1

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 Additionally, patients with small cell lung
cancer (SCLC) have an increased risk of developing BM and prophylactic cranial irradiation
(PCI) may be recommended to reduce this risk.4 Both WBRT and PCI plans have provided
sufficient coverage of the whole brain, but they have not been useful in reducing doses to organs
at risk (OAR) in the brain, such as the hippocampus.
The two hippocampi, that form the hippocampus, 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.1,6,7 Radiation-induced toxicities from WBRT and PCI have been attributed to
hippocampus damage, which has led to impairment in cognitive function and a decreased quality
of life.1,4 Studies have shown that there is a significant dose-response relationship between
increased maximum dose to the hippocampus 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 hippocampus is a challenge.4,6
Advancements in radiation therapy technology, such as multi-leaf collimators (MLC),
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.8 This has enabled
hippocampus sparing (HS) WBRT and efforts to reduce the adverse neurocognitive effects from
WBRT which are believed to be caused from radiation damage of the hippocampus.3 The
Radiation Therapy Oncology Group (RTOG0933) phase II study defined strict target coverage
and dose constraints to assess the effects of HS-WBRT. This study demonstrated that the use of
IMRT or VMAT allowed reduced dose to the hippocampus, following the guidelines of the trial
in HS-WBRT treatments, and resulted in less neurocognitive toxicity and benefits to patients’
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memory, recall, and quality of life at subsequent follow-ups compared to historical WBRT
treatments.3,8,9 Additionally, the NRG-CC001 phase III trial found that reducing hippocampal
radiation dose along with adding memantine had similar positive results in reduced cognitive
toxicity at follow ups 4 to 6 months after HS-WBRT.1,6
Many facilities have implemented the dose constraints of NRG-CC001 for HS-WBRT
treatments and use IMRT or VMAT planning techniques to address the neurocognitive decline
from radiation dose to the hippocampus from PCI and 3D-CRT WBRT. Nevertheless, because of
its location within the brain, avoidance of the hippocampus has required complex treatment
planning to achieve a reasonable dose gradient.3,10 The steep dose-response relationship between
radiation dose to the hippocampus and cognitive decline has suggested that tighter dose
constraints may be beneficial.11 Treatment planning has been 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.3
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 is to compare VMAT HS-WBRT techniques that decrease
the dose to the hippocampus and hot spots in brain tissue while maintaining PTV coverage and
NRG-CC001 OAR dose constraints. This research hypothesizes that one of the VMAT planning
techniques will produce a HS-WBRT plan that will decrease the dose to the hippocampus to <
1600 cGy and the high doses within the brain to < 110% of the prescribed dose. Previous
researchers have tested the hypotheses that that hippocampi sparing in radiation treatment plans
helps avoid shrinkage of the hippocampus (H1A), there is a dose-response relationship between
the maximum dose to the hippocampus and impaired neurocognitive function (H2A), and VMAT
in comparison to 3DCRT can decrease dose to OAR in WBRT (H3A).
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References
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2 – how far can we reduce dose? Med Dosimetry. 2022;47:258-263.
https://doi.org/10.1016/j.meddos.2022.04.003
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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
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