
substantially less than the threshold injury doses described by
Lind et al. (17) and Carr et al. (18). This suggests that for select
APBI could result in a reduced risk of cardiovascular morbid-
ity and mortality. With 3D-CRT APBI there is a significant
proportional reduction in the mean dose to the entire heart, as
well as the mean dose to the cardiac apex that includes the path
of the left anterior descending coronary artery. Current data
(12, 19) strongly suggest that it is this specific region of the
heart that is most critical when considering the risk of radia-
tion-induced cardiovascular injury from tangential whole-
In conclusion, although the risks of tangential breast
radiotherapy may be minimal in the general population of
patients, in the highly select subset of patients with
unfavorable cardiac anatomy as exemplified in this study,
3D-CRT APBI may become an important option in lim-
iting toxicity of modern radiotherapy.
Fig. 4. Comparison dose–volume histograms of representative patients with a lateral or medial excision cavity.
1373External beam techniques from NSABP B-39/RTOG 0413 ● J. R. HIATT et al.
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