1

A predictable planning method for left-sided breast cancer

Authors

ABSTRACT

Key Words:

Introduction:

Radiation therapy (RT) in the treatment of breast cancer is well documented as an
effective treatment for improving overall survival, howeverUnfortunately, this treatment has
been shown to cause negative health effects, especially for patients with disease of the left breast.
Commented [P1]: Thisintrosentencedoesnotdoagoodjobof
tellingthereaderaboutwhatthewholeparagraphisabout.After
readingthesentence,Iwouldthinkitwouldbeaboutthe
documentedeffectivenessofRTforbreastcancerbutinstead,you
focusmoreonhearteffectsfromRT.Rewordthissentence.

One of these complications is an increased risk of heart disease induced by their RT.1-3 The Commented [P2]: Nopersonalizations,onlyscientificbased
writing.
development of these cardiac morbidities depends on many factors such as dose to the heart, age
at the time of radiation treatment, and prognosis of the cancer. Aforementioned cardiac
complications often develop from the mechanism of coronary microvascular endothelial
damage brought on by substantial dose to the heart.2 Although exact dosing constraints to the
heart are not yet known, recent studies have focused on achieving a mean dose to the heart that is
< 4 Gy.4
Although there have been significant improvements in RT techniques for breast cancer, Commented [P3]: Muchbetterintrosentence!

another complication arises from excess dose to the ipsilateral lung which can often be 2 to 3
times that of the contralateral lung dose.1 Darby et al1 compared the long-term mortality ratios
between left and right sided breast patients and showed an increase in mortality from heart and
lung cancer following radiation therapy to the left-sided group. This has been replicated in
several other studies indicating significantly increased levels of secondary lung cancer in the
ipsilateral lung occurring 10-20 years post RT for breast cancer.1-5
A treatment technique designed to combat these treatment related complications is the
use of deep inspiration breath-hold (DIBH). This technique has been developedwasis designed Commented [P4]: Makesureyouarewritinginpasttense.

to elevate the chest wall so that there is a separation between the breast and adjacent organs at
risk (OR). One systematic review indicated that DIBH can decrease the mean heart dose by
approximately 3.4 Gy, resulting in a 13.6% reduction in the risk of developing heart
 2

disease.6 This result has been verified by numerous other studies, showing that DIBH is an
effective means of reducing lung and heart doses when compared to free breathing (FB)
treatments.7-9 Commented [P5]: Newparagraphheresinceyoushiftthe
paragraphfocus.
Yet, even with the published benefits of utilizing DIBH over FB for left-side breast
patients, drawbacks still exist. Deep inspiration breath-hold can be more challenging to
reproduce on a daily basis and has been shown to lead to higher contralateral breast dose.10 For
these reasons, some cancer centers tend to perform CT simulation with both FB and DIBH CT
scans with the intention of using the FB CT for planning purposes due to ease of reproducibility.
If the FB plan fails to achieve normal tissue constraints, then the plan will be recreated on the
DIBH CT in order to lower the normal tissue dose. This process creates a major decrease in
efficiency, often requiring multiple plans to be created before knowing which technique will be
used for the final treatment plan.
In order tTo help solve the problem of inefficiency, efforts have been made to find a
method for predicting which patients would benefit from using DIBH prior to creating a
treatment plan. Studies have been completed attempting to evaluate anatomical metrics from
patient CT scans to find a dependable way to determine which patients would require the use of
the DIBH technique.11,12 These studies were unsuccessful in determining a reliable anatomical
parameter that was useful and oftentimes required the addition of treatment fields.
Recently in the field of dosimetry, knowledge based treatment planning (KBP) has
become increasingly used to improve planning efficiency. RapidPlan (RP) (Varian Medical
Systems, Palo Alto, CA) is a commercially available KBP tool that provides the practitioner with
a predicted dose-volume histogram (DVH) prior to intensity modulated radiation therapy
(IMRT) optimization. In order for RP to generate a DVH, a database of previous treatment plans
for patients of a specific disease site needs to be created. RapidPlan extracts the DVH
information for assigned ORs from plans included within the database and then uses this
information for new patients by creating optimization objectives based on target and OR
geometries.
Knowledge based planning has been researched for various disease sites such as head and
neck, lungs, esophagus, spine, liver and pelvic cancers.13-18 In the majority of these studies, RP
generated quality IMRT plans with equivalent target coverage and improved organ sparing when
compared to clinically achieved IMRT plans. Due to RP being a tool for IMRT optimization,, to
 3

the knowledge of the authors no studies have been completed utilizing a database consisting of
conformal treatment plans. It wasis the objective of this study to determine if RP can be used as
a reliable prediction method to determine left-sided supine breast cancer patients that would
benefit from the DIBH technique.

Methods and Materials:

Patient Selection
All patients selected for this study were treated at the same radiation oncology clinic from
2014Stephanie Spielman Comprehensive Breast Center (SSCBC) from 2014 to present for left- Commented [P6]: Sincewearelookingtopublishthisinthe
longrun,letsremovethisidentifier.
sided breast cancer. Patients were treated in the supine position with either a FB or DIBH
technique. Depending on the stage of the disease, included patients either underwent whole
breast irradiation (WBI) of theor intact breast or chest wall treatment with irradiation of regional
lymph nodes. Regional nodal irradiation included the supraclavicular, axillary, and internal Commented [P7]: Thissentencewasconfusingtome.Itriedto
makechangesbasedonwhatIthoughtyouweresayingbutplease
mammary lymph node (IMN) groups. Patients treated with IMRT or treated in the prone rewordthesentenceentirelyifthisisnotwhatyoumeanttosay.

position were not included within the scope of this study. Commented [P8]: Good!

As part of the procedure, each patient was placed in a at the SSCBC, each patient
underwent a FB and DIBH CT scan on a Qfix breast board with their arms overhead (Figure
1). A Vvaclok bag was positioned under the left arm for further immobilization of the affected Commented [P9]: Thisnameisapropernounsocapatalize.

side (Figure 2). Once properly immobilized the patient underwent both simulation techniques
using a GE Discovery scanner with 2.5 mm axial slice thickness. For the DIBH scan, Varian
Real-Time Position Management (RPM) respiratory gating was utilized. The RPM system was
used to assess the breath hold position of the patient to create an acceptable range to be
reproduced for daily treatment.
Contouring
Following simulation, patient datasets were imported into the Eclipse treatment planning
system (TPS) for delineation of target volumes and ORs. Target volumes were contoured by the
physician as described in the Breast Cancer Atlas for Radiation Therapy Planning.19 Depending
on the patient and stage of disease, the targets that were contoured included the breast clinical
target volume (CTV) or chest wall CTV, and nodal CTVs. Breast or chest wall planning target
volumes (PTVs) were generated by expanding the CTVs by 7 mm and subtracting out the most
superficial 3 mm from the skin and any of the volume that extended into the lungs, thorax or
 4

crossed midline. Organs at risk were contoured by the planning dosimetrist and included the
heart, ipsilateral lung, contralateral lung, contralateral breast, thyroid, sternum, esophagus and
spinal cord. These structures were also contoured as described in the Breast Cancer Atlas for
Radiation Therapy Planning.19
Treatment Planning
Treatment planning was completed utilizing a three-dimensional conformal radiation
therapy (3D-CRT) technique and patient plans were created using the Eclipse treatment planning
system.TPS. Depending on the stage of the disease and the decision of the treating physician,
patients were prescribed a dose of 50 Gy in 25 fractions, 42.56 Gy in 16 fractions, or 40 Gy in 15
fractions. Sequential boosts using electrons or photons were usually prescribed for 10-14 Gy in
5-7 fractions to the lumpectomy or mastectomy scar. Treatments were performed on a Varian
Truebeam linear accelerator and treatment beams utilized energies of 6 and 15 MV.
When determining the appropriate beam angles for the treatment plan, the proximity
of the contralateral breast, location of heart, left lung and PTV were all taken into account. This
was accomplished using the beams-eye view and finding the optimal angle to achieve complete
PTV coverage while avoiding the contralateral breast, heart and lung as much as possible. The
collimator rotation was dependent on several factors. If nodal volumes were included, the plan
was created using a mono-isocentric setup with a half-beam block. Collimator angles for these
plans were set to 0 to create a match line. If nodal volumes were not included, collimator angles
were dependent upon what would provide the most conformal blocking of the heart and lung.
The constraints used for planning are outlined in the Radiation Therapy Oncology
Group (RTOG) 1005 and 1304 protocols and were dependent of the prescribed dose (Figures 3
and 4a-e).20,21 The goals for target coverage were to be satisfied while also meeting all the OR
constraints. If it were impossible to meet the ideal objectives then the acceptable variation was
accepted. Commented [P10]: Whatswithalltheextraspacesbelow?

Model Creation and Validation

In order to create a comprehensive database, 72 manually created patient plans were

exported into RapidPlan. These plans were clinically approved and previously treated at the
 5

SSCBC. The exported plans consisted of 40 intact breast and 32 chest wall treatment plans. In
order tTo create a model that was representative of all patient anatomical geometries, patients
with and without nodal involvement were included in the database. Treatment plans included
breast only plans (24), breast with nodes (12), chest wall with nodes (32) and breast with axilla Commented [P11]: Youllneedtospecifywhichnodessince
thelastgroupyoulistedspecificallyindicatesaxillarynodes.
(4). The database included 34 free-breathingFB and 38 DIBH patient plans. A breakdown of the Commented [P12]: Usetheabbreviation

patient treatments included within the database can be seen in Table 1.

Structures from patient plans that were matched within the database for extraction of
DVH information included the contralateral breast, heart, left and right lung, PTV High, PTV Commented [P13]: Whatdoesthismean?

Low, sternum, and thyroid. Structures labeled PTV High included targets that were to achieve Commented [P14]: Whatdoesthismean?

95% of the prescribed dose to cover 95% of the volume. These targets included the
Lumpectomy PTV Eval, Breast PTV Eval, Chestwall PTV Eval, Mastectomy Scar PTV Eval, Commented [P15]: Meaningwhat?
Commented [P16]: Meaningwhat?
Supraclavicular PTV, and Axillary PTV. The structure labeled PTV Low included the Internal
Mammary Node (IMN) PTV. Due to this nodal group often being deep-seated within the chest Commented [P17]: Shouldalreadybespelledoutabove.

and located close to the heart, coverage requirements are lesser, requiring 90% of the
prescribed dose to cover 90% of the volume as outlined in RTOG 1304.21 Studies have shown
that recurrence within the IMN lymph node chain is very rare, even when the nodes are excluded
from radiation treatment fields altogether.22 For this reason, less coverage to the IMN PTV was
justified.
Following the completion of the database, the model was trained using the clinical 3D-
CRT treatment plans. During training, RP analyzes the patient data and runs statistical measures
on the matched structures included within the database. For this study, any matched structures
from patient plans with a Cooks distance greater than 20 were excluded from the database. The Commented [P18]: Whatisthis?

Cooks distance is a measure of how influential a data point is on the rest of the data. The model Commented [P19]: Thedescriptionneedstobelistedright
afteryouusetheterm.
was then exported to Varian Model Analytics in order to flag patient structures that were
identified as outliers within the model. All structures suggested to be excluded from the model
were then removed and the model was retrained.
In order tTo ensure that the trained model created accurate treatment plans, 10 new
patient data sets were introduced in order to create plans using the RP model. Previously
approved patient plans that were not used in the training of the model were used for validation.
All patient plans were copied so that all multileaf collimators (MLCs) and reduced fields could
be deleted to allow for optimization. Treatment beam energies were changed to 10 MV photons
 6

in order to best approximate a mixed energy treatment plan that would be used clinically.
Photon optimization was completed using the Photon Optimizer (PO) version 13.6.23 and dose
calculations were performed using Acuros External Beam version 13.6.23.
Prior to optimization, the created RP model was applied to each new patient dataset in
order to create a predicted DVH for the matched patient structures. Predicted dose- volume data
values were recorded for the heart, ipsilateral lung, and contralateral breast. The recorded
constraints for the heart included the dose to 5% (D5), dose to 35% (D35), and the mean heart Commented [P20]: Gooddescriptions!

dose. Recorded lung data included the volume receiving 20 Gy (V20), the volume receiving 10
Gy (V10), and the volume receiving 5 Gy (V5). The predicted dose-volume value recorded for
the contralateral breast included the volume receiving 3 Gy (V3). Finally, optimization was
completed utilizing the optimization objectives shown in Figure 5. The completed RP plan doses
to the heart, left lung, and contralateral breast were compared to the predicted and clinically
achieved values.

Model Testing
After validating the performance of the RP model, RP generated plans were then created
from the FB CT scan for patients treated clinically using DIBH that were included within the RP
model. For these patients, planning had been attempted on the FB scan, but due to not meeting
heart constraints, the patient was replanned using the DIBH CT. From clinical experience, the
heart mean dose is usually the deciding factor as to why a patient is unable to be treated with a
FB scan. For this reason, only mean heart doses from clinical plans were recorded for
comparison to RP generated plans. The RapidPlan model was then used to create new plans
utilizing the same process described above during the model validation phase. In total, 29 new
patient plans were created using the FB CT data sets.

Results

Model Validation
Upon analyzing the DVH data, RP generatesd statistics which wereare based off of the
matching of patient structures to the corresponding structures within the existing model. For the
purpose of this study, structures that were flagged by the researchers for the evaluation dose by
RP included the PTV high, PTV low, heart, left lung, right lung, contralateral breast, sternum
 7

and thyroid. A regression analysis was performed by RP and a strong correlation was
observedseen between the heart, left lung, sternum and thyroid structures within the model
(Figure 6). These structures resulted in R2 values of 0.867, 0.929, 0.869, and 0.950, respectively.
This regression analysis is a measure of how accurately the model will predict doses to new
patients that are introduced to the model. Commented [P21]: Sotellreaderwhatthevaluesarereflective
of.
Following the completion of the RapidPlan generated patient plans, several values were
recorded including the RP predicted value, the RP generated plan value, and the clinical plan
value. These results can be found in Table 2. In order tTo evaluate the correlation between these
values, scatterplots were created and R2 coefficients (which measure the degree of correlation) Commented [P22]: Youshouldmentionthisthefirsttimeyou
startdiscussingR2thentellthereaderwhattheyshouldbelooking
were determined for each constraint that compared the RP generated plan and the clinical plan forintermsofthevalueasitrelatestothescale.ForexampleR
squaredvaluesrangebetween0and1andthecloserthevalueis
values. These plots and values can be found in Figure 7. A strong correlation was observedseen to1,thebettercorrelationthemodelhastothedataect.
Somethingtothateffectsincenotallofyourreaderscomefroma
between the heart and lung constraints with the strongest correlation seen observed for V20 of the statisticalbackground,youllwantthemtoknowexactlywhatyour
measurementsmeantovalidateyourresearch.
left lung. The R2 values for these constraints were as follows: 0.8025 (5% of heart), 0.8216
(35% of heart), 0.8206 (heart mean), 0.9789 (lung V20), 0.9788 (lung V10), 0.9835 (lung V5).
The only constraint that did not show a strong correlation within the model was the V3 for the
contralateral breast which resulted in an R2 value of 0.5781. Upon evaluation of these results, it
was concluded the model was valid for further research.

Prediction Ability on Free BreathingFB Scans

Following the completion of the FB RapidPlan generated plans, predicted and generated
values were recorded. Along with these values, heart means for the clinically attempted plan
were also recorded. Results can be seen in Tables 3a & 3b. A regression analysis was ran
between the RP predicted and RP generated plan values for the heart, left lung, and contralateral
breast through the creation of scatterplots and R2 coefficients. These results can be observedseen
in Figure 8. A strong correlation was observedseen for the lung constraints with the strongest
correlation found for the V20 of the left lung with an R2 value of 0.8916. A poor correlation was
seen noted for the heart and contralateral breast constraints when comparing RP predicted and
RP generated plan values. A regression analysis was also performed for the RP generated plan
versus the clinical plan value for the mean heart dose. These results can be seen noted in Figure
9. The R2 value resulted in 0.914 and p-testing further validated this correlation, showing a p-
value of 2.90E-19. From the scatterplot, a slope formula was generated from the trend line which
represents the relationship between the two variables (Figure 9). The resulting formula was:
 8

y = 1.1137x + 0.1217

The x variable correspondeds to the RP generated plan values and the y variable
representeds a predicted clinical plan value. This formula was then applied to the RP generated
plan values and results were recorded (Table 4). The standard deviation was then found between
the value created by the formula and the clinical plan value which resulted in 48.6 cGy.

Discussion

The preliminary results from our this study correspond to results of other researchers
analyzing RapidPlan. ThisOur research showed that RP generated plans could achieve lower
doses to ORs while maintaining the coverage to PTVs. However, this is expected due to the
clinically achieved plans being conformal plans that utilize few reduced fields in comparison to
optimized IMRT plans.
It was also found that the RapidPlan generated plans were able to accurately predict heart
doses within +/- 50cGy and were therefore able to predict that our free-breathing plansthe FB
plans would have exceeded clinical acceptance values. This confirms that theour model could
potentially be used to predict which patients will benefit from DIBH. Further evaluation will
need to be completed to confirm this theory. If successful, only a few contours would need to be
created on the FB CT before a RP plan were to be generated. These contours will include a
chestwall/breast PTV and the heart contour. This practice could be beneficial to both physicians
and planning dosimetrists by saving time in eliminating the need to fully contour on multiple
scans throughout the planning.

Conclusion

References

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cancer after radiotherapy for early breast cancer: prospective cohort study of about 300000
women in US SEER cancer registries. Lancet Oncol. 2005;6(8):557-565.
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10. Zurl B, Stranzi H, Winkler P, Kapp KS. Quantification of contralateral breast dose and risk
estimate of radiation-induced contralateral breast cancer among you women using tangential
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19. White J, Tai A, Arthur D, et al. Breast cancer atlas for radiation therapy planning:
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20. Vicini F, Freedman G, White J, et al. RTOG 1005: A phase iii trial of accelerated whole
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https://www.rtog.org/clinicaltrials/protocoltable/studydetails.aspx?study=1005. Commented [P24]: Missinginformation.

21. Wolmark N, Curran WJ, Momounas E, et al. RTOG 1304: A randomized phase III trial
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regional nodal XRT in patients with positive axillary nodes before neoadjuvant
chemotherapy who convert to pathologically negative axillary nodes after neoadjuvant
chemotherapy. https://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1
304. Commented [P25]: Missinginformation.

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Figures Commented [P26]: Makesureallofthefiguresthatyouhave

createdareinTNR,size12font.

Figure 1. Example of patient setup lying supine on the breastboard from Qfix with the arms
positioned overhead.

Figure 2.: Image showing positioning of the vaclock bag under the left arm. Commented [P27]: Capatalize.
 13

Figure 3. Target and normal tissue constraints outlined by RTOG 1005.13 Commented [P28]: Thisfigureistoosmall.Youmayhaveto
recreatethistableinawordtablesothatsbiggerforthereader.
 14

Commented [P29]: Thistablesizeisgreat.Trytomakethe

tableforotherRTOGprotocolthesamesize,evenifyouhaveto
breakitupintosections.

Figure 4a. Target and normal tissue constraints outlined in RTOG 1304.14
 15

Figure 4b. Target and normal tissue constraints outlined in RTOG 1304.14
 16

Figure 4c. Target and normal tissue constraints outlined in RTOG 1304.14
 17

Figure 4d. Target and normal tissue constraints outlined in RTOG 1304.14
 18

Figure 4e. Target and normal tissue constraints outlined in RTOG 1304.14
 19

Figure 5. Image showing optimization objectives created for RapidPlan.

Figure 6. Summary of model training results.

 20

Figure 7. Scatter plots representing RP generated values against clinical generated values for the
constraints of interest for the 10 patients used for model verification.
 21

Figure 8. Scatter plots representing RP predictions against RP generated values for the
constraints of interest for 29 FB patients.
 22

Figure 9. Scatter plot comparing RP plan and clinical plan values.

 23

Tables Commented [P30]: Makesureallofthetablesyouhave

manuallycreatedwereinTNR,size12font.

Table 1. Complete composition of patients included within the created database.

FB DIBH
Breast Only 15 9
Breast and regional nodes 4 8
Chestwall and regional nodes 12 20
Breast and Axillary Nodes 3 1
TOTAL 72 Commented [P31]: Isthistableuseful?Youalreadydescribed
thisinthetextabovesoeliminate.

Table 2. Model validation results. Commented [P32]: Thisisnotacompletesentence.

 24

Table 3a. Prediction ability results on free-breathingFB CT scans.

 25

Table 3b. Prediction ability results on free-breathingFB CT scans.

Commented [P33]: RemovethesecondlistofPatient#

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Table 4. Difference in applied formula values versus the clinical plan value for free-breathing
scans.