1

A comparison of VMAT optimization techniques to evaluate left anterior descending artery

dose for lung radiotherapy
Bryn Dahms, BS; Jessalyn Mitchem, BS, RT(T); Nishele Lenards, PhD, CMD, RT(R)(T),
FAAMD; Ashley Hunzeker, MS, CMD; Ashley Cetnar, PhD, DABR
Medical Dosimetry Program at the University of Wisconsin-La Crosse

Abstract
Current radiation therapy planning techniques mainly rely on constraint metrics related to the
mean heart dose (MHD); however, MHD has been shown to be an inadequate predictor of dose
to cardiac substructures and future incidence of cardiotoxicities. The purpose of this study was to
retrospectively compare dose sparing for the left anterior descending artery (LAD) in volumetric
modulated arc therapy (VMAT) plans optimized with and without an LAD planning organ at risk
volume (PRV) in medial, left-sided, upper lobe non-small cell lung cancer (NSCLC) patients.
Twenty NSCLC patients with tumors located in the medial, left-sided, upper lobe were selected
for this study. The LAD was retrospectively contoured, and new plans were generated for each
selected patient. Treatment plans were compared by evaluating the differences in the LAD
volume receiving 15.0 Gy (V15Gy) between treated and research plans using a Wilcoxon signed
rank test. Plans optimized with an LAD PRV demonstrated a significant reduction in LAD V15Gy
dose compared to plans optimized without an LAD PRV (P < 0.001). Although further research
and larger sample sizes are warranted, these findings highlight the potential for improved cardiac
sparing and a reduction in cardiotoxicities in NSCLC patients treated with radiation therapy
when the LAD is considered during treatment planning.

Key Words: VMAT, left anterior descending artery, non-small cell lung cancer, dose sparing

Introduction
Lung cancer is responsible for the most cancer related deaths worldwide. Of the
estimated 238,000 new lung cancer cases diagnosed in the United States in 2023, non-small cell
lung cancer (NSCLC) is expected to account for 82% of these cases.1 Recent advancements in
lung cancer detection, increases in screening programs, and improvements in treatment regimens
have led to sharp increases in two-year survival rates.2,3 Whether alone or in conjunction with
other treatment modalities, radiation therapy has widely been used in the treatment of NSCLC.2
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As the life expectancy for NSCLC patients continues to increase, greater care must be taken to
spare critical organs at risk (OAR) during radiation treatments. Technological improvements
have allowed for the continuous advancement of radiation delivery, resulting in techniques that
allow for greater conformality in the delivery of radiation and better sparing of OAR for these
lung patients.
Volumetric modulated arc therapy (VMAT) is a form of intensity modulated radiation
therapy that delivers a precise dose of radiation to a tumor while minimizing exposure to nearby
normal tissues. Through inverse planning, VMAT utilizes provided dose constraints to create the
most optimal plan that maximizes planning target volume (PTV) coverage while minimizing
dose to surrounding OAR. For this reason, VMAT is a common technique used to treat NSCLC.
An important consideration in VMAT planning for NSCLC is the potential impact of
radiation exposure to the left anterior descending artery (LAD). In particular, the volume of the
LAD receiving ≥ 15.0 Gy (V15Gy) has been identified as a predictor of cardiac events after
radiation therapy.4 Current planning techniques mainly rely on constraint metrics related to the
mean heart dose (MHD); however, researchers have shown that MHD is an inadequate predictor
of dose to cardiac substructures and future incidence of cardiotoxicities.5 Additionally,
researchers have demonstrated that increased dose to the LAD correlates with an increased risk
of major adverse cardiac events (MACE) and coronary heart disease (CHD) in NSCLC
patients.4,6 Despite evidence that 10% of the LAD volume receiving ≥ 15.0 Gy (V15Gy ≥ 10%)
predicts an almost 10% increase in risk of the occurrence of cardiac events, this dose-limiting
constraint has not been consistently considered as standard of care in treatment planning and
evaluation for lung cancer treatment.4,6,7 Once previously thought to be a side effect that occurs
many years after radiation treatment, recent evidence demonstrates that the onset of CHD
develops an average of 20 months after radiation treatment in NSCLC patients without prior
history of heart disease.7-9 Recently, researchers have demonstrated the need to evaluate
planning techniques that reduce dose to the LAD while effectively targeting tumors in NSCLC
patients treated with VMAT.4,5,7,8 As treatment for NSCLC continues to improve and patients
live longer, it is necessary to investigate planning techniques that reduce the risk of cardiac
related side effects shortly after the conclusion of treatment for NSCLC.3,8
With the increase in NSCLC patient survival, evaluating planning techniques that reduce
the risk of cardiac-related side effects after the conclusion of radiation therapy treatment has
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become a pressing concern.3,8 Researchers in prior studies have demonstrated the need for dose
constraints related to cardiac substructures.4-6,8 Considering that the LAD V15Gy ≥ 10% has been
found to more accurately predict cardiotoxicities than MHD, planning techniques that reduce
dose to the LAD must be evaluated.4 The problem is that there is an increased risk for MACE
and CHD for medial, left-sided, upper lobe NSCLC patients when the LAD V15Gy ≥ 10%. The
purpose of this study was to retrospectively compare dose sparing for the LAD in VMAT plans
optimized with and without an LAD planning organ at risk volume (PRV) in medial, left-sided,
upper lobe NSCLC patients. Researchers tested the hypothesis (HA) that plans optimized with an
LAD PRV will have lower LAD V15Gy dose than plans optimized without an LAD PRV, while
maintaining the volume of PTV receiving 60.0 Gy (V60Gy).
Materials and Methods
Patient Selection and Setup
Twenty NSCLC patients from a single institution were selected for this retrospective
study. Inclusion criteria were patients treated with VMAT to tumors located medially in the
upper lobe of the left lung. Distance from the LAD to the PTV ranged from 0.0 mm to 99.0 mm.
Distance between the PTV and LAD was determined by measuring the minimum distance
between these structures on the axial plane. The volumes of PTV ranged from 90.4 cm3 to
1592.5 cm3. Additionally, all patients received dose to the LAD during treatment. Dose
constraints for the whole heart were utilized in the planning process for both treated and research
plans; however, the LAD V15Gy < 10% dose constraint was used only in the optimization of
research plans in this retrospective study.
Patients were CT simulated in the supine position, head-first, with a head rest, indexed
wing board, and Vac-lok bag immobilizing their arms, head, and shoulders. Patients’ arms were
positioned above their head to avoid inclusion in the treatment fields. After immobilization of the
patient, a Phillips Big Bore RT CT was used to acquire a 4-dimensional CT simulation (4DCT)
with 1.5 mm slices. Patients were scanned from just below the mandible through the superior
portion of the iliac crests.
Contouring
After completion of the 4DCT, datasets were exported to Radformation (Version 2.2.8,
Radformation, New York, NY) and Eclipse treatment planning system (Version 15.0; Varian
Medical Systems, Palo Alto, CA) for contouring. The internal target volume (ITV) was
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contoured by the attending radiation oncologist on the 4DCT average. The ITV included the
range of tumor motion observed on the 4DCT. After contouring the ITV, a 5.0 mm expansion
was applied to this structure to obtain the PTV.
Organs at risk were initially auto-contoured through Radformation on the 4DCT average
and reviewed and edited by a medical dosimetrist. Contoured OAR included the heart, right and
left lungs, spinal canal, and esophagus. The lungs were combined into a total lung structure and a
total lung structure minus the volume of the ITV for further analysis. The LAD was
retrospectively auto-contoured through Radformation and reviewed by a medical dosimetrist for
this study.
Treatment Planning
After the delineation of OAR and target volumes, VMAT treatment plans were created in
Eclipse. Isodose distributions were calculated using the analytical anisotropic algorithm (AAA;
Version 15.6.05) for both treated and research plans. The AAA was used because this was the
only algorithm available to researchers. Plans used for treatment were created with 2 or 3 partial
arc rotations each with a photon energy of 6 MV. For each arc, the collimator was set to 10⁰ for
clockwise arcs, and 350⁰ for counterclockwise arcs. The field size and range of each arc varied
between patients but was consistent between treated and research plans. Treatment plans were
delivered by a Varian 23iX linear accelerator or a Varian Edge linear accelerator. Research plans
were created on the same treatment machine with the same field arrangements as the treated
plan. Jaw tracking was utilized on plans delivered via the Varian Edge linear accelerator.
All plans were prescribed to 60.0 Gy in 30 fractions. The volume of the PTV receiving
60.0 Gy was prioritized over dose constraints for OAR. If the PTV V60Gy decreased in research
plans, the priority of the LAD PRV V15Gy < 10% constraint in the optimizer was reduced.
Planning objectives and priorities for OAR remained the same for treated and research plans.
The only difference between treated and research plans was the use of a 3.0 mm LAD PRV in
the optimization process. Upon completion of optimization, research plans were normalized to
match the normalization method of the corresponding treated plan.
Plan Comparison
Treatment plans were compared by evaluating the differences in the LAD V15Gy metric
between treated and research plans. Although analyzing dose variations to other OAR was not in
the scope of this study, dose to these structures was monitored throughout the research treatment
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planning process. Radiation Therapy Oncology Group trial 0617 was used as a guide for
establishing dose constraints for OAR (Table 1).10 Monitored OAR include the heart, spinal
canal, total lung minus ITV volume, and esophagus. Constraint metrics for OAR remained
consistent between treated and research plans. Dose to the PTV was evaluated to ensure adequate
coverage with prescription dose. Failure to adequately treat the PTV to spare the LAD was not
considered an acceptable trade-off because inadequate treatment of the PTV may increase the
risk of disease recurrence.11
There were 2 threshold metrics used to analyze differences in dose to OAR between
treated and research plans. Variations in volume-type OAR constraint metrics > 5% were
determined by the researchers to be significant; however, research plans exceeding the 5%
criteria did not necessarily exceed the OAR constraints outlined in Table 1. The absolute value of
the dose change for OAR with dose-type objectives were planned within a tolerance of < 3.0 Gy
to reflect < 5% difference for a 60.0 Gy prescription dose.
Statistical Analysis
Differences in dose to the LAD between treated plans and research plans was assessed
via the Shapiro-Wilk test for normality. The smaller sample size and non-normal distribution, as
demonstrated by the Shapiro-Wilk test, required analysis via one-sided Wilcoxon signed rank
test. Correlation between the distance from the LAD to the PTV and the reduction in dose to the
LAD was evaluated via Spearman’s correlation test. P-values of less than 0.05 (P < 0.05) were
considered significant. Data were analyzed in RStudio (Version 4.3.1).
Results
LAD Dose
The difference in the LAD V15Gy was calculated by subtracting the research plan LAD
V15Gy metric from the treated plan LAD V15Gy metric (difference = treated – research). The LAD
V15Gy in treated plans ranged from to 1.36% to 100.00%. The LAD V15Gy in research plans
ranged from to 0.00% to 100.00% (Figure 1). Differences in the LAD V15Gy between treated and
research plans ranged from 0.00% to 45.20%. The median difference in the LAD V15Gy dose
between treated and research plans was 5.50% and the mean difference in the LAD V15Gy dose
was 7.93%. The one-sided Wilcoxon signed rank test demonstrated a statistically significant
decrease in LAD V15Gy dose in research plans (P < 0.001). Therefore, the null hypothesis (H0)
that plans optimized with an LAD PRV will have the same LAD V15Gy dose as plans optimized
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without an LAD PRV, while maintaining the volume of PTV receiving 60.0 Gy (V60Gy), was
rejected.
The distance between the LAD and PTV ranged from 0.0 mm to 99.0 mm. In 4 cases, the
patient’s LAD was partially contained within the PTV. Spearman’s correlation demonstrated a
weak negative correlation between the distance from the LAD to the PTV and the reduction in
dose to the LAD; however, the correlation was not statistically significant (𝜌(18) = -0.377, P =
0.102).
Discussion
Cardiotoxicities are a common side effect of radiation therapy treatments in NSCLC
patients.7 In a recent study conducted by Atkins et al,7 32.1% of NSCLC patients that had
undergone radiation therapy treatments developed at least one cardiac related side effect within 2
years following the conclusion of treatment. Atkins et al9 demonstrated that current constraint
metrics for the heart, mainly the mean heart dose, were not adequate predictors of
cardiotoxicities. Additional studies further supported the need for constraint metrics related to
cardiac substructures; specifically, the LAD V15Gy was found to more accurately predict MACE
in NSCLC patients than MHD.4-6,8,9 Researchers in the current study evaluated the effects of
optimizing with an LAD PRV on reducing LAD V15Gy in VMAT plans. Optimizing with an LAD
PRV was found to significantly reduce dose to the LAD (Figure 2). Of the research plans, 10 of
20 did not meet the LAD V15Gy < 10% constraint metric. In 4 of these cases, the LAD was
partially contained within the PTV. Because of the importance of PTV coverage, adequate dose
to the PTV was prioritized over sparing of OAR. This approach greatly influenced the ability to
spare the LAD, among other OAR. Despite these limitations, all but 1 research plan
demonstrated a reduction in dose to the LAD, in which case 100% of the LAD received 15.0 Gy
for both the treated and research plan (LAD V15Gy = 100%).
Of the 20 plans evaluated in this study, 10 research plans demonstrated no change in the
PTV V60Gy. For the other 10 research plans, variations in dose were within 3% of the treated
plans. Dose to the target volume decreased between treated and research plans twice; the greatest
decrease in the percentage of the PTV receiving prescribed dose was 0.22%. Eight research plans
demonstrated a slight increase in the percentage of the PTV receiving prescribed dose. The
increase in the research plan PTV V60Gy ranged from 0.03% to 2.46%.
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Despite evidence to suggest that dose constraints for the LAD are necessary to reduce
cardiotoxicities, application of such constraints has been slow to gain traction across the
radiation oncology community. Lack of long-term data regarding the efficacy of the LAD V15Gy
< 10 % constraint in reducing incidence of cardiotoxicities in both NSCLC patients as well as
left-sided breast patients have contributed to this gap in clinical implementation. Current studies
regarding dose to the LAD have been retrospective in nature. Additional barriers that influence
dose tracking for the LAD are related to the difficulties with contouring this structure on the CT.
In the past 2 decades, implementation of MR imaging in radiation therapy has allowed for
greater visualization of soft tissue structures, allowing for more accurate delineation and
therefore dose tracking to these structures; however, implementation of MR imaging within
radiation oncology departments is limited.12
When sparing multiple OAR, the decision of which OAR was highest priority was
determined by an analysis of current constraint metrics and a discussion of trade-offs. For the
current research study, dose to the total lung minus ITV, heart, esophagus, and spinal canal was
monitored to determine if constraint metrics could still be met with additional sparing of the
LAD; however, variations in the OAR constraint metrics were not statistically analyzed. The
OAR difference thresholds were exceeded 7 times. Five of these 7 deviations remained within
the constraint metrics outlined in Table 1. One deviation exceeded the constraint metrics only for
the research plan. The final deviation exceeded the constraint metrics for both the research and
treated plans. Threshold deviations occurred most often in the total lung minus ITV receiving 5.0
Gy (V5Gy) < 60-65% constraint metric, where a > 5% difference was observed in 3 research
plans. Other constraint metrics that exceeded the outlined threshold deviation include the total
lung minus ITV volume receiving 20.0 Gy (V20Gy) < 35%, the volume of the heart receiving 30.0
Gy (V30Gy) < 50%, the spinal canal maximum dose < 50.0 Gy, and the dose to 0.03 cm3 (D0.03cm3)
of the spinal canal < 45.0 Gy.
Conclusion
Researchers in prior studies have demonstrated the need for dose constraints for cardiac
substructures.4-6,8 Considering that the LAD V15Gy ≥ 10% has been found to more accurately
predict cardiotoxicities in NSCLC patients than MHD, planning techniques that reduce dose to
the LAD must be evaluated.4 The problem is that there is an increased risk for MACE and CHD
for medial, left-sided, upper lobe NSCLC patients when the LAD V15Gy ≥ 10%. The purpose of
 8

this study was to retrospectively compare dose sparing for the LAD in VMAT plans optimized
with and without an LAD PRV in medial, left-sided, upper lobe NSCLC patients. Plans
optimized with an LAD PRV demonstrated a significant reduction in V15Gy dose to the LAD
when compared to plans optimized without an LAD PRV (P < 0.001), while maintaining V60Gy
dose to the PTV.
Limitations of this study included the small sample size (n = 20) and data collection
limited to a single institution. Increasing the sample size and number of institutions would
increase the statistical power and thus the ability to accurately detect a true difference in dose to
the LAD between plans optimized with and without an LAD PRV. Suggestions for future
research include a large-scale, scientific study and analysis of variations in dose to other thoracic
OAR, such as the lungs, heart, esophagus, and spinal cord. Prospective long-term studies are
needed to confirm the efficacy of the LAD V15Gy < 10% metric in reducing cardiotoxicities in
NSCLC and left-sided breast patients alike.
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Figures

Treated Research

Figure 1. Boxplots demonstrating the difference in the volume of the left anterior descending
artery receiving 15.0 Gy between treated and research plans.
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B
Figure 2. Sample dose distribution in a plan optimized (A) with and (B) without an LAD PRV.
The LAD is in dark blue, the LAD PRV is light blue.
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Tables
Table 1. Dose constraints for organs at risk for non-small cell lung cancer patients with tumors
located medially in the upper lobe of the left lung.a
Organ Constraint
Body Maximum < 115%
Spinal Canal Maximum < 50.0 Gy
D0.03 cm3 b < 45.0 Gy
Total Lung minus ITVc V5Gyd < 60-65%
V20Gye < 35%
Mean < 20.0 Gy
Esophagus Mean < 34.0 Gy
V35Gyf < 50%
V60Gyg < 17%
Heart Maximum < 70.0 Gy
Mean < 20.0 Gy
V45Gyh < 35%
V30Gyi < 50%
a
Constraints are from Radiation Therapy Oncology Group Trial 0617 10; b Dose to 0.03 cm3; c Internal tumor volume;
d
Volume receiving 5.0 Gy; e Volume receiving 20.0 Gy; f Volume receiving 35.0 Gy; g Volume receiving 60.0 Gy; h
Volume receiving 45.0 Gy; i Volume receiving 30.0 Gy