1

A comparison of volumetric modulated arc radiotherapy optimization techniques to

evaluate left anterior descending artery dose sparing in left non-small cell lung tumor
patients
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
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 been a mainstay in the treatment of NSCLC. 2
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 radiation therapy that delivers a
precise dose of radiation to a tumor while minimizing exposure to nearby normal tissues.
Through inverse planning, VMAT utilizes dose constraints provided by the medical dosimetrist
and radiation oncologist 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 Gy 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, emerging evidence
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suggests that increasing dose to the LAD correlates with an increased risk of major adverse
cardiac events (MACE), coronary heart disease (CHD), and all-cause mortality in NSCLC
patients.4-6 Despite evidence that 10% of the LAD volume receiving greater than or equal to 15
Gy (V15 Gy ≥10%) predicts an almost 10% increase in risk of the occurrence of cardiac events,
this dose-limiting constraint has not been followed systematically in instances of lung cancer. 4,6,7
Once previously thought to be a side effect that occurs many years after radiation treatment,
recent evidence suggests 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 This suggests the need to
evaluate planning techniques that reduce dose to the LAD while effectively targeting tumors in
NSCLC patients treated with VMAT.
As treatment for NSCLC continues to improve and patients continue to 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 The problem is that there is an increased
risk for major adverse cardiac events and coronary heart disease for medial, left-sided, upper
lobe NSCLC patients when the LAD V15 Gy ≥ 10%. The purpose of this study was to compare
dose to the LAD in 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 patients to evaluate
dose sparing of the LAD while maintaining 95% coverage of the PTV with prescribed dose.
Researchers tested the hypothesis that plans optimized with an LAD PRV will have lower LAD
V15 Gy dose than plans optimized without an LAD PRV, while maintaining 95% coverage of the
PTV with prescribed dose.
Materials and Methods
Patient Selection and Setup
Twenty NSCLC patients from a single institution were selected for this retrospective
study. Inclusion criteria were patients initially 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 mm to 99 mm.
The volumes of PTV ranged from 90.4 cc to 1592.5 cc. Additionally, all patients had received
dose to the LAD during their treatment. Dose constraints for the whole heart were utilized in the
planning process for both treated and research plans; however, LAD specific dose constraints
were used only in the creation of research plans.
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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 of such 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
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 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 include 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 of site-specific dose
objectives. The LAD was retroactively auto contoured in Radformation and reviewed by a single
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)
for both treated and research plans. Treated plans 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 10 o for clockwise
arcs, and 350o for counterclockwise arcs. The field size and range of each arc varied between
patients but was consistent between the treated and research plans. Plans were delivered by a
Varian 23iX linear accelerator or a Varian Edge linear accelerator. Jaw tracking was utilized on
plans delivered via the Varian Edge linear accelerator.
Research plans were created for each patient by a single medical dosimetrist using the
same fields and treatment machine as the treated plan. The only difference between treated and
research plans was the use of a 3 mm LAD PRV in the optimization process. All other primary
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planning objectives and priorities were kept the same. All plans were either prescribed to or
adjusted to reflect a prescribed dose of 60 Gy in 30 fractions.
The volume of the PTV receiving 60 Gy was prioritized over dose constraints for OAR.
Adequate dose to the PTV in treated plans was achieved through the manipulation of planning
objectives and priorities of OAR in the optimizer. If the PTV V 60 Gy began to lose coverage in
research plans, the priority of the LAD PRV in the optimizer was reduced.
Plan Comparison
Treatment plans were compared by evaluating the differences in the LAD V 15 Gy metric,
and the PTV V60 Gy metric between paired treated and research plans. Although analyzing dose
variations to other OAR was not the goal of this study, dose to these structures was monitored
throughout the research treatment planning process (Table 1). Dose constraints for OAR are
based on Radiation Therapy Oncology Group trial 0617. 10 Volume-type dose objectives for OAR
were to vary by less than 5% between treated and research plans. Dose-type OAR objectives,
such as the mean and maximum dose, were to vary by less than 300 centigray (cGy) between
treated and research plans. Organs at risk that were monitored but not evaluated 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 that this critical structure received adequate prescription dose coverage while reducing
dose to the LAD. 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
Statistical Analysis
Data relating to the differences in dose to the LAD within treated plans and research
plans were assessed for normality 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
Wilcoxon signed rank tests in place of a paired t-test. A two-sided Wilcoxon signed rank test was
conducted on the LAD V15 Gy planning metric. Raw p values of less than 0.05 (P < 0.05) were
considered significant. Data were processed in RStudio.
Results
PTV Dose
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Plan normalization methods varied between plans but remained consistent within treated
and research plan pairs. Research plans were normalized following the same method of
normalization as that of the treated plan. At least 95% coverage of the PTV with prescribed dose
was not achieved in 6 research plans. In all of these cases, this metric was also not achieved in
the treated plan. The greatest difference in the percentage of the PTV dose receiving prescribed
dose was a decrease of 0.223% from the treated plan to the research plan.
LAD Dose
The difference in the LAD V15 Gy was calculated by subtracting the research plan LAD
V15 Gy metric from the treated plan LAD V15 Gy metric (difference = treated – research). The
LAD V15 Gy in treated plans ranged from to 1.36% to 100.0%. The LAD V 15 Gy in research
plans ranged from to 0.0% to 100.0%. Differences in the LAD V 15 Gy between treated and
research plans ranged from 0.0% to 45.20%. The Wilcoxon signed rank test demonstrated a
statistically significant difference in the LAD V15 Gy between treated and research plans (P <
0.001). Therefore, the null hypothesis that plans optimized with an LAD PRV will not have
lower LAD V15 Gy dose than plans optimized without an LAD PRV was rejected.
OAR Dose
Research plans exceeded the 300 cGy difference threshold for dose-type OAR constraints
twice, both of which relate to the same patient (Patient A) and the same OAR. The greatest
observed difference was an increase of 420.0 cGy in the maximum dose for the spinal canal. The
dose to 0.03 cc of the spinal canal increased by 324.6 cGy. The research plan remained within
the outlined dose constraints in both instances of dose-type threshold deviation.
Research plans exceeded the 5% difference threshold for volume-type OAR constraints 5
times. The greatest percent increase between treated and research plans for all volume-type
constraints was 9.335%. This deviation was observed for the lung minus ITV V 5 Gy < 60-65%
constraint metric. Deviations for this metric occurred a total of 3 times. In one instance, both the
research plan and treated plan remained within the acceptable range. In another instance, the
treated plan was within the acceptable range, but the research plan was not. In the last instance,
the threshold deviation for the lung minus ITV V5 Gy < 60-65% metric was not met in both the
treated plan and the research plan. Other metrics that deviated from the 5% volume-type
difference threshold include the V20 Gy < 35% for the total lung minus ITV structure and the
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heart V30 Gy < 50% metric. Both deviations occurred in the research plan for Patient A and
remained within the acceptable range for each respective dose constraint.
Discussion
Adequate coverage of the PTV with prescribed dose is vital to ensuring that the tumor
volume is sufficiently treated. Statistical models created by Davey et al 10 demonstrated that
patients with high dose variability on the periphery of tumor volumes were at an increased risk of
local disease recurrence. Planning target volumes typically encompass the gross tumor volume
(GTV) with an additional margin to ensure complete treatment of the GTV and potential
microscopic disease. Failure to adequately treat the PTV with prescribed dose would increase the
risk of local disease recurrence. Considering the importance of PTV coverage, adequate dose to
this structure was prioritized over sparing of OAR. This approach greatly influenced plan
outcomes and the ability to spare the LAD, among other OAR.
Cardiotoxicities are a common side effect of radiation therapy treatments in NSCLC
patients. Further, Atkins et al9 demonstrated that current constraint metrics for the heart, mainly
the mean heart dose, are not adequate predictors of cardiotoxicities. Additional studies conducted
by Atkins et al,4 McKenzie et al,5 Reshko et al,6 and Yegya-Raman et al8 further supported the
need for constraint metrics related to cardiac substructures. Specifically, the LAD V 15 Gy was
found to more accurately predict MACE in NSCLC patients than MHD. 4,9 Researchers in the
current study evaluated the effects an LAD PRV on reducing LAD V 15 Gy dose when optimizing
VMAT plans. Optimizing with an LAD PRV was found to significantly reduce dose to the LAD,
but the degree to which the LAD was spared from radiation depended on the structure’s
proximity to the PTV. Of the research plans, 10 of 20 did not meet the LAD V 15 Gy < 10%
constraint metric. In four of these cases, the LAD was contained within the PTV. Despite failure
to meet this constraint metric, all but one research plan demonstrated a reduction in dose to the
LAD. Considering this, dose to the LAD should at least attempt to be reduced when optimizing
radiation therapy plans for NSCLC patients with centrally located tumors.
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 V 15 Gy
< 10 % constraint in reducing incidence of cardiotoxicities in both NSCLC patients as well as
left-sided breast patients have contributed to this. Current studies regarding dose to the LAD
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have been retrospective in nature. Though beneficial to identifying potential constraint metrics,
prospective long-term studies are needed to confirm the efficacy of the LAD V 15 Gy < 10%
metric in reducing cardiotoxicities in NSCLC and left-sided breast patients alike. Additional
barriers that influence dose tracking for the LAD are related to the difficulties with contouring
this structure on the CT images that are acquired for treatment planning. The recent
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 CT-MR imaging within radiation oncology departments
is limited.12
As with the sparing of multiple OAR, the conversation of which OAR to spare more than
others comes down to 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 metrics were not statistically analyzed. Of the 7 cases of
OAR constraints exceeding the 5% or 300 cGy dose threshold, 4 deviations occurred in Patient
A. Despite the failure to meet dose threshold metrics, all OAR metrics for Patine A’s research
plan remained below their respective constraints. Further trends in the threshold deviation of
OAR related to the total lung minus ITV V5 Gy < 60-65% constraint metric. Exceeding the 5%
dose threshold for this metric was not necessarily surprising. Reducing dose to one structure
typically displaces such into the surrounding tissues. In the case of sparing the LAD, the
proximity of the lungs to this structure makes the lungs a likely recipient of displaced dose.
The studies conducted by Atkins et al,4 McKenzie et al,5 Reshko et al,6 and Yegya-Raman
et al8 demonstrated the need for dose constraints for cardiac substructures but do not evaluate
planning metrics to spare these substructures. Researchers in the current study demonstrated the
effectiveness of optimizing VMAT with an LAD PRV to reduce dose to the LAD. The current
study found that dose to the LAD can be effectively reduced when VMAT plans are optimized
with a 3 mm LAD PRV.
Conclusion
The problem is that there is an increased risk for major adverse cardiac events and
coronary heart disease for medial, left-sided, upper lobe NSCLC patients when the LAD V15 Gy
≥ 10%. The purpose of this study was to compare dose to the LAD in VMAT plans optimized
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with and without an LAD planning organ at risk volume (PRV) in medial, left-sided, upper lobe
non-small cell lung cancer patients to evaluate dose sparing of the LAD while maintaining 95%
coverage of the PTV with prescribed dose. Plans optimized with an LAD PRV demonstrated a
significant reduction in V15 Gy dose to the LAD when compared to plans optimized without an
LAD PRV (P < 0.001).
Limitations of this study include the small sample size (n = 20) and data collection
limited to a single institution. Increasing the sample size would likely 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. Additionally, a larger sample size would be less
susceptible to influence from outlying observations. Increasing the number of institutions would
further increase the sample size. Suggestions for areas of future research include analysis of
variations in dose to other thoracic OAR. Additionally, evaluation of the variations in dose to the
LAD in plans initially optimized with consideration of LAD constraints and plans later adjusted
to consider LAD constraints would provide further insight into planning techniques that
effectively spare the LAD.
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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.
Organ Constrainta
Body Max < 115%
b
LAD V15 Gy < 10%
Spinal Canal Max < 50 Gy
D0.03 cc < 45 Gy
c
Total Lung minus ITV V5 Gy < 60-65%
V20 Gy < 35%
Mean < 20 Gy
Esophagus Mean < 34 Gy
V35 Gy < 50%
V60 Gy < 17%
Heart Max < 70 Gy
Mean < 20 Gy
V45 Gy < 35%
V30 Gy < 50%
a
Constraints are from Radiation Therapy Oncology Group Trial 0617 10
b
Left anterior descending artery
c
Internal tumor volume