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Evaluation of DIBH breast plan robustness against isocenter positioning uncertainties

Cory Tuzzo, BS, R.T.(T); Carli Doerr, BS, R.T.(T); Benjamin Smith, BS, R.T.(T); Nishele
Lenards, PhD, CMD, R.T.(R)(T), FAAMD; Ashley Hunzeker, MS, CMD; Matt Tobler, CMD,
R.T.(T); Sabrina Zeiler, MS, CMD, R.T.(T); Ashley Fellows, MS, CMD, R.T.(T)
Medical Dosimetry Program at the University of Wisconsin-La Crosse, WI
ABSTRACT
When treating left-sided breast patients with a deep inspiration breath hold technique
(DIBH), patient positioning errors could be shifting from the planned isocenter resulting in
potential increase in cardiac dose and decreased planning target coverage. The purpose of this
study was to compare heart dose and the breast planning target volume for evaluation (Breast
PTV Eval) coverage for DIBH left breast patient plans using the ‘plan uncertainty’ feature in
Eclipse to determine whether adjustments are necessary for set up threshold tolerances. Nineteen
patients were selected for this study and were planned with conventional 3D conformal
radiotherapy (3DCRT). Isocenter shifts of 3 mm were applied in each anatomical direction for
each patient’s plan, resulting in 6 additional plans to compare to the original. Dosimetric criteria
followed the NOVEMBER protocol, a 9-fraction treatment regimen for whole left breast
patients. Plans were assessed by inspecting the Breast PTV Eval dose coverage and heart dose
within a dose volume histogram (DVH). All hypotheses tests were based on statistical
inferences. The results showed that incorporating isocenter shifts of 3 mm in any anatomical
direction did not compromise the Breast PTV Eval coverage and the mean dose to the heart
remained below the set dose criteria of 2.5 Gy (P = 1.0). Isocenter shifts of 3 mm resulted in
adequate total dose coverage of 90% of the Breast PTV Eval for all patients (P = 1.0); however,
the Breast PTV Eval in 1 patient exceeded the dose constraint at the 50% volume. Furthermore,
another patient did not meet the constraint for total dose covering more than 35% of the Breast
PTV Eval (P = 0). While the majority of patients passed the protocol’s dose criteria, threshold
tolerances should be evaluated individually for each patient due to differences in anatomy and
location of target volumes.

Keywords: Left-sided breast cancer, Cardiac dose, Deep inspiration breath hold (DIBH), Plan
uncertainty tool
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Introduction
Left breast radiation treatment objectives include adequate target coverage while
minimizing doses to organs at risk (OAR) such as the heart. Due to differences in patient
anatomy and laterality, heart dose can vary significantly. A previous study by Darby et al1
revealed that patients who received left breast radiation treatment had a 25% increased risk of
late cardiac toxicity when compared to right sided breast radiation patients.2 A study by McGale
et al3 showed that even a low dose to the heart resulted in increased risk of heart disease. Another
study by Sardaro et al4 demonstrated that a 1 Gy increase in mean heart dose results in a 4%
increase in the risk of late heart disease. Therefore, it is crucial to assess every aspect of left
breast treatment planning to ensure patient safety by reducing these possible complications from
radiation exposure to the heart while maintaining target coverage.
Deep inspiration breath hold (DIBH) treatment is a patient breathing technique monitored
by surface tracking (AlignRT) to decrease the risk of increased heart dose. Reducing radiation
dose to the heart through a treatment and planning technique such as DIBH is a viable option for
many left breast cancer patients.5 Deep inspiration breath hold treatment works by allowing the
lungs to be completely full of air, shifting the treatment volume anteriorly and laterally away
from the heart.6 There are 2 types of DIBH with 1 involving an active breathing coordinator in
which the patient is coached to breathe through a specified mouthpiece when instructed.7 The
other type of DIBH is performed in a voluntary manner where the patient holds their breath for a
set amount of time.8 With the patient in the fixed breath hold position, the motion of the treated
volume is more controlled during irradiation. However, this does not account for the uncertainty
of patient movement during the entire treatment process. This uncertainty is further affected with
the longer treatment time needed for DIBH to be completed. One particular tool, AlignRT, can
assist in tracking patient movement throughout treatment. This surface image tracking system
provides real-time, non-invasive monitoring of the patient’s surface anatomical position to help
reduce patient movement uncertainties during the DIBH treatment.9 While AlignRT is not able to
remove this treatment uncertainty entirely, this technology remains a frontrunner for DIBH
treatments. Even though DIBH is designed to reduce the patient movement uncertainty of the
treated breast, which can alter the planned dose distribution, it cannot account for all
uncertainties including errors in patient positioning.
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Uncertainties from patient setup can arise from various error sources, all of which can
affect the planned dose distribution. Errors such as patient positioning inaccuracies and changes
to the breast tissue factor into a patient’s treatment delivery.10 When radiation therapists align the
patient for treatment, there are often slight positioning inaccuracies. During the course of
radiation therapy treatment, the patient’s treated breast may experience edema which is a side
effect from the radiation. The difference in breast tissue size can cause a discrepancy with the
planned dose distribution.
To minimize the level of uncertainty that occurs with patient positioning as well as
movement, AlignRT incorporated threshold tolerances that are set for all linear translations
(vertical, lateral, longitudinal, roll, pitch, and yaw). The AlignRT software alerts the radiation
therapists if the patient is positioned or moves outside of the set limitations. Depending on the
facility, the threshold tolerance may be 2 mm, 3 mm, or 4 mm. Due to the fact that patients have
the tendency to move throughout treatment which is directly proportional to the amount of time
on the table, these tolerances are in place to account for this variable motion.11 Wiant et al11
discussed how patients monitored with surface imaging, such as AlignRT, may benefit from
smaller threshold tolerances. However, with the knowledge that DIBH increases the amount of
time the patient is on the table, the tolerances need to reflect this as well.11 It is the balance
between surface imaging and length of treatment that have established the threshold tolerances
which average around 3 mm between departments. Even though the threshold tolerances account
for small patient positioning errors and movement, the patients planned dose distribution may be
inaccurate should the maximum tolerances be reached daily throughout the course of treatment.
A new tool, known as plan uncertainty, was introduced in the Eclipse treatment planning
system (TPS) version 13 to help assess the robustness of plans with simulated isocenter shifts.
When this tool is applied to a plan, Eclipse will generate and calculate dose distributions of
several model plans according to the predetermined shifts of isocenter defined by the user.12 The
simulated isocenter shifts represent the various errors that create uncertainties within the
treatment plan and help to decipher whether the threshold tolerances in AlignRT need to be
adjusted to pass all protocol constraints.
The research problem is that patient positioning errors could be shifting from the planned
isocenter resulting in a potential increase in cardiac dose and decreased breast planning target
volume for evaluation (Breast PTV Eval) dose coverage for left-sided breast patients treated with
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DIBH. The purpose of this study was to compare heart dose and Breast PTV Eval coverage for
DIBH left breast patient plans using the plan uncertainty feature in Eclipse to determine whether
adjustments are necessary for threshold tolerances. Incorporating isocenter shifts of 3 mm in the
X, Y, and Z directions using the uncertainty tool, researchers tested the following hypotheses:
(H1A) meet all criteria for breast PTV and heart dose goals for < 100% of patients, (H2A) show
10% of the entire heart receiving > 22 Gy, (H3A) show mean heart dose receiving > 2.5 Gy,
(H4A) show 90% of the Breast PTV Eval receiving < 90% of the prescription dose, (H5A) show
unacceptable dose constraints with > 35% of the Breast PTV Eval receiving 100% of the boost
prescribed dose of 39.6 Gy, (H6A) show 50% of the Breast PTV Eval receiving > 38.3 Gy.
Methods and Materials
Patient Selection and Setup
Nineteen patients were selected for this retrospective study. Included criteria were
patients diagnosed with early stage left breast cancer treated to the entire breast using voluntary
DIBH technique. Patients not fit for the DIBH technique were excluded from this study.
All patients were simulated on a Siemens Somatom Confidence CT scanner using a slice
thickness of 2 mm. For the simulation and treatments, patients were positioned supine, head-first,
both arms above the head, with the head turned away from the affected side, and the knees
slightly bent over a foam cushion. An alpha cradle immobilization device was used to keep the
upper bodies in a reproducible position.
Contour Delineation
The structures contoured for each patient followed the clinical trial protocol at the
facility. The OAR included the lungs, contralateral breast, heart, ribs, and thyroid. The lungs
were contoured using the auto-segmentation with manual verification. The contralateral breast
and heart contours followed the Radiation Therapy Oncology Group (RTOG) Breast Atlas and
RTOG 1106 contouring guidelines, respectively. The ribs and thyroid structures were contoured
manually.
The target volumes drawn by the physicians included: Lumpectomy Gross Tumor
Volume (GTV), Lumpectomy and Breast Clinical Target Volumes (CTVs), Lumpectomy and
Breast PTVs, and Lumpectomy and Breast PTV Eval structures, which consisted of the PTVs but
excluded the first 5 mm of tissue under the skin as well as any expansion that extended beyond
the posterior extent of breast tissue. 13 Both PTV Eval structures were used for dose volume
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histogram (DVH) constraints and plan analysis.13 Only the heart and Breast PTV Eval structures
were used for evaluation. The other structures were contoured but not used for evaluation in
collecting data. All structures contoured were reviewed and approved by the attending physician.
Treatment Planning
All patients were planned in the Eclipse treatment planning system (TPS) version 15.5,
and the dose was calculated with the Acuros External Beam algorithm version 15.5. The plans
were all optimized with Radformation EZFluence software to eliminate any bias during plan
evaluation. Plans were created for a Varian Clinac iX Linear Accelerator using portal imaging as
well as AlignRT for surface guidance monitoring to confirm patient positioning. Each patient
was prescribed a 9-day course of whole breast radiotherapy adhering to the NOVEMBER
Clinical Trial’s protocols.13 The breast was prescribed 3.8 Gy for 9 fractions to a total of 34.2 Gy
with a lumpectomy boost prescribed to 0.6 Gy for 9 fractions to a total of 5.4 Gy. For the current
study, the Breast PTV Eval total dose was evaluated based on the contribution from the whole
breast radiotherapy as well as lumpectomy boost. All plans had the same dose constraints based
on the NOVEMBER Protocol.13
In this study, the plan uncertainty tool was used to simulate patient setup errors with an
isocenter shift of 3 mm. The 3 mm metric is a standard AlignRT tolerance in the department
where the patients were planned and treated. Seven plans were calculated for each patient: the
original plan and the 6 plans generated after a simulated isocentric shift of ±3 mm along the axis
in all directions (X, Y, and Z). A total of 133 plans were calculated for evaluation based on the
19 patients included in this study.
Statistical Analysis
Each null hypothesis states that 100% of patients in the intended population will satisfy a
specific criterion, therefore when a null hypothesis failed to be rejected, it would be impossible
to observe patients in any sample not satisfying the criteria. If none of the patients in the sample
failed to meet the criterion, the P-value would be 1. If 1 or more of the patients in the sample
failed to meet the criterion, the null hypothesis was rejected, and the P-value would be 0. With
the P-value at 0, this would imply the results were of high clinical significance.
Results
Overall Dose Criteria
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The 7 plans that were calculated for each patient were reviewed in a DVH to evaluate the
original plan’s robustness (Figure 1). The hypotheses tests were based on the basic and defining
characteristics of statistical inference. Seventeen of the 19 left breast patients (89.5%) passed all
5 dose criteria. Two patients did not meet at least 1 of the dose criteria. Both instances occurred
in examining the Breast PTV Eval (Table 1). There was sufficient evidence to conclude that
incorporating isocenter shifts within departmental setup margins of 3 mm in the X, Y, and Z
directions using the uncertainty tool met all criteria for breast PTV and heart dose goals for <
100% of patients. Therefore, researchers rejected the (H10) null hypothesis (P = 0).
Dose to 10% of Heart
All 19 patients in this study met the dose constraint that 10% of the entire heart receive <
22 Gy. There was insufficient evidence to conclude that incorporating isocenter shifts within
departmental setup margins of 3 mm in the X, Y, and Z directions using the uncertainty tool will
show 10% of the entire heart receiving > 22 Gy. Therefore, researchers failed to reject the (H20)
null hypothesis (P = 1.0).
Mean Heart Dose
All 19 patients in this study met the mean heart dose constraint of < 2.5 Gy. There was
insufficient evidence to conclude that incorporating isocenter shifts within departmental setup
margins of 3 mm in the X, Y, and Z directions using the uncertainty tool will show the mean
heart dose receiving > 2.5 Gy. Therefore, researchers failed to reject the (H30) null hypothesis (P
= 1.0).
90% Breast PTV Eval
All 19 patients in this study met the dose constraint that at least 90% of the Breast PTV
Eval receive 90% of the prescription dose. There was insufficient evidence to conclude that
incorporating isocenter shifts within departmental setup margins of 3 mm in the X, Y, and Z
directions using the uncertainty tool will show < 90% of the Breast PTV Eval receiving 90% of
the prescription. Therefore, researchers failed to reject the (H40) null hypothesis (P = 1.0).
Breast PTV Eval Boost Dose
One patient in this study failed the dose constraint that < 35% of Breast PTV Eval receive
100% of the prescribed 39.6 Gy boost dose. There was sufficient evidence to conclude that
incorporating isocenter shifts of 3 mm in the X, Y, and Z directions using the uncertainty tool
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will show > 35% of the Breast PTV Eval receiving 100% of the boost prescribed dose of 39.6
Gy. The researchers rejected the (H50) null hypothesis at (P = 0).
50% of Breast PTV Eval Dose
One patient in this study failed the dose constraint that 50% of the Breast PTV Eval
receive < 38.3 Gy. There was sufficient evidence to conclude that incorporating isocenter shifts
within departmental setup margins of 3 mm in the X, Y, and Z directions using the uncertainty
tool will show 50% of the Breast PTV Eval receiving > 38.3 Gy. The researchers rejected the
(H60) null hypothesis (P = 0).
Discussion
From comparing the results in the DVH, it is evident that incorporating isocenter shifts of
3 mm in the X, Y, and Z directions using the uncertainty tool resulted in < 100% of patients in
this study meeting all 5 dose criteria. Researchers rejected 3 of the 6 null hypotheses (H10, H50
and H60) and 17 of the 19 patients met all of the dose criteria. The instances where the 2 patients
did not meet criteria occurred in examining the Breast PTV Eval (Table 1). For the safety of
these 2 patients, it would be advisable to reassess the setup threshold tolerances for each patient
separately.
Xiao et al9 stated that common setup threshold tolerances used for AlignRT software are
3 mm and 5 mm thresholds. Similar to Xiao et al9, the current study researchers demonstrated
that the setup threshold tolerances were sufficient for most patients, and therefore recommends
the threshold tolerance of 3 mm should continue to be the starting control margin. However, 2
patients did not meet all dose constraints which suggested that each patient should be
independently reviewed to determine if tighter setup margins were needed during the course of
treatment.
Each patient in the study had considerably low heart dose with each patient meeting the
dose constraint that 10% of the entire heart receive < 22 Gy. Moreover, each patient met the
mean heart dose constraint of 2.5 Gy with only 4 patients receiving a mean heart dose over 1 Gy.
The low heart dose was due in part to DIBH, through which the treatment volume was shifted
away from the heart.6 However, Piroth et al,2 McGale et al,3 and Sardaro et al4 reported increased
risk of late heart disease with even low doses of radiation to the heart. Darby et al1 and Piroth et
al2 reported that the risk of major coronary events increases linearly with the increase in the mean
heart dose. It is apparent that caution should be given when deciding patient setup threshold
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tolerances in AlignRT to ensure not only prescribed coverage of the target but also minimal dose
to the heart.
Regarding the 90% Breast PTV Eval dose constraint, all 19 patients met this goal.
However, 1 patient failed to meet the Breast PTV Eval constraint that included the boost and 1
patient failed to meet the 50% Breast PTV Eval dose constraint. The threshold tolerance of 3 mm
did not accurately account for the setup inaccuracies of the left breast, as indicated by the results
when tolerance was reached. Wiant et al11 discussed how threshold tolerances are in place to
account for set up motion and stated that smaller tolerances may be beneficial for patients
monitored with surface tracking. The results from this current study validate those findings as
smaller threshold tolerances were needed for 2 patients in order to achieve the dose constraints.
In the current study, researchers demonstrated that using the uncertainty tool for DIBH
left breast patients provided more information about setup tolerances that need to be adjusted to
ensure acceptable dose distribution. By confirming the setup tolerances are adequate, clinicians
can be assured of prescribed dose coverage and appropriate heart sparing. Researchers in this
study recommend that the uncertainty tool be utilized with DIBH left breast patients to determine
if the setup tolerances need to be adjusted to meet the expected dose distribution for fractionated
treatments.
Conclusion
The research problem is that patient positioning errors could be shifting from the planned
isocenter resulting in a potential increase in cardiac dose and decreased Breast PTV Eval dose
coverage for left-sided breast patients treated with DIBH. The purpose of this study was to
compare heart dose and Breast PTV Eval coverage for DIBH left breast patient plans using the
plan uncertainty feature in Eclipse to determine whether adjustments were necessary for set up
threshold tolerances. Using the plan uncertainty tool, researchers showed that 89.5% of the
patients in this study met all dose criteria with the combination of DIBH and surface image
tracking. With 2 patients not meeting all the dose constraints, the uncertainty tool should be used
for DIBH left breast patients to ensure the needed coverage and dose distribution.
Limitations of this study include: all patient treatment plan data were collected from 1
cancer center, only 1 TPS was used for evaluation, and 1 calculation algorithm was tested. An
additional limitation is that results could vary slightly among different linear accelerators causing
more patient plans to fail specific dose criteria. Future research should include a larger sample
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size and collection of patient data from multiple cancer centers which would include different
TPSs and calculation algorithms. Furthermore, different threshold tolerances could be used. In
addition, there is also potential for future research to include using the plan uncertainty tool in
Eclipse to evaluate threshold tolerances for various other anatomical sites.

Acknowledgments
The authors would like to thank Dr. David Reineke and the Statistical Consulting Center at the
University of Wisconsin – La Crosse for assistance with the quantitative statistical analysis;
however, any errors of fact or interpretation remain the sole responsibility of the authors.
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References
1. Darby S, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after
radiotherapy for breast cancer. N Engl J Med. 2013;368(11):987–98.
http://doi.org/10.1056/NEJMoa1209825
2. Piroth MD, Baumann R, Budach W, et al. Heart toxicity from breast cancer radiotherapy.
Strahlenther Onkol. 2019;195(1):1-12. http://doi.org/10.1007/s00066-018-1378-z
3. McGale P, Darby SC. Commentary: a dose‐response relationship for radiation‐induced heart
disease – current issues and future prospects. Int J Epidemiol 2008; 37: 518–23.
4. Sardaro A, Petruzzelli MF, D'Errico MP, Grimaldi L, Pili G, Portaluri M. Radiation‐induced
cardiac damage in early left breast cancer patients: risk factors, biological mechanisms,
radiobiology, and dosimetric constraints. Radiother Oncol 2012; 103: 133–42.
5. Conroy L, Yeung R, Watt E, et al. Evaluation of target and cardiac position during visually
monitored deep inspiration breath-hold for breast radiotherapy. J Appl Clin Med Phys.
2016;17(4):25-36. http://doi.org/10.1120/jacmp.v17i4.6188
6. Hayden A, Rains M, Tiver K. Deep inspiration breath hold technique reduces heart dose
from radiotherapy for left sided breast cancer. J Med Imaging Radiat Oncol. 2012;56(4):464–
72. http://doi.org/10.1111/j.1754-9485.2012.02405.x
7. Latty D, Stuart KE, Wang W, Ahern V. Review of deep inspiration breath-hold techniques
for the treatment of breast cancer. J Med Radiat Sci. 2015;62(1):74-81.
http://doi.org/10.1002/jmrs.96
8. Bartlett F, Colgan R, Carr K, et al. The UK HeartSpare Study: Randomised evaluation of
voluntary deep inspiratory breathhold in women undergoing breast radiotherapy. Radiother
Oncol. 2013;108(2):242–7. http://doi.org/10.1016/j.radonc.2013.04.021
9. Xiao A, Crosby J, Malin M, et al. Single-institution report of setup margins of voluntary
deep-inspiration breath-hold (DIBH) whole breast radiotherapy implemented with real-time
surface imaging. J Appl Clin Med Phys. 2018;19(4):205-213.
http://doi.org/10.1002/acm2.12368
10. Mourik AV, Kranen SV, Hollander SD, Sonke J-J, Herk MV, Vliet-Vroegindeweij CV.
Effects of setup errors and shape changes on breast radiotherapy. Int J Radiat Oncol Biol
Phys. 2011;79(5):1557-1564. http://doi.org/10.1016/j.ijrobp.2010.07.032
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11. Wiant DB, Wentworth S, Mauer JM, Vanderstraeten CL, Terrell JA, Sintay BJ. Surface
imaging-based analysis of intrafraction motion for breast radiotherapy patient. J Appl Clin
Med Phys. 2014;15(6):147-159. http://doi.org/10.1120/jacmp.v15i6.4957
12. Warren S, Partridge M, Bolsi A, et al. An analysis of plan robustness for esophageal tumors:
comparing volumetric modulated arc therapy plans and spot scanning proton planning. Int J
Radiat Oncol Biol Phys. 2016:95(1):199-207. http://doi.org/10.1016/j.ijrobp.2016.01.044
13. Poppe M. Hypofractionated Radiation Therapy in Treating Patients With Stage 0-IIB Breast
Cancer (NOVEMBER). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03345420.
Updated May 8, 2020. Accessed July 23, 2020.
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Figures

Figure 1. Dose Volume Histogram (DVH) of the 7 plans using the uncertainty tool. The upper
DVH (A) displays the heart on the left of the DVH and the breast PTV eval on the right, and the
lower DVH (B) displays the heart in a closer view to express the differences with the uncertainty
plans. For both DVH (A) and DVH (B), the X-axis represents the Dose in centigray (cGy) and
the Y-axis represents the Ratio of the Total Structure Volume (%).
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Tables

Table 1. Frequencies and percentages of patients in the sample that met dose constraints for each
criterion.
Dose Constraints Criterion Pass Fail
Heart D10% ≤ 22 Gy 19 (100%) 0 (0%)
Mean ≤ 2.5 Gy 19 (100%) 0 (0%)
Breast PTV Eval V30.78 Gy ≥ 90% 19 (100%) 0 (0%)
V39.6 Gy ≤ 35% 18 (94.7%) 1 (5.3%)
D50% ≤ 38.3 Gy 18 (94.7%) 1 (5.3%)
Total All Constraints 17 (89.5%) 2 (10.5%)
Breast PTV Eval = breast planning target volume for evaluation; D10% = dose to 10%; V30.78 Gy = volume receiving 30.78 Gy; V39.6
Gy = volume receiving 39.6 Gy; D50% = dose to 50%; Gy = gray