Introduction
Post-mastectomy radiotherapy applied to the chest wall
(CW) and regional nodes in node-positive breast cancer
significantly reduce locoregional recurrences, general
recurrences, and breast cancer mortality.[] It has been
shown that internal mammary lymph node (IMLN)
metastases are detected at a rate of 28-52% in axillary
lymph node (LN)-positive and 5-17% in axillary LNnegative
patients.[,] After the most recent studies,
National Comprehensive Cancer Network guidelines
have been updated and IMLN radiotherapy recommendations
since 2006 suggested "category 1" when axillary
LN ≥4 positive, and as "strongly considered" if 1-3 positive
axillary LNs are found, both after mastectomy and
lumpectomy. In a cohort study examining the effect of
IMLN radiotherapy on survival, distant metastasis, and
breast cancer mortality in early-stage node-positive
breast cancer, it was shown that IMLN radiotherapy decreases
breast cancer mortality, improves survival, and
reduces rates of distant metastases.[] While the greatest
benefit was observed in node-positive medial/central
disease, the same benefit was also detected in those
with ≥4 LN positivity independent of localization. No
benefit was observed in patients with 1-3 LN positivity
and lateral lesions.[] In the light of these studies, in
recent years, we, radiation oncologists, have increased
our desire for radiotherapy applied to the field of IMLN.
However, an increase in cardiac and pulmonary toxicities,
especially in patients with the left breast cancer, is
inevitable with the addition of IMLN to the radiotherapy
protocol. The left-sided breast radiotherapy is significantly
associated with radiation-induced coronary
atherosclerosis and cardiac mortality.[] Computed
tomography (CT)-based radiotherapy plans allow for
more effective protection of normal tissue structures
and also determine the risk of toxicity. In this study,
our aim was to compare conventional tangential field
field-in-field (FIF) and dynamic-intensity-modulated
radiotherapy (d-IMRT) techniques in terms of changes
in cardiac substructure and coronary arteries doses on
dose-volume histogram (DVH) when IMLN radiotherapy
is added to post-mastectomy left CW radiotherapy.
Methods
Patient Data
Fifteen patients with the left breast cancer who received
radiotherapy to the CW after post-mastectomy
at Tokat Gaziosmanpaşa University Hospital between
January 2020 and June 2021 were selected. Fifteen patients were retrospectively recontoured. Cardiac vessels
as the left main coronary artery (LMCA), both
proximal and distal left anterior descending (LAD),
circumflex (CX) and right coronary arteries (RCA),
and heart chambers (right and left atria and ventricles)
were contoured with reference to contouring atlas presented
by the Danish Multidisciplinary Cancer Group.
[] According to the radiotherapy planning consensus
defined by the Radiation Therapy Oncology Group,
planned target volume (PTV) for CW was created and
IMLN was contoured similarly in all patients as covering
the first three intercostal areas (http://www.rtog.
org/CoreLab/ContouringAtlases/BreastCancerAtlas.
aspx.). The PTV encompassed the CW with the pectoralis
muscle, CW muscles, and ribs, and eliminated
the outermost 2 mm from the superficial skin surface.
This retrospective dosimetric study was approved by
the Institutional Review Board and Ethics committee.
Treatment Techniques
For each patient, CT simulation was created with the patient
laid in the supine position on the breast board and
vacuum bed, with his/her ipsilateral arm was elevated,
and CT images were obtained at 3 mm intervals (slice
thickness). Fraction dose of 2 Gy was prescribed amounting
to a total of 50 Gy, and four different plans were created.
These were the FIF and IMRT plans with and without
inclusion of IMLN as follows: CW-FIF technique;
CW+IMLN-FIF technique; only CW-IMRT technique,
and CW+IMLN-IMRT technique. A total of 60 plans
were made using the eclipse planning system version
13. In both FIF and IMRT plans, 6 MV photon energy
was used as it provides better dose coverage on the CW.
Dmean, V5, V10, and V30 for the whole heart (incl. both right
and left atria and ventricles); Dmean and Dmax for coronary
vessels incl. LMCA, LAD, RCA, and CX; and Dmean, V95,
V107, CI (conformity index) and HI (homogeneity index)
values for PTV were compared between plans on DVH.
The homogeneity index was calculated with (D2-D98%)/
D50%) formula (HI of zero is ideal) and the conformity
index was computed as volume of PTV covered by the
95% isodose curve/volume of PTV (CI of 1.0 is ideal).[]
Figure 1 shows the contouring of the cardiac substructures
and the dynamic-IMRT and FIF technique
plan comparisons/isodose curves covering 95% of the
prescribed dose. The study was analyzed in three parts.
In the first part, when the IMLN field is added to the
CW radiotherapy in the traditional tangential FIF technique,
doses received by the heart and its substructures,
in the second part, when the IMLN field is additionally
covered by the CW radiotherapy in the d-IMRT technique, doses received by the heart and its substructures,
and in the third part, FIF and d-IMRT techniques in
the CW+IMLN radiotherapy were compared. The purpose
of designing this dosimetric study was to find
an answer to the question: "How are the cardiac substructures
affected by IMLN radiotherapy and which
RT technique protects the cardiac substructures better
when IMLN is added to the radiotherapy protocol?"
Fig. 1. Comparison between dynamic-intensity-modulated radiotherapy, and field-in-field technique plans - isodose
curve representing over 95% of the prescribed dose delivered. Contouring: Right atrium (blue), left atrium (brown),
right ventricle (cyan), left ventricle (dark blue), left main coronary artery (light green), left anterior descending
(red), circumflex (pink), and right coronary artery (orange).
CT: Computed tomography; RT: Radiotherapy; FIF: Field-in-field; IMRT: Intensity-modulated radiotherapy; L: Left; R: Right; CX: Circumflex;
LAD: Left anterior descending; LMCA: Left main coronary artery; PTV: Planning target volume; RCA: Right coronary artery.
Statistical Analysis
The results were represented as mean±standard deviation
(SD). The two-sided paired t-test was used
when the datasets were normally distributed. Otherwise,
datasets were compared by Wilcoxon Cox test.
These analyses were performed using SPSS version
17 (SPSS Inc., Chicago, USA). All reported P-values
were two sided and p<0.05 was considered of statistical
significance.
Results
For Cardiac Substructures
In the first part, when we added the IMLN field to
the CW in the tangential FIF technique, the only unchanged
constant was LAD Dmax (p=0.195), while a
significant increase was found in the doses of all other
parameters (Table 1).
Table 1 Comparison of CW and CW+IMLN fields in FIF technique (mean±SD)
In the second part, when we added IMLN field to
CW in the d-IMRT technique, while parameters of atrial L V10 (p=109), atrial R V5 (p=0.317), ventricular
L V30 (p=0.292), LMCA Dmean (p=0.286), LMCA Dmax
(p=0.549), and LAD Dmax (p=0.485) did not change,
parameters of other cardiac substructures increased
statistically significantly when IMLN field was included
in the radiotherapy of CW (Table 2).
Table 2 Comparison of CW and CW+IMLN fields in IMRT technique (mean±SD)
In the third part, in the comparison of FIF and d-
IMRT techniques in CW+IMLN radiotherapy, the whole
heart, ventricular L and ventricular R V30 values, and
LAD Dmean and Dmax were found to be significantly superior
in d-IMRT technique. Other parameters (LMCA,
RCA, and CX Dmax and Dmean; V5 and V10 of the ventricles;
and the whole heart) were found to be statistically
significantly superior in the FIF technique (Table 3).
Table 3 Comparison of CW+IMLN radiotherapy with FIF and IMRT techniques (mean±SD)
For PTV
PTV coverage (V95), V107, and HI did not change, but
CI worsened (p<0.001) when IMLN field was added to
the CW in the FIF technique. All parameters related
to PTV (Dmean, V95, V107, CI, and HI [for all p>0.05])
did not change when IMLN field was added to CW in
IMRT technique. In the third part, in the comparison
between FIF and d-IMRT techniques in CW+IMLN
radiotherapy, PTV Dmean, V95, V107, and CI values were
found to be significantly superior in the d-IMRT technique
(for all p<0.001). Only PTV homogeneity index
was not significantly different (p=0.203).
Discussion
Cardiac toxicity is an issue that should be given great
importance, especially in the radiotherapy planning
of patients with the left breast cancer. There are many
studies in the literature showing the dosimetric benefits of IMRT compared to 3D conformal radiotherapy.
However, in recent years, the tendency to extend coverage
field of the IMLN has increased, and the IMLN
field is included in the radiotherapy protocol, however,
studies of the IMLN radiotherapy on its additional effect
on cardiac and coronary vascular toxicity are still scarce in number. Our study showed that when the
IMLN field is added to the CW, high-dose volumes
of the whole heart and ventricles (V30) and only LAD (both Dmax and Dmean) from among the coronary vessels
are significantly better protected when d-IMRT technique
is used (whole heart V30: 9.4% by 6.2%, ventricle L V30: 17.1% by 9.9%, ventricle R V30: 7.3% by 4.3%,
LAD Dmean: 38.3 Gy by 33.9 Gy, and LAD Dmax: 52.7
Gy by 51 Gy). All the low-dose volumes of the whole heart and ventricles (V5 and V10) and all coronary vessels
excepting LAD (incl. both Dmax and Dmean) were
better protected in the FIF technique. In this respect, PTV Dmean, V95,V107, and CI were significantly superior
in the d-IMRT technique (for all p<0.001), while HI
was not significantly different (p=0.203).
In a study comparing tangential beam IMRT and
3D conformal RT techniques in postmastektomi CW
radiotherapy with 20 unselected breast cancer patients,
the PTV, and organs at risk (OAR) such as lung and
heart doses were compared on DVH. Mean doses of
ipsilateral lung and heart were lower in the tangential
beam IMRT technique and for the PTV, homogeneity
index did not differ, while the conformity index was
found to be significantly better in the IMRT technique.
[] In our study, although we found a similar result for
PTV, on the contrary, mean cardiac doses were found
to be significantly higher in the IMRT technique. However,
in the aforementioned study, not only the leftsided
breast cancer patients but unselectively all breast
cancer patients were included in the radiotherapy protocol,
which may be the reason why the mean cardiac
dose was lower in the IMRT technique in their study.
However, in our study, in the 3D conformal radiotherapy
(or FIF) technique, multi-leaf collimators pulled
firmly toward target volume to protect the heart as
much as possible so the mean and low-dose volumes of
whole heart and ventricles were better protected.
In a prospective study conducted by Chargari et
al.,[] the contribution of IMLN radiotherapy to cardiac
radiation dose was investigated in 36 patients with
breast cancer. Radiotherapy at a dose of 50 Gy was applied
with standard conformal radiotherapy technique
and the effect of IMLN radiotherapy on the cardiac
dose was investigated according to the type of surgery
(breast conserving surgery [BCS] vs. mastectomy) and
the laterality of breast cancer (left vs. right breast cancer).
Compared to patients with the right breast cancer,
patients with the left breast cancer received a statistically
significantly increased cardiac dose. In the grouping
made according to the type of surgery, the cardiac
dose used was not statistically different in those who
underwent mastectomy or BCS. The authors reported
that the type of surgery performed did not affect the
cardiac dose.[] In another dosimetric study, 50 patients
with the left breast cancer were analyzed dosimetrically
by contouring the LAD and whole heart
in tangential breast radiotherapy.[] They found the
mean LAD dose as 19.06 Gy and also detected a perfect
correlation between the LAD and cardiac doses.
For every 100 cGy increase in the mean cardiac dose,
the mean LAD dose increased by 4 Gy. In this study,
we found the mean LAD dose to be 38 Gy and 33 Gy
in the classical tangential and d-IMRT techniques, respectively. The reason for our high value of LAD dose is
that the patients in our study were locally advanced so
the ribs were included in the target volume, however,
the above-mentioned study was performed with patients
with early-stage breast cancer who received only
breast radiotherapy, which was formed by excluding
the ribs in the target volume.
A similar dosimetric study was done by Zhang et
al.[] They dosimetrically compared volumetric modulated
arc therapy (VMAT) and IMRT techniques, in terms
of heart, lung doses, and PTV on DVH in the left CW and
IMLN radiotherapies applied after mastectomy. VMAT
provided slightly better but statistically insignificant protection
in the mean, V5, V10, and V30 of heart doses. The
VMAT technique provided better PTV dose coverage,
fewer monitor units, and shorter treatment time.[]
Our study has some limitations. First of all, besides
being a retrospective series, comparison with
advanced radiotherapy techniques could not be made.
In other words, breath-holding or respiratory gating
systems could be used to provide better heart protection
in patients with the left breast cancer. However,
unfortunately, these facilities were not available, so
applicable in our clinic and we were also working with
a retrospective series.
Conclusion
Only LAD Dmax did not increase with the addition of
IMLN radiotherapy in the FIF technique. When the
IMLN field was added in the IMRT technique, both maximum,
and mean doses coronary vessels of LMCA and
LAD did not change, while the doses of other coronary
vessels were increased. Consistent with the literature
data, all the low-dose volumes of heart and ventricles (V5
and V10) and all coronary vessels (excl. LAD) were better
protected in the FIF technique when compared with the
IMRT technique. In patients with the left breast cancer
who will undergo IMLN radiotherapy, especially if they
have coronary disease, RT technique can be selected according
to the vessel where the damage is located. However,
more research is warranted on this subject.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: The study was approved by
the Tokat Gaziosmanpaşa University Faculty of Medicine
Clinical Research Ethics Committee (No: 22-KAEK-011,
Date: 20/01/2022).
Financial Support: None declared.
Authorship contributions: Concept - G.G.A.; Design -
M.B.A.; Supervision - M.B.A.; Funding - G.G.A.; Materials
- H.B.; Data collection and/or processing - G.G.A.; Data
analysis and/or interpretation - M.B.; Literature search -
Y.G.; Writing - G.G.A.; Critical review - Y.G.
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