1

Evaluation of Multiple VMAT planning techniques for hippocampal sparing whole brain
radiotherapy.  

Kearla Bentz, BAS, RT(R)(T); Kristen Eberhard, BS, RT(R)(T); Allison Wright, BS, RT(T);
Nishele Lenards, PhD, CMD, RT(R)(T), FAAMD; Ashley Hunzeker, MS, CMD, RT(T);
and Matt Tobler, CMD, RT(T), FAAMD
Medical Dosimetry Program at the University of Wisconsin-La Crosse, WI

Introduction
Brain metastases (BM) is the most common form of brain cancer.1 The incidence of BM
in the United States have been estimated to be around 70,000 to 400,000 newly diagnosed cases
per year.2 Metastatic brain cancer is roughly 10 times more common than primary malignant
brain cancer, and about 10% to 40% of patients with solid tumors will develop BM.2 Whole-
brain radiation therapy (WBRT) has been a standard palliative radiotherapy treatment option for
decades for patients with multiple brain metastases.1,3 Developing BM is a risk for patients with
many different tumor types, including small cell lung cancer (SCLC), and prophylactic cranial
irradiation (PCI) may be recommended to reduce this risk.4 Previous WBRT and PCI planning
techniques have sufficient coverage of the whole brain but have not been useful in reducing
doses to organs at risk (OAR) in the brain such as the hippocampi, optic chiasm, and optic
nerves.
The hippocampus is a radiosensitive bundle of neural stem cells that is involved with
learning, memory, emotion, motor control, and endocrine regulation.1,5,6 The hippocampi are
shaped like a seahorse and are located in the medial temporal lobe of the brain, with one on the
right and one on the left side of the brain.5 Radiation-induced toxicities from WBRT and PCI
have been attributed to hippocampi damage, which has led to impairment in cognitive function
and a decreased quality of life.1,4 Redmond et al7 demonstrated that there is a significant dose-
response relationship between increased maximum dose to the hippocampi and short-term
memory deterioration.1 Therefore, it is believed that sparing of this region in WBRT and PCI
treatments may preserve cognitive function. Unfortunately, because of its central location within
the brain and unique shape, sparing the hippocampi is a challenge.4,5
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Advancements in radiation therapy technology, such as multi-leaf collimators (MLCs)

and computer-controlled delivery options, have generated new treatment options for WBRT
including intensity modulated radiation therapy (IMRT) and volumetric modulated radiotherapy
(VMAT). These new treatment options have shown comparable dose coverage of the whole
brain with lower dose to OAR.6 This has enabled hippocampal sparing (HS)-WBRT VMAT
planning. These plans are used to reduce the radiation dose to the hippocampi and other
radiosensitive organs near the brain, including the optic chiasm and optic nerves. Radiation can
damage the hippocampi and lead to adverse neurocognitive effects, as seen in traditional
WBRT.3 The Radiation Therapy Oncology Group (RTOG) 0933 phase II study defined strict
target coverage and dose constraints to assess the effects of HS-WBRT. Researchers
demonstrated during this study that the use of IMRT or VMAT reduced dose to the hippocampi
and optic structures. This resulted in less neurocognitive toxicity and vision deterioration. In
addition, patients’ memory, recall, and quality of life at subsequent follow-up appointments were
better in comparison to historical WBRT treatments.3,8,9
Additionally, the group formed by National Surgical Adjuvant Breast and Bowel Project
(NSABP), the RTOG, and the Gynecologic Oncology Group (GOG) known as NRG Oncology
(NRG) initiated the hippocampus avoidance CC001 phase III trial. The research from this trial
found that reducing hippocampal radiation dose along with adding memantine had similar
positive results in reduced cognitive toxicity at follow-up appointments 4 to 6 months after HS-
WBRT.1,5 The steep dose-response relationship between radiation dose to the hippocampi and
cognitive decline has suggested that tighter dose constraints may be beneficial.7 Nevertheless,
because of the location within the brain, avoidance of the hippocampi has required complex
treatment planning to achieve a reasonable dose gradient and reduce dose to the optic
structures.10
Hippocampus sparing WBRT treatment planning can be labor-intensive. Meeting the
hippocampus dose constraint in the NRG-CC001 protocol can also result in unwanted high doses
to the normal brain and optic structures which can result in radiation-induced side effects. The
problem is that high dose to the hippocampi can affect neurocognitive function in patients, and
increased dose within the treatment volume causes radiation-induced side effects. The purpose of
this study was to compare 3 unique VMAT HS-WBRT techniques that decrease the dose to the
hippocampi and hot spots within the treatment volume while maintaining PTV coverage and
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following the NRG-CC001 dose constraints. This research tested the hypothesis that 1 of the
VMAT planning techniques will produce a HS-WBRT planning technique that will decrease the
dose to the hippocampi to < 1600 cGy while maintaining PTV coverage and meeting the NRG-
CC001 dose constraints for the optic structures (H1A). It also tested the hypothesis that 1 of the
VMAT techniques will reduce the maximum dose within the treatment volume to < 115% of the
prescribed dose while maintaining PTV coverage and meeting the NRG-CC001 dose constraints
for the optic structures (H2A).
Materials and Methods
Patient Selection and Setup
This was a retrospective study in which 10 patients were selected and their computed
tomography (CT) planning scans were used for evaluation. Every patient included in this study
was to be treated at one facility and was prescribed HS-WBRT using VMAT planning for either
BM or PCI. The prescription dose was 30 Gy in 10 fractions, once daily. All patients underwent
a CT simulation in the supine, head-first position using a thermoplastic head mask. This helped
to make positioning reproducible, decreased the likelihood of patient movement during
treatment, and created TPS that had fewer variables in set-up (Figure 1).
Contouring
The contours included in this study followed the NRG-CC001 protocol constraint
requirements (Table 1).11 The OAR that were contoured were the hippocampi, optic chiasm, and
the right and left optic nerves. The hippocampi were delineated manually by one radiation
oncologist. An additional avoidance structure was created by three-dimensionally expanding the
hippocampi volume by 5 mm, following the NRG-CC001 protocol.12 The optic structures and
PTV of each TPS were auto contoured at one facility and approved by one radiation oncologist.
These methods were used to reduce the variability in contoured structures. The planning target
volume (PTV) was the entire brain volume minus the optic chiasm, optic nerves, and the
hippocampus avoidance region.
Treatment Planning
All the treatment planning was done by one researcher using Eclipse. The algorithm used
for dose calculation was the anisotropic analytical algorithm (AAA) version 16.1.0. All HS-
WBRT VMAT plans used the Varian TrueBeam STX with high-definition MLC’s (HD-MLCs).
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The isocenter for all plans was placed near the center of the brain. Each plan utilized 6 MV
flattening filter-free (FFF) beams.
Three different HS-WBRT planning techniques were compared in this research study.
These techniques have been used by dosimetrists at 3 cancer centers. Each plan had a unique
arrangement of beam angles and field designs. The first VMAT HS-WBRT technique “A” used
2 full arcs (181 to 179 degrees) with the couch at 0 degrees, fields covering the entire brain, and
the collimator rotations were at 30 degrees for the clockwise (CW) arc and 330 degrees for the
counter-clockwise (CCW) arc. Plan A also used 2 partial sagittal arcs (181 to 340 degrees) with
the couch at 90 degrees, the collimator at 270 degrees, and split-x technique was used that
separated the brain into left and right portions (Figure 2A and Table 2A). The second HS-WBRT
VMAT planning technique “B” used 2 full arcs (181 to 179 degrees) with the couch at 0 degrees,
the collimator at 85 degrees for the CW arc and 95 degrees for the CCW arc, and split-x
technique that separated the brain superiorly and inferiorly. Plan B also used 2 partial sagittal
arcs (179 to 25 degrees) with the couch at 270 degrees for the CW arc and 275 degrees for the
CCW, the collimator at 100 degrees for the CW and 80 degrees for the CCW, and split-x
technique that separated the brain into left and right portions (Figure 2B and Table 2B). VMAT
planning technique “C” used 4 full arcs (179 to 181 degrees) with the couch at 355 degrees for
the first two arcs and 5 degrees for the second set of arcs, with fields covering the entire brain,
and the collimators at 30 degrees for the CW arcs and 330 degrees for the CCW. Plan C also
used a sagittal arc (179 to 20 degrees) with the couch at 270 degrees, the field covered the entire
brain, and the collimator was at 330 degrees (Figure 2C and Table 2C).
A PTV optimization structure was created with a 5 mm outer margin from the PTV. It
was cropped out of the hippocampus avoidance region and given an upper and lower objective,
with the upper being slightly higher than the prescription and the lower limit being < 3300 cGy.
These objectives were given the highest priority, unless priorities needed to be adjusted for the
hippocampus to meet dose constraints. Additional contours separating the brain into upper,
middle, and lower portions were created for optimization purposes and used as targets to help
with coverage and hot spots. The hippocampus was given two upper objectives, 100% getting <
900 cGy and 0% getting < 1600 cGy, and this structure’s objectives were given the second
highest priorities. Finally, all the remaining OAR were given upper objectives of 0% getting<
3000 cGy. The researcher ran the optimization process for each planning technique as needed to
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obtain passing or variation acceptable NRG-CC001 optic dose constraints and lower the dose to
the hippocampus and hot spots within the brain.
Plan Comparison
The 3 VMAT plans were compared using the NRG-CC001 protocol’s constraints (Table
1). The evaluated metrics included dose statistics of the hippocampus, optic structures, and the
maximum dose to the treatment volume. The hippocampus dose to 100% (D100%) was compared
between the 3 planning techniques on each patient, with the goal being < 900 cGy per NRG-
CC001 guidelines with variation acceptable < 1000 cGy. The hippocampus was also assessed
based on the maximum dose (Dmax), with the goal being < 1600 cGy, per this research’s
hypothesis. Each plan was normalized so that 95% of the PTV was receiving the prescription
dose of 3000 cGy. The NRG-CC001 protocol also included constraints for the Dmax of the optic
nerves and optic chiasm to be < 3000 cGy, with variation acceptable < 3750 cGy. Furthermore,
the maximum dose to the treatment volume was compared between planning techniques with the
goal being < 115%, or 3450 cGy.
Statistical Analysis
The data from each planning technique was compared for each of the evaluated metrics
including the hippocampus Dmax (Table 3) and maximum dose to the treatment volume (Table 4).
Due to the multiple variables and non-parametric data, the Friedman’s test was performed to
compare the difference in these statistics between the 3 VMAT HS-WBRT planning techniques.
The significance value was P < 0.1 then research fails to reject the null hypothesis.
Results
Hippocampus Dose
The hippocampus dose between the 3 HS-WBRT planning techniques ranged from a
minimum of 1201.79 cGy to a maximum of 1660.35 cGy. There was a total of 3 plans that were
unable to meet the objective of the Dmax to the hippocampus < 1600 cGy. The average dose for
planning technique “A” was 1509.79 cGy, planning technique “B” was 1418.78 cGy, and
planning technique “C” was 1517.51 cGy. Planning technique “B” had the highest frequency of
having the lowest Dmax to the hippocampus with 6 out of the 10 patient data sets. The data from
each planning technique’s hippocampus Dmax on each patient data set was input into the
Friedman’s test which resulted with P=0.08208. This provided insufficient evidence to support
the hypothesis (H1A) and the first null hypothesis (H10), that none of the VMAT planning
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techniques will result in a HS-WBRT plan with dose to the hippocampi < 1600 cGy while
maintaining PTV coverage and NRG-CC001 OAR dose constraints, failed to be rejected.
Additionally, the average D100% of the hippocampus was 891 cGy for technique “A”, 887 cGy
for technique “B”, and 844 cGy for technique “C”.
Maximum Dose to the Treatment Volume
The maximum dose to the treatment volume was evaluated between the 3 HS-WBRT
planning techniques and ranged from 112.9% (3387 cGy) to 138.7% (4161 cGy). The average
maximum dose for planning technique “A” was 123.35% (3700.5 cGy), planning technique “B”
was 119.9% (3597 cGy), and planning technique “C” was 121.93% (3657.9 cGy). Planning
technique “B” had the highest frequency of having the lowest maximum dose, with 7 out of the
10 patient data sets. The data from each planning technique’s maximum dose on each patient
data set was input into the Friedman’s test which resulted with P=0.04505. This provided
insufficient evidence to support the hypothesis (H2A) and the second null hypothesis (H20), that
none of the VMAT techniques will result in a HS-WBRT plan with the maximum dose < 115%
while maintaining PTV coverage and NRG-CC001 OAR dose constraints, failed to be rejected.
NRG-CC001 constraints
The average dose for each NRG-CC001 constraint metric was calculated (Table 5). The
average dose measurements from Table 5 show that the OAR dose constraints were on average
very close to the protocol requests. Although, of the 30 total plans created only 10 plans met all
the constraints of the NRG-CC001 protocol at the protocol request, all the other plans had at
least 1 constraint that met the variation acceptable constraint (Table 6).
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References
1. Liu H, Clark R, Magliari A, et al. Rapid plan hippocampal sparing whole brain model
version 2 – how far can we reduce dose? Med Dosim. 2022;47:258-263.
https://doi.org/10.1016/j.meddos.2022.04.003
2. Lamba N., Wen P.Y., Aizer A.A. Epidemiology of brain metastases and leptomeningeal
disease. Neurol-Oncol. 2021;23(9):1447-1456. https://doi.org/10.1093/neuonc/noab101
3. Krayenbuehl J, Di Martino M, Guckenberger M, et al. Improved plan quality with automated
radiotherapy planning for whole brain with hippocampus sparing: a comparison to the RTOG
0933 trial. Radiat Oncol. 2017;12:161. https://doi.org/10.1186/s13014-017-0896-7
4. Crockett C, Belderbos J, Levy A, McDonald F, Le Péchoux C, Faivre-Finn C. Prophylactic
cranial irradiation (PCI), hippocampal avoidance (HA) whole brain radiotherapy (WBRT)
and stereotactic radiosurgery (SRS) in small cell lung cancer (SCLC): where do we stand?
Lung Cancer. 2021;162:96-105. https://doi.org/10.1016/j.lungcan.2021.10.016
5. Sprowls CJ, Shah AP, Kelly P, et al. Whole brain radiotherapy with hippocampal sparing
using Varian HyperArc. Med Dosim. 2021;46:264-268.
https://doi.org/10.1016/j.meddos.2021.02.007
6. Kazda T, Vrzal M, Prochazka T, et al. Left hippocampus sparing whole brain radiotherapy
(WBRT): a planning study. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub.
2017;161(4):397-402. https://doi.org/10.5507/bp.2017.031
7. Redmond KJ, Grim J, Robinson CG, et al. Steep dose-response relationship between
maximum hippocampal dose and memory deficits following hippocampal avoidance whole
brain radiation therapy (HA-WBRT) for brain metastases: a secondary analysis of
NRG/RTOG 0933. Int J Radiat Oncol. 2020;18(3)S176.
https://doi.org/10.1016/j.ijrobp.2020.07.956.
8. Shang W, Yao H, Sun Y, et al. Preventive effect of hippocampal sparing on cognitive
dysfunction of patients undergoing whole-brain radiotherapy and imaging assessment of
hippocampal volume changes. Biomed Res Int. April 5,2022;2022:1-10.
https://doi.org/10.1155/2022/4267673
9. Sood S, Pokhrel D, McClinton C, et al. Volumetric-modulated arc therapy (VMAT) for
whole brain radiotherapy: not only for hippocampal sparing, but also for reduction of dose to
organs at risk. Med Dosim. 2017;42:375-383. https://doi.org/10.1016/j.meddos.2017.07.005
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10. Pokhrel D, Sood S, McClinton C, et al. Treatment planning strategy for whole-brain
radiotherapy with hippocampal sparing and simultaneous integrated boost for multiple brain
metastases using intensity-modulated arc therapy. Med Dosim. 2016;41(4)315-322.
https://doi.org/10.1016/j.meddos.2016.08.001
11. NRG Oncology. NRG-CC001: a randomized phase III trial of memantine and whole-brain
radiotherapy with or without hippocampal avoidance in patients with brain metastases.
September 26, 2017. Accessed July 6, 2023.
https://classic.clinicaltrials.gov/ProvidedDocs/15/NCT02360215/Prot_SAP_000.pdf 
12. Brown PD, Gondi V, Pugh S, et al. Hippocampal avoidance during whole-brain radiotherapy
plus memantine for patients with brain metastases: phase III trial NRG oncology CC001. J
Clin Oncol. 2020;38(10):1019-1029. https://doi.org/10.1200/JCO.19.02767 
13. Ehsani O, Pouladian M, Toosizadeh S, Aledavood, SA. Registration and fusion of 3D surface
data from CT and ToF camera for position verification in radiotherapy. SN Appl Sci.
2019;1(11). https://doi.org/10.1007/s42452-019-1350-2.
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Figures

Figure 1. Patient simulation position for the HS-WBRT planning CT and treatments.13

Figure 1A. Planning technique “A” field designs showing an example of the field for the CW
and CCW full arcs (left picture) and the sagittal arcs using split-x technique that separates the
brain into left and right sides (right picture).

Figure 2B. Planning technique “B” field designs showing an example of the fields for the CW
and CCW arcs with split-x technique separating the brain into superior and inferior portions (left
picture) and the sagittal arcs with split-x technique separating the brain into left and right sides
(right picture).
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Figure 1C. Planning technique “C” field designs showing an example of the fields for the CW
and CW arcs with the couch at 355 degrees (left picture), the CW and CCW arcs with the couch
at 5 degrees (middle picture), and the sagittal arc (right picture).
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Tables
Table 1. Constraint table for the NRG-CC001 protocol.11
Name of Structure Dosimetric Parameter Per Protocol Variation Acceptable
PTV_3000 D2% (Gy) <=37.5 37.5-40

D98% (Gy) >25 22.5-25

V30Gy (%) >95 90-95
Hippocampi D100%(Gy) <=9 9-10
Dmax(Gy) <=16 16-17
OpticNerve_R Dmax(Gy) <=30 30-37.5
OpticNerve_L Dmax(Gy) <=30 30-37.5

Optic Chiasm Dmax(Gy) <=30 30-37.5

Table 2A. Planning technique “A” arc arrangements. Showing 2 full arcs and 2 sagittal arcs.
Field ID Energy MLC Gantry Rtn Colli Rtn Couch Rtn
[deg] [deg] [deg]
CW 6X-FFF VMAT 181-179 30 0
CCW 6X-FFF VMAT 179-181 330 0
Sag Arc CW 6X-FFF VMAT 181-340 90 270
Sage Arc CCW 6X-FFF VMAT 340-181 90 270

Table 2B. Planning technique “B” arc arrangements. Showing 2 full arcs and 2 sagittal arcs with
the couch at 270 and 275 degrees.
Field ID Energy MLC Gantry Rtn Colli Rtn Couch Rtn
[deg] [deg] [deg]
CCW 6X-FFF VMAT 179-181 95 0
CW 6X-FFF VMAT 181-179 85 0
Sag Arc CCW 6X-FFF VMAT 179-25 80 270
Sage Arc CW 6X-FFF VMAT 25-179 100 275

Table 2C. Planning technique “C” arc arrangements. Showing 4 full arcs with the couch at 355
and 5 degrees and the sagittal arc.
Field ID Energy MLC Gantry Rtn Colli Rtn Couch Rtn
[deg] [deg] [deg]
CCW T355 6X-FFF VMAT 179-181 330 355
CW T355 6X-FFF VMAT 181-179 30 355
CCW T5 6X-FFF VMAT 179-181 330 5
CW T5 6X-FFF VMAT 181-179 30 5
CCW T90 6X-FFF VMAT 179-20 330 90
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Table 3. Dose statistics for the Dmax of the hippocampus for each planning technique on the 10
patient data sets.
HIPPOCAMPUS Technique “A” Technique “B” Technique “C”
Patient 1 1517.86 1309.27 1525.93
Patient 2 1590.27 1527.95 1551.89
Patient 3 1418.65 1480.76 1629.65
Patient 4 1537.84 1457.62 1495.58
Patient 5 1660.35 1439.11 1201.79
Patient 6 1446.74 1510.18 1546.41
Patient 7 1581.99 1371.49 1549.82
Patient 8 1533.86 1544.43 1634.33
Patient 9 1385.87 1180.61 1459.03
Patient 10 1424.47 1366.35 1580.70
AVERAGE HC DOSE 1509.79 1418.78 1517.51

Table 4. Dose statistics for the maximum dose to the treatment volume for each planning
technique on the 10 patient data sets.
HOTSPOTS Technique “A” Technique “B” Technique “C”
Patient 1 115.4 127.2 112.9
Patient 2 129.2 113.3 125.8
Patient 3 117.2 115.9 124.8
Patient 4 117.7 115.6 118.7
Patient 5 129.3 138.7 134.9
Patient 6 129.9 116.9 116.5
Patient 7 118.1 117.9 118.0
Patient 8 122.7 116.3 120.0
Patient 9 123.9 117.8 118.2
Patient 10 130.1 119.4 129.5
AVERAGE HOTSPOT 123.35 119.9 121.93

Table 5. The average dose of each NRG-CC001 dose constraint for each planning technique.
Average Dose (Gy) Technique “A” Technique “B” Technique “C”
Left Optic Nerve 30.48 29.54 30.41
Right Optic Nerve 30.37 29.65 30.05
Optic Chiasm 30.06 29.77 30.79
PTV D2% 34.61 34.01 34.62
Hippocampus D100% 8.91 8.87 8.44

Table 6. Each planning technique’s results for each patient data set in accordance to the NRG-
CC001 dose constraints for the PTV D2%, Hippocampus D100%, optic chiasm, and optic nerve.
If all constraints were met per protocol (green), if one or more constraints variation acceptable
(orange).
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GOALS Technique “A” Technique “B” Technique “C”

Patient 1 Per Protocol Variation Acceptable Variation Acceptable
Patient 2 Variation Acceptable Per Protocol Variation Acceptable
Patient 3 Per Protocol Per Protocol Variation Acceptable
Patient 4 Per Protocol Per Protocol Per Protocol
Patient 5 Variation Acceptable Variation Acceptable Variation Acceptable
Patient 6 Per Protocol Per Protocol Variation Acceptable
Patient 7 Variation Acceptable Variation Acceptable Variation Acceptable
Patient 8 Variation Acceptable Variation Acceptable Variation Acceptable
Patient 9 Variation Acceptable Variation Acceptable Per Protocol
Patient 10 Variation Acceptable Variation Acceptable Variation Acceptable