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Running head: CANDIDATES OF HIPPOCAMPAL SPARING 1

CANDIDATES FOR HIPPOCAMPAL SPARING 3

Candidates of Hippocampal Sparing with Whole Brain Irradiation

Research Proposal Part I: Introduction/Literature Review

Abstract

This cross-sectional differential research study discusses the method of hippocampal sparing in whole brain radiation therapy (WBRT). The study will explore the anatomy and functional purpose of the hippocampus and its surrounding counterparts. The study explains the importance of sparing the hippocampus as well as the risks associated with nonconformal techniques that do not spare the hippocampus. My aim of research is to evaluate which patients should be considered higher priority candidates for conformal WBRT with hippocampal sparing. The primary variables evaluated in this study are treatment intent and age. Secondary variables an include treatment demand, urgency of symptoms, risk of cancer spread or progression of disease during the treatment planning process, physician choice and patient choice.

Candidates of Hippocampal Sparing with Whole Brain Irradiation

Introduction

Whole brain radiation therapy (WBRT) may be necessary in many cases including cranio-spinal treatments, the treatment of brain metastases, prophylactic whole brain irradiation etc. It has been found in many studies that limiting the amount of radiation delivered to the medial temporal lobes, particularly to the hippocampi, has proven to be critical in preserving neurocognitive function for patients (Dunlop, Welsh, McQuaid, Dean, Gulliford, Hansen, & Newbold, 2015). Treatment plans that spare the hippocampus are often complex and time consuming, yet hippocampal sparing has the potential to give patients a better quality of life, so we face an ethical question: are some patients better candidates than others for this method and if so, are we comprising the wellbeing of our patients who aren’t considered candidates?

The hippocampus, Latin for seahorse due to its shape, is a part of the limbic system which directs many bodily functions. The limbic system is located in the brains medial temporal lobe near the center of the brain, deep in the cerebrum. The system is largely made up of the amygdala, hippocampus, thalamus, hypothalamus, basal ganglia, cingulate gyrus, hippocampal gyrus, mammillary body and the fornix. Two very important structures in the limbic system, the amygdala and the hippocampus, function as the brain’s memory and emotional circuit. Because of this reason, both of these structures play a role in normal emotional processing as well as in mood, anxiety and memory disorders (Boundless, 2015).

There is a hippocampus in the temporal lobe of each cerebral hemisphere in the brain. For this reason, the temporal lobes of the brain are considered the memory centers in the brain. The hippocampus is a part of a larger structure in the temporal lobe known as the hippocampal formation. Although it has many functions including emotion due to its proximity to the amygdala, the hippocampus is best known for its role in memory. The hippocampus is critical to the formation, consolidation and manipulation of short and long term memories of events and facts stored in the brain. Dementia and amnesia, both associated with the inability to retain memory, is often the result of damage to the hippocampus. Because radiation damages cells, it is well known that irradiation to the hippocampus in the brain is directly correlated with neurocognitive defects that can lead to dementia and other long term side effects (Dunlop, Welsh, McQuaid, Dean, Gulliford, Hansen, & Newbold, 2015).

The early side effects of WBRT are generally insignificant and mild, where late complications are usually progressive, irreversible, and may have a profound effect on neurocognitive function and quality of life (Shaw, & Ball, 2013). Existing evidence suggests neurocognitive toxicity and deficits including short and long term memory loss are associated with irradiating a neural stem cell compartment in the hippocampus during traditional nonconformal whole brain irradiation. These side effects are known to occur within just one to four short months following treatment (Pokhrel, Sood, Lominska, Kumar, Badkul, Jiang, & Wang, 2015). Research has shown that chemotherapeutic agents also carry a risk of neurological toxicity making it difficult to distinguish between WBRT and chemotherapy induced side effects (Shaw, & Ball, 2013). Shaw and Balls research then proves that patients undergoing a chemotherapy regimen may still experience a cognitive decline making these patients not ideal participants in studies which evaluate the effects of hippocampal sparing on neurocognitive function in general.

Linear accelerator-based, intensity modulated radiation therapy (IMRT) conformal techniques are used to avoid the hippocampi and significantly reduce the amount of radiation dose to the neural stem cell compartment in the hippocampus. The problem with tomotherapy or linear accelerator-based IMRT is that these modalities require a large number of total monitor units (MU’s) and relatively longer treatment times (Pokhrel, Sood, Lominska, Kumar, Badkul, Jiang, & Wang, 2015). Avoiding the large number of total MU’s and longer treatment time while still avoiding the hippocampi can be achieved with the recently implemented approach of intensity-modulated arc therapy (IMAT). IMAT plans could decrease the dose to organs at risk, including the hippocampus, and could one day be considered the primary approach to whole brain irradiation which could ultimately improve the quality of life for patients undergoing this treatment (Pokhrel, Sood, Lominska, Kumar, Badkul, Jiang, & Wang, 2015).

For patients in need of WBRT, a conformal approach to spare the hippocampus may raise concern for missing target coverage since the target is in fact, the entire brain. Luckily, recent research proves that modern technology has allowed for a massive reduction of dose to the hippocampus while still maintaining acceptable tumor control probability (Kazda, Jancalek, Pospisil, Sevela, Prochazka, Vrzal, Laack, 2014). In addition, evidence has shown that metastatic lesions to the hippocampus are extremely rare and in approximately 86% of patients with cerebral metastases, there exists at least a 15 mm margin between the closest metastasis and the hippocampus, which would allow for effective sparing with modern WBRT without compromising therapeutic efficacy (McTyre, Scott, & Chinnaiyan, 2013). This means that WBRT with an IMAT or IMRT conformal technique does not necessarily escalate the risk of missing target coverage, making this method safe for patients.

Conformal treatment planning can be a time consuming process. Depending on the department and its treatment planning demand, this process could take a week or longer to complete. Because of this, emergency patients who cannot wait to begin treatment are likely to begin treatment with, or complete a full treatment regimen with a basic lateral WBRT treatment plan without the intricate and time consuming planning of IMRT or IMAT. Patients who get treated with a basic plan without hippocampal sparing are typically those who present with brain metastases. Brain metastases are the most common neurologic complication related to cancer. These patients often require emergency treatment to prevent or cease dangerous and often life threatening seizures, strokes or hemorrhages. Sadly, it can also be argued that palliative patients aren’t expected to live long enough to experience the negative neurocognitive effects of hippocampal irradiation. We might suspect then that these patients are less likely to be chosen as a candidate for this more complicated method of treatment (Chargari & Kirova, 2011).

Patients being treated with prophylactic intent are more likely candidates for hippocampal sparing. The aim of prophylactic WBRT is to prevent the spread of cancer to the brain. A prophylactic prescription is typically given to patients who have cancers that are reliably consistent with a tendency to spread to the brain such as small cell lung cancer and certain cancers of the breast. Because patients are being treated with preventative methods and are not officially diagnosed with cancer of the brain, these patients are usually expected to live to experience the side effects of hippocampal toxicity. We might suspect then that these patients are more likely to be chosen as candidates for conformal radiation therapy with hippocampal sparing (Lutz, 2007).

Pediatric brain research has found that radiation exposure to the temporal regions of the brain containing the hippocampus is directly related to a decrease in IQ and ability to form new memories in younger patients (McTyre, Scott, & Chinnaiyan, 2013). Because of pediatric research including studies done by McTyre, Scott and Chinnaiyan, hippocampal sparing in the pediatric population is becoming especially important. Because of this, we suspect that research will prove that pediatric patients will be more likely than other candidates to be chosen for a conformal hippocampal sparing technique. Additional research on brain development, however, shows that the brain is not considered fully developed until around age 25, so should patients under the age of 25 also take priority (Giedd & Rapoport, 2010)?

Research from multiple sources has proven the benefits of hippocampal sparing but the question still remains, are some patients better candidates than others for this method and if so, are we comprising the wellbeing of the patients who aren’t high priority considered candidates? My aim of research is to evaluate which patients should be considered higher priority candidates for conformal WBRT with hippocampal sparing. The primary variables in this study are treatment intent and age. Secondary variables included in the study will be used to provide rationale for the study’s results. Secondary variables analyzed in the study include treatment demand, urgency of symptoms, risk of cancer spread or progression of disease during the treatment planning process, physician choice and patient choice.

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