1

Including Contralateral Esophagus and Left Anterior Descending Coronary Artery as

Organs At Risk for VMAT Lung Cancer
Kerry Shroyer RT (R)(T)(CT), Ryan Monago RT(R)(MR)(T), Nishele Lenards, PhD, CMD,
RT(R)(T), FAAMD; Ashley Hunzeker, MS, CMD, Matt Tobler, CMD, RT(T) FAAMD
Medical Dosimetry Program at the University of Wisconsin-La Crosse, WI

Abstract
Researchers have shown that careful avoidance of the CE and LAD can lead to better clinical
outcomes for patients. The problem is that these structures are not routinely included as standard
avoidance structures for VMAT planning for NSCLC. The purpose of this retrospective planning
study was to determine whether prescription target volume goals could be maintained while
limiting dose to the CE and LAD for VMAT lung planning. Ten patients were selected for this
study and were reoptimized with new dose constraints for the CE and LAD. These experimental
plans were compared to the clinically treated plans to determine whether dose could be limited to
the CE and LAD without compromising planning target volume (PTV) coverage or causing
failure of other organ at risk (OAR) goals. Dosimetric data was compared using a statistical sign
test. Researchers tested whether VMAT lung plans would meet prescription PTV goals while
reducing dose to the LAD to V15Gy < 10% and reducing dose to the CE to V55Gy < 0.5 cm3,
V45Gy < 2.5 cm3 and D0.03cm3 < 60 Gy. The addition of new CE and LAD constraints resulted in
limited dose to these structures while maintaining PTV coverage and other OAR dose values.

Keywords:
Lung radiotherapy, esophagitis, cardiac toxicity, VMAT, LAD
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Introduction
Volumetric modulated arc therapy (VMAT) is an external beam radiation therapy
technique used for curative non-small cell lung cancers (NSCLC) that allows conformal dose
distribution and critical organ sparing.1 One of the primary advantages of VMAT planning is the
ability to spare healthy organs that would otherwise be at risk from other planning techniques.
Volumetric modulated arc therapy lung planning objectives often include whole-organ
constraints such as contralateral lung or heart, but it is not common practice to include the left
anterior descending coronary artery (LAD) and contralateral esophagus (CE) specifically as dose
limiting structures despite clinical research indicating that exceeding dose to these structures can
lead to severe patient complications and morbidity.
The coronary arteries, including the LAD, originate in the base of the heart.2 Radiation
dose to the base of the heart is associated with non-cancer deaths for patients with NSCLC.3
Fifteen Gy to ≥ 10% of the LAD has been associated with an increase in major adverse cardiac
events.4 When considering substructures of the heart, the LAD has the highest association with
adverse outcomes independent from other factors such as cardiac disease history. Atkins et al 4
suggest that the current use of mean dose as the primary constraint of the heart is limited in value
because it does not account for dose distribution across specific areas of the heart. McWilliam et
al5 suggested that contouring and sparing substructures in the base of the heart rather than the
whole heart for dose constraints could lead to improved patient outcomes.
The CE is the esophageal wall region contralateral to the disease and is another structure
not commonly used as an organ at risk (OAR). Al-Halabi et al6 found it is possible to limit total
esophagus cross-section dose for patients with NSCLC receiving intensity modulated radiation
therapy (IMRT) treatments. By reducing the median volume of the CE receiving 45.0 Gy (V45)
and 55.0 Gy (V55) to 2.5 cm3 and 0.5 cm3 respectively, patients were spared of grade 3
esophagitis which can cause hospital admittance and necessitate a feeding tube. 6-8 Reduction in
preventable radiation induced complications could reduce interruptions in patient treatment
courses. Based on previous studies, it can be assumed that considering the CE as a separate,
additional structure rather than the serial organ esophagus, can reduce grade 3 esophagitis as a
patient complication.9
Researchers have shown that careful avoidance of the CE and LAD can lead to better
clinical outcomes for patients. The problem is that these structures are not routinely included as
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standard avoidance structures for VMAT planning for NSCLC. The purpose of this retrospective
planning study was to determine whether prescription target volume goals could be maintained
while limiting dose to the CE and LAD for VMAT lung planning. Researchers tested the
hypotheses that VMAT lung plans will meet prescription planning target volume (PTV) goals
while (H1A) reducing dose to the LAD to V15Gy < 10% and (H2A) reducing dose to the CE to
V55Gy < 0.5 cm3, (H3A) V45Gy < 2.5 cm3, and (H4A) dose to 0.03 cm3 (D0.03cm3) < 60 Gy as
proposed by previous clinical studies.4-6
Methods and Materials
Patient Selection and Setup
Patients selected for this study were previously treated with VMAT plans for primary
lung cancer of various non-small cell histologies. Prescription dose was at least 59.4 Gy, 1.8-2.0
Gy per fraction. Patients with left-side disease or right-side disease with a PTV within 2.0 cm
lateral to the esophagus were included. Patients were all simulated headfirst, supine, with arms
raised. All patients were scanned with four-dimensional computed tomography (4DCT), 2.0 mm
CT slice thickness, and planned on the average phase series.
Contours
In addition to the previously contoured structures for traditional lung metrics such as
whole heart and, total lung minus internal target volume (ITV), the LAD and CE were contoured
on each patient. The LAD was contoured per department guidelines and approved by a radiation
oncologist as an independent structure from the heart and a 1.0 mm planning organ at risk
volume (PRV) structure was created for optimization. The CE was created following the Kamran
et al8 guidelines utilized in their phase 1 nonrandomized clinical trial. The gross tumor volume
(GTV) created by the physician was examined in the contouring window. The contralateral
esophagus was drawn with a brush tool by contouring half of the esophagus distal to the disease
on all axial slices where the GTV was present (Figure 1). Per Al Halabi et al6 guidelines, the CE
should not be within 5.0 mm of the ITV edge. All the cases utilized in this planning study had
5.0 mm expansions on the ITV to create the PTV, so the defined CE was then cropped out of the
PTV to ensure the 5.0 mm distance to ITV.
Treatment Planning
All plans were created using Varian Eclipse version 16.1, and arc geometry was not
changed from the original patient treatment so that any changes to dose metrics could be
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specifically linked to the addition of new structure constraints. Plans were calculated using
AcurosXB16101 algorithm. All plans were created for the same linear accelerator – Varian
TrueBeam, 6 MV with a 0.5 cm width multi-leaf collimator (MLC) for the inner 20.0 cm section
and a 1.0 cm MLC width for the outer 10.0 cm section of MLC. Clinical constraints were
unchanged from the previous patient plan other than the addition of LAD and CE objectives.
Optimization goals were adjusted within planning to address constraints that were exceeding
limitations. The Varian optimization tool “avoid entry” was used for LAD goals. Evaluation of
newly optimized plans assessed whether the retrospective plan still met OAR constraints
compared to the previous plan, whether prescription goals were still met, and whether the new
plan met the new LAD and CE goals.
Plan Comparison
The experimental plans were compared to the patient’s clinically treated plans by
evaluating specific metrics. Planning target volume coverage was compared based on what
percentage of the volume was receiving 100% of prescription dose. All experimental plans were
normalized within a range of 99.7 to 100% to achieve the coverage goal of 100% of prescription
dose to at least 95% of the PTV. As an accurate comparison to the clinically treated plan, the
overall hotspot within the experimental plans was limited to 0.03 cm3 <110%. Dose to the LAD
and CE was compared regarding the goals previously defined. The heart mean dose was also
evaluated, with an ideal constraint of < 20 Gy mean dose.
Statistical Analysis
To determine the significance of change in CE and LAD dose outcomes after re-
optimization with the dose constraints, the previous values were compared to the newly reported
values using a statistical sign-test. The sign test assigned a P-value and P-value to each set of
analyzed data. A P-value < 0.10 was considered significant.
Results
Maintenance of PTV coverage
Of the clinically treated plans, 9 met the goal of V100% ≥ 95%, meaning that 100% of the
prescription dose encompassed at least 95% of the PTV. One plan, patient 3, did not meet this
constraint at 91.5%. All experimental plans maintained previous PTV coverage. To evaluate the
LAD and CE data, maintenance of PTV coverage was required. The ability to meet the LAD and
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CE goals while maintaining PTV prescription coverage rejected the null hypotheses H1 0, H20,
H30, H40.
LAD V15Gy ≤ 10%
Eight of the 10 clinically treated plans failed to meet the LAD V15Gy ≤ 10% goal. The
range of values for this constraint were between 0% and 69% with a mean value of 34% and a
standard deviation of 24%. All 10 experimental plans met this constraint ranging from 0% to 9%,
with a mean value of 4%, and a standard deviation of 4% (Figure 2). The P-value of this
constraint was 0.002, therefore the null hypothesis H10 was rejected.
CE V55Gy < 0.5 cm3
Four of the clinically treated plans failed the CE V55Gy goal of < 0.5 cm3 prior to this
study. Of the 6 passing plans, 5 had a value of 0 for this category. The plans ranged from 0.0 cm3
to 1.53 cm3 receiving 55 Gy, with a mean value of 0.439 cm3 and a standard deviation of 0.571.
All 10 experimental plans were less than 0.5 cm3 for this category. The range of V55Gy was 0.0
cm3 to 0.49 cm3 with a mean of 0.091 cm3 and standard deviation of 0.157 (Figure 3). The P-
value of this constraint was 0.013, therefore, the null hypothesis H20 was rejected.
CE V45Gy < 2.5 cm3
Only 1 clinically treated plan failed the V45Gy < 2.5 cm3 constraint at 6.71 cm3. The
range of V45Gy was between 0.0 cm3 to 6.71 cm3 with a mean value of 1.362 cm3 and standard
deviation of 2.039. The clinically treated plan that exceeded this metric was reduced from 6.71
cm3 to 1.11 cm3. All experimental plans met the V45Gy constraint with a range of 0.0 cm3 to 1.76
cm3, a mean value of 0.645 cm3 and a standard deviation of 0.703 (Figure 4). The P-value of this
constraint was 0.007, therefore the null hypothesis H30 was rejected.
CE D0.03cm3 < 60 Gy
Two of the 10 clinically treated plans did not meet the goal of CE D0.03cm3 < 60 Gy. The
range for this constraint was 25.6 Gy to 60.8 Gy with a mean value of 47.42 Gy and a standard
deviation value of 15.22. All 10 experimental plans met this constraint, with a range from 24 Gy
to 59.4 Gy, a mean value of 46.7 Gy, and a standard deviation value of 12.21 (Figure 5). The P-
value of this constraint was 0.102, indicating this was not a statistically significant change,
however the null hypothesis H40 was rejected because all plans were able to meet this constraint
without compromising PTV coverage.
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Discussion
The inclusion of 3 additional constraints to the clinically treated plans for re-optimization
resulted in a reduction of dose to the LAD and CE for all 10 experimental plans while
maintaining PTV coverage, indicating that these constraints are attainable planning goals. There
were statistically significant changes to the LAD V 15Gy, CE V55Gy, and CE V45Gy after adding
these constraints into optimization. This dose reduction is especially important given previous
researchers have indicated that the LAD and CE are valuable OAR when assessing potential
patient clinical outcomes.2-9 Researchers have found that limiting the V15Gy to the LAD can lead
to better patient outcomes and reduce non-cancer cardiac morbidity.4 In studies surrounding dose
to the CE, researchers have found that by reducing the V45Gy and V55Gy dose, there may be a
significant decrease in grade III esophagitis.4,6,7 By implementing these proposed dose
constraints for VMAT NSCLC treatments, there is potential for less cardiac complication and
fewer treatment breaks as a result of esophagitis.6,7
In addition to the new CE and LAD goals, the original OAR goals were re-evaluated to
determine any changes that could be linked directly to the addition of the new LAD and CE
constraints. There were statistically insignificant changes to the heart mean, global maximum
dose, total lung minus ITV mean dose, and total lung minus ITV Volume of 20 Gy (V 20Gy);
therefore, adding the CE and LAD constraints did not significantly change these values. The total
lung minus ITV V5Gy volume, however, had significant change with a P-value of 0.006. In 9 of
the 10 plans, there was an increase in V5Gy to the total lung minus ITV statistically, but the new
V5Gy value was still within the specified dose constraints for this metric of V 5Gy < 65% The
clinically treated plans had an average V5Gy of 42.2%, and the experimental plans had an
average V5Gy of 48.5%.
Changes to other OAR dose were statistically insignificant other than the ITV V 5Gy,
which can be attributed to redirecting the low dose of the plan to accommodate these new
treatment goals. However, the V5Gy was still within acceptable tolerance based on the clinically
treated dose constraints. The significance of certain OAR constraints such as the low dose
distribution from VMAT planning may differ based on physician preference, and priority of
clinical objectives must be discussed when planning.
Current protocols for VMAT treatment of NSCLC include dose constraints for the
esophagus and heart, but do not indicate dose limitation specifically to the CE or LAD. For
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example, RTOG 1306, recommends whole esophagus maximum and mean values alone for
esophagus constraints.10 Adding the CE and LAD as a dose limiting structure to existing
protocols may improve clinical outcomes.
Conclusion
Researchers have shown that careful avoidance of the CE and LAD can lead to better
clinical outcomes for patients. The problem is that these structures are not routinely included as
standard avoidance structures for VMAT planning for NSCLC. The purpose of this study was to
determine whether prescription target volume goals could be maintained while limiting dose to
the CE and LAD for VMAT lung planning. The addition of new constraints for the CE and LAD
were shown to reduce dose to these structures while not reducing coverage to the PTV or
compromising other OAR structures.
The primary limitation of this study was a small sample size (n=10). Researchers did not
make changes to beam geometry, therefore, further studies with variable treatment factors may
yield new results. Researching these outcomes on a wider population of NSCLC VMAT
treatments at varying distance from the esophagus and heart could provide insight into whether
these constraints can consistently be met. Further research may include larger variance in tumor
size and distance from new optimization structures.
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References
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treating locally advanced lung cancer. Semin Radiat Oncol. 2015;25(2)110-116.
https://doi.org/10.1016/j.semradonc.2014.11.004
2. Stam B, Peulen H, Guckenberger M, et al. Dose to heart substructures is associated with non-
cancer death after SBRT in stage I-II NSCLC patients. Radiother Oncol. 2017;123(3):370-
375. http://doi.org/10.1016/j.radonc.2017.04.017
3. Tjong M, Bitterman D, Brantley K, Nohria A, Hoffman U, Atkins K, Mak R. Major adverse
cardiac event risk prediction model incorporating baseline Cardiac disease, Hypertension,
and Logarithmic Left anterior descending coronary artery radiation dose in lung cancer
(CHyLL). Radiother Oncol. 2022; 169:105-113.
4. Atkins KM, Chaunzwa TL, Lamba N, et al. Association of left anterior descending coronary
artery radiation dose with major adverse cardiac events and mortality in patients with non–
small cell lung cancer. JAMA Oncol. 2021;7(2):206–219.
http://doi.org/10.1001/jamaoncol.2020.6332
5. McWilliam A, Kennedy J, Hodgson C, Vasquez Osorio E, Faivre-Finn C, van Herk M.
Radiation dose to heart base linked with poorer survival in lung cancer patients. Eur J
Cancer. 2017;85:106-113. http://doi.org/10.1016/j.ejca.2017.07.053
6. Al-Halabi H, Paetzold P, Sharp GC, Olsen C, Willers H. A contralateral esophagus-sparing
technique to limit severe esophagitis associated with concurrent high-dose radiation and
chemotherapy in patients with thoracic malignancies. Int J Radiat Oncol Biol Phys.
2015;92(4):803-810. http://doi.org/10.1016/j.ijrobp.2015.03.018
7. Kamran SC, Yeap BY, Ulysse CA, et al. Assessment of a contralateral esophagus–sparing
technique in locally advanced lung cancer treated with high-dose chemoradiation: a phase 1
nonrandomized clinical trial. JAMA Oncol. 2021;7(6):910–914.
http://doi.org/10.1001/jamaoncol.2021.0281
8. Ma L, Qiu B, Li Q, et al. An esophagus-sparing technique to limit radiation esophagitis in
locally advanced non-small cell lung cancer treated by simultaneous integrated boost
intensity-modulated radiotherapy and concurrent chemotherapy. Radiat Oncol.
2018;13(1):130. https://doi.org/10.1186/s13014-018-1073-3
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9. Bowes C, Durgin B, Thomas S, Keane F.K, Khandekar M.J, Willers H. Esophagitis

outcomes with or without contralateral esophagus sparing in locally advanced lung cancer.
Int J Radiat Oncol Biol Phys. 2021; 111(3S)2889. DOI: 10.1016/j.ijrobp.2021.07.1225
10. Govindan, Ramaswamy MD. NRG Oncology. A Randomized Phase II Study of
Individualized Combined Modality Therapy for Stage III Non-Small Cell Lung Cancer
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https://classic.clinicaltrials.gov/ProvidedDocs/96/NCT01822496/Prot_SAP_000.pdf
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Figures

Figure 1. Contralateral Esophagus (CE) contour created by delineating one half of the esophagus
on the side distal to the treatment volume and limited to slices containing GTV.
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Figure 2. Change in LAD V15Gy dose from the original plans to the re-optimized plans.
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Figure 3. Change in CE V55Gy dose from the original plans to the re-optimized plans.
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Figure 4. Change in CE V45Gy dose from the original plans to the re-optimized plans.
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Figure 5. Change in CE 0.03 cm3 maximum dose from the original plans to the re-optimized
plans.