Introduction
In early-stage breast cancer, mastectomy and breastconserving
surgery (BCS) plus whole breast radiation
therapy (WBRT) have similar local control and survival rates.[-] In addition, it has been shown that local
control is enhanced with WBRT after BCS.[,] Therefore,
BCS + WBRT is the preferred treatment method
for patients who prefer organ preservation and have no
contraindications for RT.
In the treatment planning of WBRT without lymphatic
irradiation, the target volume and critical organ
doses were quantitatively documented by 3D conformal
RT (3DCRT) unlike in conventional RT [] thus,
the RT side effects became more predictable. With
technical improvements, intensity-modulated RT
(IMRT) started to be performed, and more homogeneous
dose distributions could be obtained in target
volumes (reduction of hot spots), also there would be a
possibility to keep the heart and ipsilateral lung doses
at lower limits.[] Afterward, tomotherapy and volumetric
modulated arc therapy (VMAT) provided more
homogeneous dosimetry. 3DCRT, inverse planned
IMRT, forward planned IMRT, tomotherapy and
VMAT were compared dosimetrically in many studies.
[-] As a conclusion of all these studies, the percentage
volumes of the ipsilateral lung exposed to 20Gy or
30Gy and above (V20, V30) by 3DCRT are higher than
inverse-IMRT, tomotherapy and VMAT; however, by
these three treatment planning techniques, low radiation
doses such as normal tissue V5 and V10 have been
demonstrated to be higher than 3DCRT. In forward-
IMRT, both target volume homogeneity and coverage
are better than 3DCRT, additionally normal tissue V5,
V10 values do not increase.
In planning WBRT, the ipsilateral lung is a major
organ at risk, because of the risk of radiation pneumonitis
(RP) and radiation fibrosis. RP is an early inflammatory
reaction that occurs four to twelve weeks after
completion of thoracic irradiation, while radiation fibrosis
is observed after six months of completion of the
RT.[] The mean dose of the lung (Dmean) >10 Gy and
V20 of the lung is the predictive dose-volume parameters
for RP due to thoracic RT.[,] RP is relatively
much rarer after breast cancer RT because of the lower
lung doses and single lung exposure. Because the incidence
of RP after breast cancer RT is 1.2-13%[-],
the institutes should take into consideration the ipsilateral
lung dose limits according to institutional consensus
despite the bilateral lung dose limits in lung cancer
treatments are suggested as Dmean<20Gy and V20<35-
40%.[,]
In our radiation oncology department, early-stage
breast cancer RT treatment planning is performed as
forward-IMRT (field-in-field) and ipsilateral lung doses
are considered to be limited as Dmean≤15Gy, V20 ≤25%
and V30≤20%. Patients, whose ipsilateral lung doses
could not be limited as detailed above, are informed
about the other treatment techniques like inverse-IMRT
or VMAT. The lung dose parameters are documented after
hours of procedures such as simulation, target tissue and critical organ delineation by the radiation oncologist
and treatment planning by the medical physicist.
The aim of our study is to investigate whether there is
a correlation between simple anatomic measurements
that can be performed on the computerized tomography
(CT) slices of the patient and ipsilateral lung doses;
before all the RT planning procedures. If such a correlation
is detected, there will be a chance to inform patients
about ipsilateral lung radiation exposure before target
volume delineation and treatment planning.
Methods
Study Population and Treatment Planning
This is a single-center study and histopathologically
diagnosed early-stage breast cancer patients who underwent
BCS and adjuvant WBRT consecutively between
the years of 2014 and 2019 were enrolled in this
study. BCS was performed as consisting of lumpectomy
or quadrantectomy and also sentinel lymph node
biopsy (SLNB). The patients, who were pathologically
staged T1-3N0 after BCS and undergone whole breast
RT without any lymphatic irradiation, were the target
population of this study.
All patients were scanned in a supine position with
breast board immobilization equipment. CT images
were obtained with a 2.5-mm slice thickness for the thorax
region, from the upper abdomen to the bottom of
the chin, a using CT scanner (General Electric Medical
Systems). Treatment plans were created using the Eclipse
treatment planning system (TPS) on Varian DHX linear
accelerator. Anisotropic Analytical Algorithm (AAA)
dose calculation algorithm was used in the planning
process. A total of 50Gy was planned in 25 fractions
with a daily dose of 2Gy/fraction as the prescribed dose.
Tumor bed boost was prescribed as 10Gy in 5 fractions
or 8 fractions if there is a positive surgical margin. For
WBRT, the field-in-field (FIF) planning technique was
performed with two open tangential fields by using 6
MV x-rays. All the treatment plans were performed by
the same two medical physicists.
Ipsilateral lung dose data were collected from the
dose-volume histograms after treatment planning.
Dmean, V20, V25 and V30 values of the ipsilateral lung
of each patient were noted. The patients were divided
into two subgroups according to the mean values of
lung doses as high lung dose and low lung dose groups.
Anatomical Parameters
RT simulation CT images were used to make the linear
measurements. Lung and breast volumes were calculated by TPS after delineation. All the parameters are
defined below.
Cranio-caudal length of the treated breast (LBreast)
Cranio-caudal length of the ipsilateral lung (Llung)
The intersection length of treated breast and ipsilateral
lung (ILbreast-lung)
The absolute volume of the treated breast (VBreast)
and the absolute volume of the ipsilateral lung (VLung)
The maximum height of the contralateral breast
(HContrBreast): measured from the chest wall to the skin
surface (Fig. 1a)
The thickness of the soft tissue over the sternum
(Tsternum): measured at the level of manubriosternal joint
(Fig. 1b)
The distance between two breasts (Dbreasts): measured
at the level of manubriosternal joint (Fig. 1b)
The anterior-posterior diameter of the thorax at the
level of the sternal notch (AP-Dnotch<7sub>) (Fig. 1c)
The left-right diameter of the thorax at the level of the sternal notch (LR-Dnotch) (Fig. 1c)
The anterior-posterior diameter of the thorax at the
level of xiphisternal joint (AP-Dxiphi) (Fig. 1d)
The left-right diameter of the thorax at the level of
xiphisternal joint (LR-Dxiphi) (Fig. 1d)
Fig 1: (a) The CT slice showing the maximum height of the contralateral breast (HContrBreast): measured from chest wall to
the skin surface, (b) the CT slice at the level of manubriosternal joint showing the thickness of the soft tissue over
sternum (Tsternum) and the distance between two breasts (Dbreasts), (c) the CT slice at the level of sternal notch showing
the anterior-posterior (AP-Dnotch) and left-right diameter of thorax at the level of sternal notch (LR-Dnotch), (d) the
CT slice at the level of xiphisternal joint showing the anterior-posterior (AP-Dxiphi) and left-right (LR-Dxiphi) diameter
of thorax.
Additionally, the ratio of AP-Dnotch and LR-Dnotch
(Rnotch); the ratio of AP-Dxiphi and LR-Dxiphi (Rxiphi);
the difference between AP-Dxiphi and AP-Dnotch (APDdiff);
the difference between LR-Dxiphi and LR-Dnotch
(LRDdiff); the ratio of Tsternum and Dbreasts (Ts/Db) were
calculated.
Statistical Analyses
Statistical analyses were performed by the Statistical
Package for the Social Sciences software program version
21.0 (SPSS Inc., Chicago, IL, USA). All the anatomical
and dose parameters were evaluated about normal
distribution. Pearson's correlation coefficient was performed
to analyse the correlations between anatomical
and dose parameters which are normally disturbed
and Spearman's correlation test was performed for
non-parametric data. Additionally, a receiver operating
characteristics curve (ROC curve) was performed
for the anatomical parameters which were detected as
significantly correlated with lung doses to determine
the best cut-off value.
Results
Data of 102 consecutive patients who underwent whole
breast RT between September 2014 and August 2019 in
our radiation oncology department were reviewed. 53
(51.96%) left and 49 (48.03%) right-sided breast cancer
patients were enrolled in the study. The mean or median
values of all dose parameters and anatomic parameters
are detailed in Table 1. The anatomical parameters
were compared in low and high lung dose groups and
as a result Llung and APDdiff were statistically significant
higher(p=0.046 and p=0,002 respectively); HContrBreast,
Tsternum, AP-Dnotch, ,AP-Dxiphi, Rnotch, Rxiphi,
LRDdiff and Ts/Db were statistically significant lower (p=0.009, 0.031, 0.008, 0.003, 0.002, 0.015, 0.009 and
0.049 respectively) in high lung dose group.
Table 1: Localization of the treated breasts and the mean or median values of dose and anatomical parameters
Afterward, a Spearman correlation test was conducted
for the nonparametric anatomical parameters
and a Pearson correlation test was conducted for normally
disturbed anatomic parameters to evaluate the
correlations between anatomical measurements and
the ipsilateral lung dose parameters (Table 2). Llung,
Lbreast, ILlung-breast, VBreast, VLung, HContrBreast,
Tsternum, Dbreasts , LR-Dnotch, LR-Dxiphi
and Ts/Db were weakly correlated with the ipsilateral
lung doses and the p values were not significant. APD
notch, AP-Dxiphi, Rnotch, Rxiphi, and LRDdiff were negatively
statistically significantly correlated with ipsilateral lung
doses. In contrast, APDdiff, was the only parameter
that statistically significantly positively correlated with
the ipsilateral dose parameters. The best correlated anatomic
parameters were Rnotch and APDdiff, (p values
are between <0.001-0.001 for both of them).
Table 2: The Correlation results of the anatomical parameters with ipsilateral lung dose parameters.
ROC curve analyses were performed for each statistically
significant correlated anatomic parameter to
define a cut-off value which canindicate that the ipsilateral lung doses will be high. The cut-off values for
AP-Dnotch, AP-Dxiphi, Rnotch, Rxiphi, APDdiff, and LRDdiff
were 17.5cm, 23.5cm, 0.91cm, 0.86cm, 1.95cm and
6.96cm respectively. The area under the curves (AUC),
p values, 95% confidence intervals (CI), sensitivity and
specificity values are detailed in Table 3.
Table 3: The ROC curve analysis results of anatomical parameters showing statistically significant correlation with high
lung doses
Discussion
3DCRT, based on two tangential fields, is the conventional
treatment planning technique for breast RT.
Forward-IMRT is a treatment technique conducted by
adding a few field-in-fields to the tangential fields to
homogenize the dose distribution.[-] The novel RT
techniques as inverse-IMRT, tomotherapy and VMAT
provide lower V20, V30 and Dmean for the ipsilateral
lung and heart. In inverse-IMRT, the monitor units
(MU) and treatment time (TT) are prolonged while
it is necessary to use additional immobilizing equipment
such as breast thermoplastic mask or breathing
adaptation; there is no need for extra immobilizing
technique in VMAT since MU and TT are shorter than
both 3DCRT and inverse-IMRT.11 Therefore forward-
IMRT is considered to be cost-effective and convenient
for WBRT.
In breast cancer RT, the lungs are exposed to less
radiation than RT of lung cancer therefore there is no
consensus on the ipsilateral lung dose limitations. The
institutes are used to specify their own dose limit suggestions
for organs at risk in breast RT. Exemplarily
the Radiation Oncology Department of University of
California San Francisco (UCSF), ipsilateral lung V20
is limited to ≤10% with two-field tangents and ≤20%
with three-field (supraclavicular region) technique.
[] In our study patients treated with WBRT were
enrolled in the study, not the ones with regional lymphatic
irradiation, thus the effect of patients" anatomical features on the tangential fields could be evaluated.
Conventionally patients are simulated in a supine
position on breast inclined board which provides to
eliminate the inclination of the sternum and prevents
the breast from sliding up. Thus, it is aimed to minimize
the ipsilateral lung irradiation. Also, prone or
lateral decubitus positions are known to be beneficial
for lung and heart doses, especially for large and pendulous
breasts.[,] In the current study patients
were simulated with a breast board in a supine position
which is most commonly used for WBRT therefore the
results were considered to be useful for many radiotherapy
centers.
AP-Dnotch, AP-Dxiphi, Rnotch, Rxiphi and LR-Ddiff were
negatively correlated with the ipsilateral lung doses
and the only parameter that was positively correlated
was APDdiff. The best-correlated parameters were
Rnotch and APDdiff (p≤0.001). Although the p values are
≤0.001 the correlation coefficients are between 0.330-
0.356; which indicates the power of the study.[]
Consequently, one would have a risk of high ipsilateral
lung doses in WBRT if the anatomical parameters
are as AP-Dnotch<17.5cm, AP-Dxiphi<23.5cm,
Rnotch<0.91cm, Rxiphi<0.86cm, APDdiff>1.95cm, and
LRDdiff<6.96cm.
The volumes of ipsilateral lung or treated breast were
not statistically significantly correlated with the ipsilateral
lung doses (p=0.111-0.229). The volumetric parameters
could be calculated by the treatment planning
system (TPS) after delineation by a radiation oncologist.
Our hypothesis of predicting ipsilateral lung doses before
RT procedures was realized as the linear parameters
measured on CT scans are predictive but the volume parameters
measured after delineation are non-predictive.
The underlying logic of the geometrical relationship
of the lung dose parameters, which are negatively correlated
to Rnotch and Rxiphi but positively correlated to APD-diff, is shown in Figure 2 and Figure 3, respectively.
Since Rnotch is the ratio of AP-Dnotch (Fig.2a and
Fig.2b green line) to LR-Dnotch (Fig.2a and Fig.2b yellow
line), possible changes in the parameters that make
up Rnotch, also affect lung dose parameters. The possible
differences of LR-Dnotch, which is defined for the lung
at the sternal notch level, can change the volume of the
lung irradiated by the radiation beam dramatically. The
possible two scenarios were seen in Fig. 2a and Fig. 2b
that when the treatment beam enters the body surface
with the same θ gantry angle. In the first case, if the length of the LR-Dnotch is short, a small portion of
the lung will irradiate (Fig. 2a - the shaded area with
cyan color). Oppositely, if LR-Dnotch length is longer,
a larger portion of the lung will irradiate (Fig. 2b - the
shaded area with cyan color). The obtained results with
this approach are verified that changes in Rnotch values
were found statistically significant correlated with lung
dose parameters. All these statements could be mentioned
about Rxiphi.
Fig 2: The diagram demonstrating the correlation between the ratios of anterior-posterior and left-right diameters of
thorax with lung irradiation in tangential field. Figure 2a shows a shorter left-right diameter and Figure 2b shows a
longer left-right diameter with a same anterior-posterior diameter.
On the other hand, since APDdiff is the difference
between AP-Dxiphi (Fig. 3a light green line) and AP-Dnotch (Fig. 3a pink line), variations in the parameters
that formulate APDdiff, also affect lung dose parameters.
AP-Dxiphi and AP-Dnotch values, which are used in
the calculation of APDdiff value, are associated with
the diaphragm and apex regions of the lung, respectively.
Therefore, it would be logical to approach AP-Dxiphi
and AP-Dnotch by using the width or radii of the lungs
at the diaphragm and apex, respectively (Fig.3a). It can
be said that the shape of the human lung resembles the
cones the most as a geometric shape.. Since the volume
of the cone is directly proportional to the square of the
radius of the base, small alterations in the radius of the
base have a big effect on the volume changes. As seen
from Fig. 3b (beam eye view of breast treatment planning)
the effect of length changes in the radius r2 on
the change in lung volume, will be much greater than
the effect on the change in lung volume as a result of
length changes in the radius r1. To be more precise, the
rise in the subtraction of r2-r1 value will increase the
lung dose parameters as it will increase the net lung
volume covered by the radiation beam. In this study,
calculations were made by using the AP-Dxiphi and APD
notch values that adjacent to the r1 and r2 radius values,
respectively. As a result of these findings, changes in
lung dose parameters were found statistically significant
with the APDdiff value.
Fig 3: The digitally reconstructed radiograms showing the effect of difference between anterior-posterior diameters of
thorax (APDdiff) on the irradiated lung volume. Figure 3a shows the AP diameters at the level of sternal notch and
xiphisternal joint; figure 3b is the beam eyes view of the tangential field.
Conclusion
This is the first study that is evaluating the correlation
between the patients" anatomical features and the ipsilateral
lung doses in WBRT. AP-Dnotch, AP-Dxiphi, Rnotch,
Rxiphi, AP-Ddiff, LR-Ddiff were identified as significantly
correlated with the high ipsilateral lung doses and the
cut-off values with best sensitivity and specificity were
denoted. If the patient is evaluated with these parameters
before RT planning and in case the ipsilateral
lung dose is predicted to be over average; WBRT may
be considered to be performed by arc therapy, not with
tangential fields. Further studies are needed to specify
more sensitive and specific cut-off values or some formulas
in order to high lung dose risk assessment in
tangential breast RT.
Peer-review: Externally peer-reviewed.
Conflict of Interest: The authors declare that they have no
conflict of interest.
Ethics Committee Approval: This study was approved by
the Süleyman Demirel University Faculty of Medicine Clinical
Research Ethics Committee (no. 378, date: 23.12.2019).
Financial Support: Financial and material support was not
received.
Authorship contributions: Concept - Z.A.K., A.O.; Design
- Z.A.K.; Supervision - Z.A.K.; Materials - Z.A.K.,
A.O.; Data collection &/or processing - Z.A.K., A.O.; Analysis
and/or interpretation - Z.A.K.; Literature search - Z.A.K.;
Writing - Z.A.K., A.O.; Critical review - Z.A.K., A.O.
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