Vol. 3 No. 1 - Mar 2017

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Quantitative Analysis of the Spatial Distribution of Metastatic Brain Lesions Ted K. Yanagihara 1 , Albert Lee 1 , and Tony J. C. Wang 1,2 1 Department of Radiation Oncology and 2 Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York Corresponding Author: Ted K. Yanagihara, MD, PhD Department of Radiation Oncology, Columbia University Medical Center, 622 West 168th St., CHONY Basement North Room B11; E-mail: Key Words: brain metastases, MRI, breast cancer, lung cancer Abbreviations: Brain metastases (BMs), whole-brain radiotherapy (WBRT), magnetic resonance imaging (MRI), intensity-modulated radiation therapy (IMRT), Montreal Neurological Institute (MNI), regions of interest (ROIs) Brain metastases (BMs) are the most common intracranial malignancy and afflict ;10%–20% of patients with cancer. BMs tend to present at the boundaries of gray and white matter because of the distribution of small vessels. In addition, metastases may not be randomly distributed across gross anatomical regions of the brain, but this has not previously been quantified. We retrospectively analyzed a series of 28 patients with recurrent BMs with a total of 150 lesions. Each lesion was manually defined based on T1 gadolinium-enhanced imaging. Stan- dard brain atlases were used to identify the anatomical brain region affected by each BM and the frequency of metastases in each region was compared with the expected probability, which was assumed to be a random distribution based on the brain volume. After correction for multiple comparisons, the paracingulate gyrus was found to have a statistically significant increase (P 5 4.731 3 10 29 ) in the rate of BMs relative to the random spatial distribution. A nonstochastic spatial distribution of metastases may be used to guide partial brain radiother- apy with risk-adapted dose delivery and reduce the risk of neurotoxicity due to overtreatment. INTRODUCTION Whole-brain radiotherapy (WBRT) for patients with brain metas- tases (BMs) is a commonly used technique to treat both visible and subclinical disease. Neurotoxicity is a major concern and protocols to reduce the volume of brain receiving a full dose are currently being tested in clinical trials. However, there are currently no available methods to risk-stratify regions of the brain on the basis of the probability of developing a BM. Accurate segmentation of the brain based on BM risk would permit the radiation dose to be spatially tailored to improve disease control in high-risk regions and spare neurotoxicity by reducing dose to low-risk regions. More accurate radiation delivery has the potential of affect- ing numerous patients because BMs are the most common in- tracranial malignancy, with an annual incidence of .150 000 in the USA (1), and are diagnosed in ;10%–20% of patients with cancer (2, 3). Patients who have previously been treated for BMs or who are at an increased risk for developing BMs often un- dergo surveillance imaging with serial magnetic resonance im- aging (MRI) scans, and treatment may involve focal radiother- apy, such as with stereotactic radiosurgery, or WBRT. Although WBRT remains the standard of care for many patients with BMs, improvements in systemic therapy have led to gains in survival for patients with metastatic disease, and the long-term neuro- cognitive toxicities associated with WBRT must now be weighed against the benefits of treatment. Therefore, several lines of inves- tigation are now directed toward mitigating long-term toxicities associated with full-dose irradiation to the entire brain. Partial brain techniques have recently been tested in an effort to reduce late neurocognitive decline that is associated with WBRT. RTOG 09-33 was a phase II study using intensity- modulated radiation therapy (IMRT) to selectively spare the hippocampi bilaterally while delivering a full dose to the re- mainder of the brain (4). Results showed that neurocognitive toxicities improved with IMRT relative to standard WBRT. In sparing the hippocampi from radiation toxicity, one would as- sume that patients would then be at an increased risk of devel- oping metastatic foci in regions receiving a low radiation dose. On the contrary, local control appears to be maintained with IMRT, and extensive interrogation of the hippocampi revealed that it is at a very low risk for developing BMs (5). The finding that a critical brain structure can be safely spared the damaging effects of high-dose irradiation without compromising efficacy is intrigu- ing and motivates investigation into other areas that might be at a low risk of developing BMs. Some studies have reported that the distribution of BMs may be based on the vasculature (6-8), but others have found that the pattern of spread is influenced by other factors, such as disease histology (9). The majority of the published work has relied on broad classifications of the brain, and there are currently no accepted atlases that segregate brain regions based on the risk of developing BMs. Here, we hypothesized that discrete brain regions are in- volved with metastatic lesions beyond that which would be expected by chance. To test this, we identified 150 BMs in 28 patients treated at a single institution and compared the BMs' RESEARCH ARTICLE ABSTRACT © 2017 The Authors. Published by Grapho Publications, LLC This is an open access article under the CC BY-NC-ND license ( ISSN 2379-1381 16 TOMOGRAPHY.ORG | VOLUME 3 NUMBER 1 | MARCH 2017

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