1

To determine which VMAT planning technique for HCS-WBRT minimizes the dose to the
hippocampi and hot spots within the plan while maintaining PTV coverage and OAR dose
constraints.  
Kearla Bentz, RT (R)(T); Kristen Eberhard, RT (R)(T); and Allison Wright RT (R)(T)
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
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.
The 2 hippocampi are called the hippocampus in singular form with one on each side of
the brain. The hippocampi are located in the medial temporal lobe of the brain and are shaped
like a seahorse.5 The hippocampus is a radiosensitive bundle of neural stem cells that are
involved with learning, memory, emotion, motor control, and endocrine regulation.1,5,6 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 Studies, such as
Redmond et al7, have shown 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
Advancements in radiation therapy technology, such as multi-leaf collimators (MLCs),
have generated new treatment options for WBRT including intensity modulated radiation therapy
(IMRT) and volumetric modulated radiotherapy (VMAT). These new treatment options have
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shown comparable dose coverage of the whole brain with lower dose to OAR.6 This has enabled
hippocampal sparing (HS)-WBRT planning. These plans are used to reduce the adverse
neurocognitive effects from WBRT, which are believed to be caused from radiation damage of
the hippocampi.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 allowed reduced dose to the
hippocampi. This resulted in less neurocognitive toxicity, and patients’ memory, recall, and
quality of life at subsequent follow-ups 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) called NRG
Oncology (NRG) initiated the hippocampus avoidance CC001 phase III trial. This trial found
that reducing hippocampal radiation dose along with adding memantine had similar positive
results in reduced cognitive toxicity at follow up 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.10
Treatment planning can be labor-intensive and meeting organs at risk (OAR) dose
constraints has resulted in unwanted high doses to the normal brain, the planned target volume
(PTV), 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. Therefore, the purpose of this study was
to compare VMAT HS-WBRT techniques that decrease the dose to the hippocampi and hot spots
in brain tissue while maintaining PTV coverage and NRG-CC001 dose constraints. This research
tested the hypothesis that one of the VMAT planning techniques will produce a HS-WBRT
planning technique that will decrease the dose to the hippocampi to < 1600 cGy (H1A). It also
tested the hypothesis that one of the VMAT techniques will reduce the high dose within the brain
to < 115% of the prescribed dose (H2A).
Materials and Methods
Patient Selection and Setup
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This was a retrospective study that used 10 patients’ computed tomography (CT)
treatment planning scans (TPS). 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. Treatment scans were excluded that
were > 3 years prior. All patients underwent a CT simulation where they were simulated 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.
Contouring
The contours included in this study followed the NRG-CC001 protocol requirements with
additional contours for OAR structures near the brain.11 The OAR that were contoured were the
hippocampi, spinal cord, lacrimal glands, cochleae, brainstem, oral cavity, and optic structures.
The optic structures included each eye, lens, optic nerve, and the optic chiasm. Additional
contours separating the brain into upper, middle, and lower portions were created for
optimization purposes. The planning target volume (PTV) was the entire brain volume minus the
optic chiasm and the hippocampus with 5mm margin. A PTV optimization structure was created
with a 5 mm outer margin from the PTV. The OAR and (PTV) was the entire brain volume
minus the optic chiasm and the hippocampus with 5mm margin. The optic structures and PTV of
each TPS were auto contoured at one facility and adjusted and approved by one radiation
oncologist. An additional structure was created by three-dimensionally expanding the
hippocampi volume by 5 mm, following the NRG-CC001 protocol.12 These methods were used
to reduce the variability in contoured structures.
Treatment Planning
All the treatment planning was done by one researcher using the same treatment planning
hardware and software. The treatment planning software was Eclipse. The algorithm used for
dose calculation was the anisotropic analytical algorithm (AAA) version 16.1.0. All HS-WBRT
VMAT plans were planned for the same machine, the Varian TrueBeam STX, using high-
definition MLCs (HD-MLCs). The isocenter for all plans was placed near the center of the brain.
Each plan used 6 megavoltage (MV) flattening filter-free (FFF) beams.
There were 3 different HS-WBRT planning techniques used in this research study. Each
plan had a unique arrangement of beam angles and field designs. The first VMAT HS-WBRT
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technique “A” used 2 full arcs (181 to 179 degrees) with the couch at 0 degrees, these fields
covered 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 rotations were at 270 degrees,
and split-x technique was used that separated the brain into left and right portions (Figure 1A and
2A). The second HS-WBRT VMAT planning technique “B” used 2 full arcs (181 to 179
degrees) with the couch at 0 degrees and collimator rotations of 85 degrees for the CW arc and
95 degrees for the CCW arc. Each of these fields used 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 rotations
were at 100 degrees for the CW and 80 degrees for the CCW, and split-x technique was used that
separated the brain into left and right portions (Figure 1B and 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. These fields covered the entire brain, and the collimators
were set 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 3A and 3B).
The optimization process was completed by the same researcher that performed the
treatment planning contours and field set-ups. The PTV with 5 mm margin was used for
optimization. It was given an upper and lower objective, with the lower being slightly higher
than the prescription and the upper limit being less than 3300 cGy. These objectives were given
the highest priority, unless priorities needed to be adjusted for the hippocampus to meet dose
constraints. The hippocampus was given two upper objectives, 100% getting less than 1600 cGy
and 0% getting less than 900 cGy, and this structure’s objectives were given the second highest
priorities. Finally, all the remaining OAR were given upper objectives of 0% getting less than
3000 cGy or less, depending on the cost function. The researcher used the optimization process
within the TPS multiple times to achieve PTV coverage, meet NRG-CC001 OAR dose
constraints or variable accepted constraints, and lower the hot spots within the brain. When plans
either met the requested dose constraints or it was decided that they could not meet the requests,
they went through plan comparison with the other techniques for each patient.
Plan Comparison
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The 3 VMAT plans were compared using the NRG-CC001 protocol’s constraints (Table
1). The evaluated metrics included dose statistics of the hippocampus, PTV, and optic structures.
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. The hippocampus was
also assessed based on the maximum dose (Dmax), with the goal being < 1600 cGy per this
research’s hypothesis. The coverage of the PTV was compared between plans, with the goal of
each plan to have the volume at 3000 cGy > 90 to 95% of the PTV. Additionally, the PTV of
each plan was compared based on the dose to 98% (D98%) receiving > 2500 cGy. Both of these
constraints followed the NRG-CC001 protocol. The OAR constraints of the NRG-CC001
protocol also included the optic nerves and optic chiasm. The goal for each of these structures
was for the Dmax of each to be < 3000 cGy. Furthermore, because of the hypothesis of this study,
the maximum dose to the brain, or dose to the hottest 2% (D2%) was compared between planning
techniques with the goal being < 115% of the prescribed dose, or 3450 cGy.
Statistical Analysis
The PTV and OAR dose statistics were reviewed to determine the applicable analysis
methods. Data from each planning technique was compared for each of the evaluated metrics
including the hippocampus (Table 2), PTV (Table 3), and OAR dose (Table 4). Due to the
multiple variables and non-parametric data, the Friedman’s test was performed to compare the
differences between the 3 VMAT HS-WBRT planning techniques. For every metric evaluated
each plan was given a ranked value of 1 to 3 depending on which plan had the optimal dose. The
ranks for each planning technique were summed and applied into the Friedman (FM) equation to
find the F value. The calculated F value was compared to the FM critical value of 6.20. The null
hypothesis was rejected if the calculated F value was larger than the FM critical value. (Waiting
to hear back from UW-L Stat Center for feedback on additional or more fitting statistical
analysis methods. Will update this section and add tables when we hear back.)
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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
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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
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 
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Figures

Figure 1A. Planning technique “A” field designs showing the fields for the CW, CCW, and
sagittal arcs using split-x technique that separates the brain into left and right sides.

Figure 2A. Planning technique “B” field designs showing the fields for the CW and CCW arcs
with split-x technique separating the brain into superior and inferior portions, and the sagittal
arcs with split-x technique separating the brain into left and right sides.

Figure 3A. Planning technique “C” field designs showing the fields for the CW and CW arcs
with the couch at 355 degrees, the CW and CCW arcs with the couch at 5 degrees, and the
sagittal arc.

Figure 1B. Planning technique “A” arc arrangements. Showing 2 full arcs and 2 sagittal arcs.
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Figure 2B. Planning technique “B” arc arrangements. Showing 2 full arcs and 2 sagittal arcs
with the couch at 270 and 275 degrees.

Figure 3B. Planning technique “C” arc arrangements. Showing 4 full arcs with the couch at 355
and 5 degrees and the sagittal arc.
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Tables