Introduction
Breast cancer is the most common cancer among women
worldwide.[] Radiation therapy (RT) plays an important
role in the treatment of breast cancer. A meta-analysis,
including nearly 42.000 women, showed that the local control, breast cancer-specific survival, and overall
survival could be improved using RT after mastectomy
or lumpectomy.[] Unfortunately, the same Oxford meta-
analysis also showed that using RT for breast cancer
is related to a hazard ratio pertaining to death secondary
to heart disease.[,] There have been many studies indicating that patients with breast cancer who received
RT had a higher risk of cardiac disease and/or death
compared with those treated by surgery alone.[,] Previous
studies also showed that those who were irradiated
for left-sided breast cancer had a higher risk of cardiac
disease and/or death compared with those who were
irradiated for right-sided breast cancer.[,] In some
studies, the incidence of cardiac events was low in the
first 5 years of follow-up, and it increased over time and
persisted after year 18.[,] The study by Nilssons et al
[] suggested that RT for breast cancer increases the risk
of cardiovascular diseases, including pericarditis, coronary
artery disease (CAD), conduction abnormalities,
congestive heart failure, and valvular disease. Radiation
exposure to the left-sided anterior descending coronary
artery (LAD) is a major cause of these complications.
Recent studies show that the number of patients with
heart disease after RT has now decreased compared with
that in previous decades.[] By developing technologies
(such as IMRT, breath-hold technique, and active breath
control), the risk of CAD could be reduced with the decrease
in the maximum LAD (LADmax) dose.
Field-in-Field (FIF) intensity-modulated radiotherapy
(IMRT) is presently the most commonly used
technique. Two opposed tangential fields are generally
chosen to cover the entire breast. Similar beam orientations
to 3D-CRT are utilized, but additional fields are
used to block hotspots instead of wedges to improve the
dose homogeneity. Another chosen technique is inverse
IMRT offering the ability to provide more options in the
planning process.[] It allows more homogeneous dose
distribution and low organ at risk (OAR) dose.
In this study, we aimed to evaluate various radiotherapy
treatment planning techniques and their effects on
LAD doses. For this purpose, we compared field-in-field
IMRT, 4-field inverse IMRT, and 5-field inverse IMRT
radiation doses to LAD among 45 left breast cancer patients.
During this study, we realized that if LAD is closer
than 2.5 cm from the pectoral muscle, the LADmax dose
increases irrespective of the radiotherapy technique.
Methods
Forty five consecutive left-sided early breast cancer patients
ranging from 32 to 76 years of age were examined
in this study. All the patients underwent breast-conserving
surgery and were irradiated after lumpectomy. None
of the patients were irradiated post-mastectomy. All the
patients had and outer quadrant tumor so that none of
the irradiated volumes included the inner quadrant. Immobilization
and CT simulation were performed for 45 left-sided breast cancer patients, as is routine for breast
cancer patients receiving IMRT in our department. The
patients received free-breathing CT scans. We could not
conduct 4D-CT scans for the deep-inspiration breathhold
technique; furthermore, our study was retrospective.
The treatment position was supine with breast
board. Using the simulator lasers, patients were aligned
and marked to define the coordinate system to be used
for treatment planning. The patients were scanned in
treatment position on Siemens Emotion Duo using
5-mm slice thickness. The data were transferred to the
treatment planning system (Prowess Panther DAQ). The
determination of the 45 breast cancer patient"s target
volume and critical tissues was initially done using CT
images obtained in our clinic.
After determining the critical organs, which were
the left lung, heart, LAD, and contralateral breast, three
different radiotherapy techniques, field-in-field IMRT,
4-field inverse IMRT, and 5-field IMRT, were performed.
The initial calculation of the field-in-field technique was
performed with two equally weighted, open, tangential
photon beams. Hot-spot volumes blocking two or three
subfields were determined to improve dose homogeneity
while decreasing overdoses in PTV. The main field
and the subfields were merged into one portal.
For 4-field inverse IMRT, the fields were special for
each patient. We used two opposed tangential beams
for the field-in-field technique, and for the other techniques,
beams were obtained by placing them at a 10°
refraction angle.
Finally, for the 5-field IMRT technique, we chose
300°, 330°, 30°, 120°, and 150° beam angles for optimization.
After obtaining the IMRT plans, we dosimetrically
compared the doses of OARs. We also tried to determine
the critical distance from the chest wall to LAD causing
an increase in the LADmax dose. After figuring out this
distance, we studied the doses of OAR"s smaller distances
than this critical distance.
The Statistical Package for Social Sciences (SPSS)
version 22.0 was used for statistical analysis (SPSS Inc.
Chicago, II., USA). Paired samples t-test was used for
comparisons. A p value of <0.05 was considered to be
significant.
Results
After performing the techniques for the first 5 patients,
we figured out that the 5-field inverse IMRT technique
is not useful for decreasing the LADmax dose. Ipsilateral
lung and heart LADmax doses significantly increased using the 5-field inverse IMRT technique because of the
30° field. Therefore, we decided not to use this technique
for the rest of our study.
Then, we compared doses of OARs leading to maximum
doses of LAD, 25% dose of ipsilateral lung, 5%
dose of heart, and mean dose of contralateral breast
for field-in-field IMRT and 4-field inverse IMRT techniques.
We used Quantitative Analyses of Normal Tissue
Effects in the Clinic (QUANTEC) recommendations
for dose-volume comparisons.
The doses and standard deviations (SDs) of OAR
are shown in Table 1. The mean doses of the contralateral
breast were significantly increased with inverse the
IMRT technique (p value of <0.05 for breast). There were
no significant changes in the LADmax for the ipsilateral
lung (25%) and heart (5%) with the 4-field inverse IMRT
technique (p value > 0.05).
Table 1: Doses and p values of OAR *p < 0.05, statistically
significant
Second, we figured out from our study that there is a
relation between the distance from pectoral muscle to
LAD and the LADmax dose.
As can be seen in Figure 1, if the distance from pectoral
muscle to LAD is less than 2.5 cm, the LADmax dose
could be greater than 10 Gy. In our study, 18 of our 45
patients had an LADmax dose greater than 10 Gy. Only
one of these patients had a pectoral muscle to LAD distance
greater than 2.5 cm. As a result of these findings,
we decided to perform paired sample t-test using SPSS
(between FIF and inverse IMRT) on LADmax doses in
which LAD was located not deeper than 2.5 cm. The p
value was smaller than 0.05, implying that the change in
the LADmax dose was significantly decreased by 4-field
inverse IMRT.
Fig 1: Distance versus LAD max graph. Red line shows 2.5 cm distance from the chest wall to LAD.
Our results indicated that ipsilateral lung and heart
doses were significantly decreased (p<0.05) by inverse
IMRT, while contralateral breast dose significantly increased
for the 18 patients (p<0.05) in whom the chest wall to LAD distance was greater than 2.5 cm (Table 2 ).
Table 2: Doses and p values of OAR for 18 patients having
a chest wall to LAD distance lesser than 2.5 cm
Discussion
RT plays an important role in the treatment of breast
cancer. Unfortunately, it also a dark side like secondary
heart disease. A significant increase in mortality from
heart disease, that is sustained 18 years following RT to
the left-sided breast, has been demonstrated in previous
studies.[,] The right coronary artery (RCA) and leftsided
main coronary artery (LMCA) arise from the aorta
near its root. The LMCA bifurcates into LAD artery and
the left circumflex artery. Radiation exposure of the left
is a major cause of these complications. A previous study
showed that in the event of LAD doses greater than 10
Gy, the probability of CAD increases.[] Radiation tolerance
of the coronary arteries has not been well-studied
until recently. Historically, the dose?volume histogram
(DVH) has been used for the heart as an organ.[] The
heart is a "serial-parallel" organ. Because the myocardium
is a parallel organ, small volume of the heart can
tolerate even higher dose levels. Coronary arteries are
in fact a "serial" organs like spinal cord.[] Any partial
damage to the coronary artery will cause potential
devastating toxicity even if the rest of the artery is not
irradiated. Therefore, heart DVH determinations are of
little use to estimate the risk of CAD.[] There are only
few studies that address whether RT acts additively with
known CAD risk factors such as smoking, hypercholesterolemia,
hypertension, and diabetes mellitus.[,]
In an effort to better define radiation-associated
cardiac toxicity, Darby et al. published a study in 2005
in which they compared cardiac mortality for women
who received radiation for left-sided versus right-sided
breast cancer and found that radiation for left-sided
sided breast cancer increased the risk of cardiac disease
and death.[] In 2013, Darby et al. published a casecontrolled
study analyzing the risk of major coronary
events and again found that women with left-sided sided
breast cancer had more major coronary events than
those treated for right-sided breast cancer.[] In this literature,
rates of major coronary events increased linearly
with the mean dose to the heart by 7.4% per gray (95%
confidence interval, 2.9 to 14.5; p<0.001), and the CAD
risk started within 5 years after radiotherapy and continued
into the third decade after radiotherapy.
According to a review, which collected all data from
2003 to 2013, if the treatment volume did not include
the internal mammary chain (IMC), average mean heart
dose was 4.2 Gy, and this value varied with the irradiated
target tissues. For IMRT, the mean heart dose was approximately 5.6 Gy. Where the IMC was irradiated
average mean heart dose was around 8 Gy and varied
little according to other irradiated targets.[] Jöst et al.
suggest using IMRT and volumetric modulated arc radiotherapy
(VMAT) technique together for decreasing
the heart doses.[] In our study, heart doses changed
due to different radiation treatment techniques, as can
be seen in Table 1.
In some new researches, intraoperative radiotherapy
can be used in early-stage breast cancer.[,] In these
studies LAD doses are lower than the external irradiation
doses, but Darby et al. suggest that special attention
must be given to valvular disease in this situation. In the
near future, if we continue to give external radiotherapy
to the patients, we should pay extra attention not only to
heart doses but also to LAD doses. Prone positions or
the semi-decubitus technique have been used to exclude
the heart from additional irradiation fields in many patients.[,] However, in some author series, incidental
dose to the coronary arteries is higher in prone than in
supine whole-breast irradiation.[] Respiratory gating,
which means intermittent irradiation synchronous with
the free breathing cycle and administered in the supine
position, should be further analyzed.
In our study, we have tried to determine radiation
doses among various radiotherapy treatment planning
techniques; field-in-field IMRT and inverse IMRT for
45 left-sided breast cancer patients. As can be seen in
Table 1, the mean LADmax dose was smaller than 10
Gy. There is no significant difference between 4-field inverse
IMRT and field-in-field techniques. However, the
patients" in whom the chest wall to LAD distance was
smaller than 2.5 cm, the LADmax dose was higher than
10 Gy.
Unfortunately, by reducing the LADmax dose, the
contralateral breast dose could be increased with only
the 4-field inverse IMRT technique. This is another important
point to be aware of. In our study, we investigated
whether or not the LAD doses can be reduced for
patients in whom LAD is located not deeper than 2.5 cm
using 4-field inverse IMRT. The lung and heart doses can
also be reduced using this technique.
Conclusion
Previous studies have shown that in the event of LAD
doses greater than 10 Gy, the probability of CAD is increased.
In our study, we tried to figure out radiation
doses of LAD among various radiotherapy treatment
planning techniques for 45 left breast cancer patients retrospectively.
There is no a significant difference between 4-field inverse IMRT and field-in-field IMRT. However,
we could not use the 4D irradiation technology for
breast radiotherapy. If LAD is located closer than 2.5 cm
from the pectoral muscle, the dose of LADmax could increase
and could be decreased under 10 Gy using 4-field
inverse IMRT. The lung and heart doses can also be reduced
using this technique. In conclusion, LAD doses
can be reduced with various IMRT techniques, and future
prospective studies should be conducted using the
4D breast irradiation technology.
Peer-review: Externally peer-reviewed.
Conflict of Interest: None declared.
Authorship contributions: Concept - M. A; Design - M. A;
Supervision - B. D; Materials - E. K; Data collection &/or processing
- E. K; Analysis and/or interpretation -B. D; Literature
search - A. Y; Writing - E. S; Critical review - M. A
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