Introduction
According to the Global Cancer Observatory (GLOBOCAN)
2022, breast cancer is the prevailing form of
cancer among women globally.[] Despite advances in
the modalities of management, it remains the leading
cause of cancer-related death in women.[]
Synchronous bilateral breast cancer (SBBC) is defined
as two malignant tumors identified within 6
months, one in each breast.[-] This unusual disease
affects 1-3.5% of all breast cancer (BC) patients.[]
However, it has not yet been proven that SBBC has a
worse prognosis than unilateral breast cancer. Some
studies found that synchronous bilaterality was not
an independent predictive risk factor in multivariate
analysis compared with unilateral breast cancer.[,]
SBBC occurs more frequently in younger patients and
presents unique challenges, especially in radiation
treatment planning. The treatment planning and dose
delivery of SBBC are significantly more difficult and
time-consuming than unilateral breast cancer radiation
treatment planning due to the large radiation field,
the complex anatomy, and the difficulty in achieving
organ sparing, especially for the heart and lungs.[]
Three-dimensional conformal radiotherapy
(3DCRT) tangent field configuration is a common
treatment approach for SBBC.[,] However, this
may be associated with lesser organ sparing and lead
to field overlaps.[] To overcome these difficulties
and preserve normal tissues, especially in complicated
situations such as SBBC, advanced treatment
planning including intensity-modulated radiotherapy
(IMRT) and volumetric modulated arc therapy
(VMAT) have been developed.[-]
Improvements in technology have significantly enhanced
the efficiency of radiation therapy planning and
delivery. RapidArc is a method that uses volumetric
modulated arc treatment (VMAT) to generate modulated
radiation beams by adjusting three parameters at
once: the multileaf collimator (MLC) field aperture, dose
rate, and gantry rotation speed. The main goal of VMAT
treatment is to provide highly conformal radiation distributions
while optimizing treatment and minimizing
dose to the organs at risk (OARs), thereby improving
treatment outcomes.[] Studies by Popescu et al.,[]
Zhang et al.,[] and Zhao et al.[] have shown that
VMAT treatment techniques are suitable for unilateral
breast cancer and reduce the dose to the ipsilateral lung,
heart, and contralateral breast/lung compared to IMRT.
Advances in radiation technology have also been
made with the Varian TrueBeam linear accelerator.
This cutting-edge technology offers both flattened and
flattening filter-free (FFF) beams, with the FFF beams
providing advantages such as lower scatter, higher dose
rates, and improved beam-on time (BOT) for better
treatment outcomes.[,] However, the lack of research
on the effectiveness of FFF radiation in SBBC
treatment highlights the need for further research in
this area. The purpose of this study is to evaluate the
dosimetric parameters, including radiobiological assessment
(NTCP for lungs and heart), in treatment
plans with 6X_FF and 6X_FFF beams.
Methods
Patient Selection
A retrospective analysis was conducted on three patients
treated for SBBC from November 2021 to January
2023 in the Department of Radiation Oncology,
State Cancer Institute, IGIMS, Patna, Bihar. Each patient
underwent a modified radical mastectomy, chemotherapy,
and adjuvant external radiotherapy.
The characteristics of the three SBBC patients are
presented in Table 1.
Table 1 Patients characteristics of the three SBBC cases
CT Simulation and Contouring
The patients were positioned in a supine position with
their arms raised above their heads using a breast
board and a thermoplastic mask to immobilize them.
CT scans were taken with a slice thickness of 2.5 mm
using a Revolution EVO scanner from GE Healthcare
while the patients were free-breathing.
The CT images in DICOM format were imported
into the Eclipse treatment planning system (version
16.1, Varian Medical Systems, USA) for detailed analysis
and contouring. Contouring of all targets and OAR
structures was performed by a single radiation oncologist
according to ESTRO[] and RTOG (Radiation
Therapy Oncology Group contouring atlas group)
recommendations.[] Planning target volume (PTV)
margins given to the chest wall clinical target volume
(CTV) were 10 mm in anterior, lateral, and supero-inferior
directions, with only 5 mm in posterior and medial
directions. The CTV supraclavicular fossa (SCF)
was given a 5 mm margin symmetrically. The organs
at risk (OARs) contoured included the left and right
lungs, heart, left anterior descending (LAD) artery,
esophagus, thyroid, and spinal cord.
Treatment Planning
All treatment plans were created on Eclipse TPS (Varian
Medical Systems, Palo Alto, CA, USA), version 16.1, using the Anisotropic Analytical Algorithm (AAA) for
dose calculation. To ensure consistency in dose, dose
limits, and inverse optimization parameters of the
TrueBeam linear accelerator with the Millennium 120
multileaf collimator (MLC), the Photon Optimization
(PO) algorithm was employed to optimize the 6X_FF
and 6X_FFF plans. The prescribed dose for all patients
was 50 Gy in 25 fractions, with each fraction delivering
2 Gy over a period of five weeks.
Retrospectively, VMAT plans were designed for
all selected patients with 6X_FF and 6X_FFF beams
at a dose rate of 600 MU/min and 1400 MU/min. A
total of six treatment plans were used for three patients
in this study. For plan creation, each plan was
created using two isocenters with a total of ten coplanar
partial arcs evenly divided, with five arcs at each
isocenter, as shown in Figure 1.
Fig. 1. The isodose distribution of (a) 6X_FF VMAT and (6) 6X_FFF VMAT plans of SBBC.
VMAT: Volumetric modulated arc; SBBC: Synchronous bilateral breast cancer.
For the right-sided target volume, five partial arcs of
50°-319°, 279°-195°, 195°-279°, 29°-195°, and 319°-55°
with collimator angles of 345°, 17°, 10°, 350°, and 5° were used. For the left-sided target volume, 310°-41°, 81°-
160°, 331°-160°, 160°-81°, and 41°-310° with collimator
angles of 17°, 343°, 80°, 357°, and 3° were used to design
both types of competing treatment plans, respectively.
To ensure fairness, the VMAT treatment plan using
6X_FFF was created with the same planning and optimization
parameters as the VMAT plan using a 6X_FF
photon beam. The dose was adjusted to ensure that
95% of the PTV received the prescribed amount while
keeping the PTV below 107% of the prescribed dose.
During the optimization of the treatment plan, these
constraints were applied to the OARs: heart mean dose
≤6 Gy, V30 ≤12%, V5 ≤20%; mean dose of both lungs
≤15 Gy, V5Gy ≤65%, V10Gy ≤40%, V20Gy ≤30%,
V30Gy ≤15%; mean LAD ≤25 Gy, esophagus mean dose
<20 Gy, and the maximum spinal cord dose ≤45 Gy.
Treatment Plan Evaluation
Cumulative dose-volume histograms (DVHs) were
used to evaluate the dosimetric parameters for each plan. Key metrics were examined for PTV, including
mean dose (Dmean), V105%, V107%, D98%, and V95%
(percentage of volume receiving at least 95% of the required
dose). Target coverage was reported as V95% of
PTV. HI was calculated using the following equation:
HI=(D2% - D98%)/D50%
Where D2%, D98%, and D50% denote the doses
corresponding to 2%, 98%, and 50% of the PTV volume,
respectively.[]
CI was calculated based on the reference dose of the
prescription dose to PTV using the following equation:
CI=Vref/TV
Where Vref denotes the total volume of all areas
surrounded by the reference isodose (reference isodose
= 95%) on the body, and TV denotes the physical
volume of the PTV. A CI of 1 corresponds to an ideal
conformation. A CI greater than 1 indicates that the
irradiated volume is larger than the target volume and
includes healthy tissue. If the CI is less than 1, the target
volume is only partially irradiated.[]
Radiobiological Assessment
In the Eclipse treatment planning system, two models?
Poisson LQ and Lyman-Kutcher-Berman?are used for
radiobiological assessment of NTCP values for lungs
and heart. The NTCP from DVH data of the Lyman-
Kutcher-Berman model was used to calculate the NTCP
for radiation-induced pneumonitis, grade ≥ 2, in the
lungs (D50=30.80 Gy, α/β=3, n=0.99, and m=0.37[]);
symptomatic pneumonitis ≤ 6 months in lungs (D50=21
Gy, α/α=3, n=1.02, and m=0.26), and symptomatic fibrosis
> 6 months in the lungs (D50=25 Gy, α/α=3,
n=0.15, and m=0.85[]). The Poisson-LQ model was
used to calculate the NTCP for radiation-induced mortality
in the heart (D50=52.4 Gy, seriality (s)=1.0, α/α=3,
and γ=1.3[]) and NTCP for radiation-induced pneumonitis
(D50=34.00 Gy, s=0.06, α/α=3, and γ=0.9[]).
For OARs, the lungs, heart, LAD, esophagus, thyroid,
and spinal cord were subjected to mean and
maximum dose analysis, along with a set of appropriate
Vx (Gy) values. Furthermore, the treatment
parameters, including the monitor units (MU) and
beam-on time (BOT), for each treatment plan were
documented for evaluation purposes. BOT, defined
as the radiation delivery time, excluded patient positioning
and imaging procedures.
Statistical Analysis
The collected data were entered into Microsoft Excel
and analyzed using SPSS 26.0 software. Continuous
variables were expressed as mean and standard deviation (SD). A non-parametric test, Mann-Whitney U
test, was computed to compare two groups (6MV_FF
RapidArc and 6MV_FFF RapidArc). A p-value less
than 0.05 was considered statistically significant.
Results
To compare the 6X_FF and 6X_FFF VMAT treatment
plans, the dosimetric characteristics and OAR dose
were evaluated, along with the radiobiological evaluation
of the NTCP value of the OARs analysis using the
DVH. All patients" means and standard deviations for
each assessment parameter were provided.
Figures 1a and 1b show the color wash isodose line
distributions from the maximum PTV dose to the
20% line for the 6X_FF VMAT plan and the 6X_FFF
VMAT plan, respectively. Dose-volume histograms
(DVH) for target volumes and OARs in both plans are
shown in Figure 2.
Fig. 2. The dose volume histogram showing both the target volumes and OAR of both techniques.
OAR: Organ-at-risk.
Dosimetric Parameters Related to PTV
Table 2 shows the comprehensive assessment of the dosimetric
properties of PTV along with the corresponding
p-values. When both techniques were compared,
no significant difference was found in the maximum
dose, mean dose, D98%, and V107% within the two
PTVs (p>0.05).
Table 2 The dosimetric results for the clinical target volume (PTV) in 6X_FF VMAT& 6X_FFF
VMAT plan
The left and right PTV mean of the volume receiving
105% of the prescribed dose (V105%) in the 6X_FF
VMAT plan was 10.1 cc, 3.31% higher than the 3.05%,
1.50% in the 6X_FFF VMAT plan. Additionally, there
was a statistically insignificant variation in the homogeneity
index (HI) values for both PTVs (p>0.05).
Moreover, the conformity index showed a statistically
significant increase in the 6X_FF VMAT (0.984 ±
0.008) when compared to the 6X_FFF VMAT (0.955 ±
0.036) in the right-sided PTV (p=0.050).
Total MUs and BOT were collected and analyzed.
The VMAT plans utilizing 6X_FFF had a higher requirement
for MUs and demonstrated a statistically
significant decrease in BOT compared to the 6X_FF
VMAT plan, with a p-value of 0.050.
Dosimetric Parameters Related to OARs
Table 3 provides a statistical analysis comparing dosimetric
parameters for OARs between the two treatment
plans.
Table 3 The dosimetric parameters for organ-at-risk (OAR) in 6X_ FF VMAT& 6X_ FFF VMAT
plan
Left Lung Dose Analysis
When comparing the mean lung dose (Dmean), V5Gy,
V10Gy, V20Gy, and V30Gy (14.70 Gy, 68%, 40.99%, 26.03%, and 18.5%) in the 6X_FF VMAT plan with the
6X_FFF VMAT plan, no statistically significant difference
was found. The value was lower (13.98 Gy, 66.9%,
38.13%, 23.47%, and 17.07%) compared to the 6X_FF
VMAT plan (p>0.05).
Right Lung Dose Analysis
The analysis for the right lung revealed a similar result.
A statistically insignificant difference was found
in the Dmean, V5Gy, V10Gy, V20Gy, and V30Gy in
the 6X_FF VMAT plan (14.98 Gy, 66.1%, 42.7%,
27.47%, and 19.63%) compared to the 6X_FFF
VMAT plan (14.63 Gy, 65.93%, 40.43%, 25.97%, and
18.57%) (p>0.05).
Both Lungs Dose Analysis
Analyzing both lungs together, lower values were
found in the 6X_FFF VMAT plan for Dmean, V5Gy,
V10Gy, V20Gy, and V30Gy with 14.35 Gy, 66.33%,
39.4%, 25.37%, and 18.57% when compared to
the 6X_FF VMAT plan (14.86 Gy, 66.9%, 42.13%,
26.87%, and 19.1%). These values are statistically not
significant (p>0.05). Regarding the 6X_FF VMAT
plan, the overall results were slightly better with the
6X_FFF VMAT plan.
Heart and LAD Dose Analysis
The mean cardiac doses were found to be approximately
the same for each technique. The mean cardiac
dose was 5.30 Gy and 5.31 Gy, respectively, for both
planning techniques. The volume doses to the heart
in V5Gy, V10Gy, V20Gy, and V30Gy in the 6X_FF
VMAT plan (23.5%, 9.47%, 4.17%, and 1.74%) were
slightly higher than in the 6X_FFF VMAT plan (22.8%,
9.63%, 4.47%, and 2.10%) (p>0.05). Likewise, the maximum
and mean LAD doses for the 6X_FF VMAT plan
were higher at 8.88 Gy and 5.58 Gy than at 7.12 Gy and
4.79 Gy, but there was no significant difference.
Spinal Cord, Thyroid, Esophagus Dose Analysis
The maximum doses in the esophagus, thyroid, and
spinal cord were higher in the 6X_FF plan. Although
the mean dose of the thyroid in the two plans was similar,
there was no statistically significant difference.
Radiobiological Assessment of OARs
Table 4 shows the comparison of the normal tissue complication
probability (NTCP) model (Poisson-LQ and Lyman-
Kutcher-Berman) outcomes for 6X_FF and 6X_FFF
VMAT plans across various OARs and endpoints. By utilizing
the Poisson-linear quadratic (Poisson-LQ) model, we found that the mean mortality risk for the heart was
similar between the two techniques, with a value of
0.19±0.18 for 6X_FF RapidArc and 0.18±0.17 for 6X_FFF
RapidArc (p=0.658). Similarly, when assessing the risk of
pneumonitis for the lungs, we observed comparable results,
with values of 2.47±1.88 for 6X_FF RapidArc and
2.16±2.08 for 6X_FFF RapidArc (p=0.268).
Table 4 NTCP mean value in both VMAT plan with endpoints for Heart &Lungs
Furthermore, the Lyman-Kutcher-Berman model
analysis revealed no significant differences in the risk of
grade ≥2 pneumonitis (5.76±2.44 for 6X_FF RapidArc
and 5.25±2.80 for 6X_FFF RapidArc, p=0.275), symptomatic
pneumonitis within six months (6.84±5.77 for
6X_FF RapidArc and 6.00±6.31 for 6X_FFF RapidArc,
p=0.275), or symptomatic fibrosis after six months
(65.25±4.25 for 6X_FF RapidArc and 64.43±4.30 for
6X_FFF RapidArc, p=0.275).
Discussion
Our study showed no statistical difference in the dosimetric
parameters between both treatment planning methods. The use of FFF photon beams to implement
SBBC treatment plans aims to increase the effectiveness
and precision of radiation therapy. In this study,
we found that the 6X_FFF treatment plan has similar
PTV coverage, CI, and HI value as 6X_FF RapidArc,
as depicted in Figures 1, 2, and Table 2. Previous publications[,] evaluated the dosimetric parameters of
different methods based on 3DCRT, IMRT, and VMAT
for SBBC patients. Table 5 shows that few studies have
investigated the dosimetric parameters of VMAT for
SBBC with 6X_FF and 6X_FFF. Our study differed from
others in the use of five arcs instead of only two or three.
Techniques such as VMAT or IMRT promise a
more even distribution of radiation doses across the
lung volume, with dose limitations for V5, V10, and
V15 correlating with the incidence of symptomatic
radiation pneumonitis (RP)[] and subsequent pulmonary
fibrosis.[] A V5 value of less than 65% is
aimed to mitigate the risk of RP.
Based on previously published work,[-] to reduce
the risk of severe pulmonary toxicity for bilateral breast radiation and locally advanced BC, the threshold
value of the mean lung dose (MLD) is limited to below
12-15 Gy and V20Gy > 30% without sacrificing the necessary
RT field coverage. A published study by Karlsen et
al.[] found that MLD was associated with an increased
risk of radiation pneumonitis (RP) and radiation fibrosis
(RF). Specifically, they found that the chance of RP increased
by 12% for every 1 Gy increase in MLD.
In our present study, the reduction of MLD to both
lungs from 4.42% lower in the FFF VMAT plan remained
within acceptable thresholds. For the 6X_FFF
VMAT plan, a reduction in both lung mean doses was
found to be 3.8% compared to the 6X_FF VMAT plan.
In a previous published work,[] it was found that
for each percentage increase in V20, there was a 6%
higher occurrence of RP. In our current research, we observed a decrease of 16.73% in the V20 Gy of the 6X_FFF
VMAT plan, while the 6X_FF VMAT plan decreased by
10.99%. Both reductions are within the acceptable limit.
Concerning V10Gy, we observed a decrease of 6.5% in
our 6X_FFF VMAT plan compared to the acceptable
plan limit, as well as 7.57% according to Wu et al.[]
In our present study, we found a reduction in lung volume
at V30Gy of 4.44% in the 6X_FFF VMAT plan compared
to the 6X_FF VMAT plan. Published work by Vogelius
& Bentzen[] observed that for every 1% increase
in V30Gy, there was an incremental risk of 10% for RP.
As can be seen in Figure 3a, our current study reveals
that the V5Gy in the 6X_FFF VMAT is 66.3% and
66.9% in the 6X_FF VMAT plan. These results are 2.9%
higher in the 6X_FF VMAT plan and slightly higher
than the acceptable limit of 2% in the 6X_FFF VMAT
plan. As indicated in Table 5, the current V5Gy result is
lower than that of earlier published work.
Fig. 3. (a) Volume doses of lungs and hearts between
6X_FF and 6X_FFF VMAT plan. (b) NTCP values
for lungs in both model between 6X_FF and
6X_ FFF. (c) NTCP value for Poission-LQ model
between 6X_FF and 6X_FFF.
OAR: Organ-at-risk; NTCP: Normal tissue complication
probability; VMAT: Volumetric modulated arc.
Not reported in other studies in the past, we conducted
an NTCP assessment, which is not utilized directly
in assessing radiotherapy plans at present, but
it may be a crucial tool for comparing such plans and
methods. NTCP analysis aids in discovering novel approaches
to reduce complication rates caused by radiotherapy.[] The NTCP values of OARs, including both
lungs and heart, comparing the 6X_FF VMAT with 6X_
FFF VMAT are shown in Table 4and Figures 3a, 3b, and
3c. The 6X_FFF VMAT plans demonstrate a reduction
in these parameters of 13.39% (pneumonitis), 10.18%
(pneumonitis grade ?2), 13.08% (symptomatic pneumonitis
(?6 months)), and 1.26% (symptomatic fibrosis
>6 months) compared to the 6X_FF VMAT plans. Both
radiotherapy techniques demonstrate statistically similar
NTCP outcomes for the heart and lungs across the
evaluated endpoints, based on the findings.
Darby et al.[] reported in a population-based
case-control study of major coronary events that they
underestimated standard radiotherapy for unilateral
breast cancer, reporting that a mean cardiac dose of 3-4 Gy was an acceptable value and that the frequency
of major coronary events increased linearly with a cardiac
mean dose increase of 7.4% per 1 Gy. The study by
Cho et al.[] reported that a median cardiac dose of 5
Gy was acceptable for SBBC patients with 50 Gy in 25
fractions delivered to the PTV breast and is consistent
with other cardiac toxicity studies. Similarly, according
to Bergom et al.,[] trials have found that a mean
dose to the heart of 3-5 Gy is considered acceptable for
treatment planning of breast cancer radiation therapy.
Our study results show the advantage of five partial
arcs on each side with dual isocenters for SBBC
patients, finding that the mean cardiac dose of about
5.31 Gy is only 0.19% higher in FFF plans compared to
6X_FF plans. This is lower than the findings of Wu et
al.,[] Nagaraj & Veluraja,[38] Tamilarasu et al.,[]
and Cho et al.,[] as shown in Table 5. Fiorentino et
al.[] published a study of 50 Gy in 25 fractions of
VMAT treatment administered to 16 women with
SBBC. Their reported average cardiac Dmean was 8.3±3.3
Gy. Furthermore, our study results showed that V10Gy
was 9.47% in the 6X_FF VMAT plan and 9.63% in the
6X_FFF plan, which was lower than the findings of Nagaraj
& Veluraj.:[] 77.59% in the 6X_FF VMAT plan
and 78.23% in the 6X_FFF plan. Details of the study
are shown in Table 5. In addition, the biological evaluation
based on the NTCP value of the heart with cardiac
mortality can be seen in Table 4, and Figure 3c shows
that the NTCP value of the heart for 6X_FFF VMAT
was 5.26% lower than that for the 6X_FF VMAT plan.
Table 5 Literature review summary on synchronous bilateral breast cancer (SBBC) with focus on lung and heart doses
This research highlights the importance of tailoring
strategies to specific situations due to the variability in
dosimetric outcomes among different treatment methods.
The potential use of 6X_FFF and DIBH radiation
in clinical settings could potentially lower pulmonary
and cardiac doses for patients undergoing treatment.
However, it is important to recognize the limitations
of this study. Notably, the current study included
only three patients.
Conclusion
For SBBC patients, the 6X_FFF photon beams provide
a radiation treatment plan that is both dosimetrically
acceptable and has an insignificant dose difference in
target coverage compared to 6X_FF VMAT plans. In
addition, patients treated with a 6X_FFF photon beam
demonstrate improved OAR sparing, improving patients"
quality of life by reducing the risk of lung and
heart complications. Thus, the FFF photon beam can
be used effectively for SBBC treatment planning.
Ethics Committee Approval: The study was approved by
the Indira Gandhi Institute of Medical Sciences Ethics Committee
(no: 1225/IEC/IGIMS/2023, date: 05/10/2023).
Authorship contributions: Concept - D.P., M.Z., R.M.,
K.K., S.R.; Design - D.P., M.Z., S.R.; Supervision - M.Z.,
K.K.; Data collection and/or processing - D.P., M.Z., R.M.;
Data analysis and/or interpretation - D.P., M.Z., S.D.; Literature
search - M.Z., D.P., S.R.; Writing - M.Z., D.P., K.K.;
Critical review - D.S., R.S., M.Z., D.P.
Conflict of Interest: All authors declared no conflict of interest.
Use of AI for Writing Assistance: No AI technologies utilized.
Financial Support: None declared.
Peer-review: Externally peer-reviewed.
References
Ferlay J, Laversanne M, Ervik M, Lam F, Colombet
M, Mery L, et al. Global Cancer Observatory: Cancer
Tomorrow (version 1.1). Lyon, France: International
Agency for Research on Cancer.
Arnold M, Rutherford MJ, Bardot A, Ferlay J, Andersson
TM, Myklebust TÅ, et al. Progress in cancer survival,
mortality, and incidence in seven high-income countries
1995?2014 (ICBP SURVMARK-2): A population-based
study. Lancet Oncol 2019;20(11):1493-505.
Heron DE, Komarnicky LT, Hyslop T, Schwartz GF,
Mansfield CM. Bilateral breast carcinoma: Risk factors
and outcomes for patients with synchronous and
metachronous disease. Cancer 2000;88(12):2739-50.
Kheirelseid EA, Jumustafa H, Miller N, Curran C,
Sweeney K, Malone C, et al. Bilateral breast cancer:
Analysis of incidence, outcome, survival and
disease characteristics. Breast Cancer Res Treat
2011;126(1):131-40.
Gogas J, Markopoulos C, Skandalakis P, Gogas H. Bilateral
breast cancer. Am Surg 1993;59(11):733-5.
Fiorentino A, Mazzola R, Naccarato S, Giaj-Levra
N, Fersino S, Sicignano G, et al. Synchronous bilateral
breast cancer irradiation: Clinical and dosimetrical
issues using volumetric modulated arc therapy
and simultaneous integrated boost. Radiol Med
2017;122(6):464-71.
Schubert LK, Gondi V, Sengbusch E, Westerly DC,
Soisson ET, Paliwal BR, et al. Dosimetric comparison
of left-sided whole breast irradiation with 3DCRT,
forward-planned IMRT, inverse-planned IMRT, helical
tomotherapy, and topotherapy. Radiother Oncol
2011;100(2):241-6.
Yamauchi C, Mitsumori M, Nagata Y, Kokubo M,
Inamoto T, Mise K, et al. Bilateral breast-conserving therapy for bilateral breast cancer: results and
consideration of radiation technique. Breast Cancer
2005;12(2):135-9.
Fung MC, Schultz DJ, Solin LJ. Early-stage bilateral
breast cancer treated with breast-conserving surgery
and definitive irradiation: The University of Pennsylvania
experience. Int J Radiat Oncol Biol Phys
1997;38(5):959-67.
Thilmann C, Zabel A, Kuhn S, Bendl R, Rhein B, Wannenmacher
M, et al. Inversely planned intensity modulated
radiotherapy for irradiation of a woman with
breast cancer and funnel chest. Strahlenther Onkol
[Article in German] 2002;178(11):637-43.
Seppala J, Heikkila J, Myllyoja K. Volumetric modulated
arc therapy for synchronous bilateral whole
breast irradiation - A case study. Rep Pract Oncol Radiother
2015;20(5):398-402.
Nicolini G, Clivio A, Fogliata A, Vanetti E, Cozzi
L. Simultaneous integrated boost radiotherapy for
bilateral breast: A treatment planning and dosimetric
comparison for volumetric modulated arc and
fixed field intensity modulated therapy. Radiat Oncol
2009;4:27.
Kim SJ, Lee MJ, Youn SM. Radiation therapy of synchronous
bilateral breast carcinoma (SBBC) using
multiple techniques. Med Dosim 2018;43(1):55-68.
Balasubramanian S, Shobana MK. A dosimetric and
radiobiological comparison of intensity modulated
radiotherapy, volumetric modulated arc therapy and
helical tomotherapy planning techniques in synchronous
bilateral breast cancer. Asian Pac J Cancer Prev
2022;23(12):4233-41.
Teoh M, Clark CH, Wood K, Whitaker S. Volumetric
modulated arc therapy: A review of current
literature and clinical use in practice. Br J Radiol
2011;84(1007):967-96.
Popescu CC, Olivotto IA, Beckham WA, Ansbacher W,
Zavgorodni S, Shaffer R, et al. Volumetric modulated
arc therapy improves dosimetry and reduces treatment
time compared to conventional intensity-modulated
radiotherapy for locoregional radiotherapy of
left-sided breast cancer and internal mammary nodes.
Int J Radiat Oncol Biol Phys 2010;76(1):287-95.
Zhang Q, Yu XL, Hu WG, Chen JY, Wang JZ, Ye JS, et
al. Dosimetric comparison for volumetric modulated
arc therapy and intensity-modulated radiotherapy on
the left-sided chest wall and internal mammary nodes
irradiation in treating post-mastectomy breast cancer.
Radiol Oncol 2015;49(1):91-8.
Zhao LR, Zhou YB, Sun JG. Comparison of plan optimization
for single and dual volumetric-modulated
arc therapy versus intensity-modulated radiation therapy
during post-mastectomy regional irradiation. Oncol
Lett 2016;11(5):3389-94.
Yan Y, Yadav P, Bassetti M, Du K, Saenz D, Harari P, et al.
Dosimetric differences in flattened and flattening filterfree
beam treatment plans. J Med Phys 2016;41(2):92-9.
Sun WZ, Chen L, Yang X, Wang B, Deng XW, Huang
XY. Comparison of treatment plan quality of VMAT
for esophageal carcinoma with: Flattening filter
beam versus flattening filter free beam. J Cancer.
2018;9(18):3263-68.
Offersen BV, Boersma LJ, Kirkove C, Hol S, Aznar MC,
Biete Sola A, et al. ESTRO consensus guideline on target
volume delineation for elective radiation therapy
of early-stage breast cancer, version 1.1. Radiother Oncol
2016;118(1):205-8.
Radiation Therapy Oncology Group (RTOG). Contouring
Atlases: Breast Cancer Atlas. Available at:
https://www.rtog.org/CoreLab/ContouringAtlases/
BreastCancerAtlas.asp. Accessed Apr 8, 2018.
Hodapp N. The ICRU Report 83: prescribing, recording
and reporting photon-beam intensity-modulated
radiation therapy (IMRT). Strahlenther Onkol [Article
in German] 2012;188(1):97-9.
Feuvret L, Noël G, Mazeron JJ, Bey P. Conformity
index: A review. Int J Radiat Oncol Biol Phys
2006;64(2):333-42.
Seppenwoolde Y, Lebesque JV, de Jaeger K, Belderbos
JS, Boersma LJ, Schilstra C, et al. Comparing different
NTCP models that predict the incidence of radiation
pneumonitis. Normal tissue complication probability.
Int J Radiat Oncol Biol Phys 2003;55(3):724-35.
Moiseenko V, Craig T, Bezjak A, Van Dyk J. Dose-volume
analysis of lung complications in the radiation
treatment of malignant thymoma: A retrospective review.
Radiother Oncol 2003;67(3):265-74.
Gagliardi G, Lax I, Ottolenghi A, Rutqvist LE. Longterm
cardiac mortality after radiotherapy of breast
cancer - application of the relative seriality model. Br J
Radiol 1996;69(825):839-46.
Salim N, Popodko A, Tumanova K, Stolbovoy A,
Lagkueva I, Ragimov V. Cardiac dose in the treatment
of synchronous bilateral breast cancer patients between
three different radiotherapy techniques (VMAT,
IMRT, and 3D CRT). Discov Onc 2023;14:29.
Balaji K, Ramasubramanian V. hypofractionated
hybrid radiotherapy techniques for synchronous
bilateral breast cancer. Asian Pac J Cancer Prev
2021;22(12):3933-39.
Lind PA, Marks LB, Jamieson TA, Carter DL. Predictors
for pneumonitis during locoregional radiotherapy
in high-risk patients with breast carcinoma treated
with high-dose chemotherapy and stem-cell rescue.
Cancer 2002;94(11):2821-29.
Jo IY, Kay CS, Kim JY, Son SH. Significance of lowdose
radiation distribution in development of radiation
pneumonitis after helical-tomotherapy-based
hypofractionated radiotherapy for pulmonary metastases.
J Radiat Res 2014;55(1):105-12.
Gokula K, Earnest A, Wong LC. Meta-analysis of incidence
of early lung toxicity in 3-dimensional conformal
irradiation of breast carcinomas. Radiat Oncol
2013;8:268.
Lind PA, Wennberg B, Gagliardi G, Fornander T. Pulmonary
complications following different radiotherapy
techniques for breast cancer, and the association
to irradiated lung volume and dose. Breast Cancer Res
Treat 2001;68(3):199-210.
Kahán Z, Csenki M, Varga Z, Szil E, Cserháti A, Balogh
A, et al. The risk of early and late lung sequelae after
conformal radiotherapy in breast cancer patients. Int J
Radiat Oncol Biol Phys 2007;68(3):673-81.
Karlsen J, Tandstad T, Sowa P, Salvesen Ø, Stenehjem
JS, Lundgren S, et al. Pneumonitis and fibrosis after
breast cancer radiotherapy: Occurrence and treatment-
related predictors. Acta Oncol 2021;60(12):1651-58.
Wu X, Huang J, Lin X, Zhang X, Lu H, Sun W, et al.
Dosimetric comparison of postmastectomy radiotherapy
plans for synchronous bilateral breast cancer,
including regional lymph node irradiation. Technol
Cancer Res Treat 2023;22:15330338231214449.
Vogelius IR, Bentzen SM. A literature-based metaanalysis
of clinical risk factors for development
of radiation induced pneumonitis. Acta Oncol
2012;51(8):975-83.
Nagaraj J, Veluraja K. Is synchronous bilateral breast
irradiation using flattening filter-free beam-based volumetric-
modulated arc therapy beneficial? A Dosimetric
Study. J Med Phys 2020;45(4):226-33.
Darby SC, Ewertz M, McGale P, Bennet AM, Blom-
Goldman U, Brønnum D, et al. Risk of ischemic heart
disease in women after radiotherapy for breast cancer.
N Engl J Med 2013;368:987-98.
Cho Y, Cho YJ, Chang WS, Kim JW, Choi WH, Lee
IJ. Evaluation of optimal treatment planning for radiotherapy
of synchronous bilateral breast cancer including
regional lymph node irradiation. Radiat Oncol
2019;14(1):56.
Bergom C, Bradley JA, Ng AK, Samson P, Robinson C,
Lopez-Mattei J, et al. Past, present, and future of radiation-
induced cardiotoxicity: Refinements in targeting,
surveillance, and risk stratification. JACC Cardiooncol
2021;3(3):343-59.
Tamilarasu S, Saminathan M, Sharma SK, Dewan A.
Treatment planning with unflattened as compared to
flattened beams for bilateral carcinoma of the breast.
Asian Pac J Cancer Prev 2017;18(5):1377-81.
Fiorentino A, Mazzola R, Naccarato S, Giaj-Levra
N, Fersino S, Sicignano G, et al. Synchronous bilateral
breast cancer irradiation: Clinical and dosimetrical
issues using volumetric modulated arc therapy
and simultaneous integrated boost. Radiol Med
2017;122(6):464-71.
