Background: Of patients with solid tumors, an estimated 10-40% develop brain metastases. This incidence likely is rising due to improvements in cancer survival rates (1). When brain metastases are diagnosed, radiation therapy may be an option, but several factors need to be taken into consideration. The first point of decision-making is to consider if any cancer-directed therapy is appropriate. Many patients with untreated brain metastases, especially those with a short prognosis (weeks or less) and comfort-focused goals of care, may die peacefully and comfortably with the help of good supportive care. If radiation-based therapy is indicated and pursued, patients and clinicians should be aware of the common radiation-based treatment modalities. This Fast Fact provides a primer for the generalist clinician regarding the most commonly available radiation-based treatment modalities: stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), and hippocampal avoidance WBRT (HA-WBRT).

Decision-making: When deciding treatment options for patients with brain metastases, clinicians must consider tumor factors (primary tumor site, molecular profile, number, volume, and location of brain lesions, presence of extracranial or leptomeningeal disease), patient factors (age, functional status, comorbidities, goals of care, prognostic understanding), and symptom burden (presence or likelihood of tumor-related headaches, seizures, motor deficits, etc.). Both SRS and WBRT involve a significant time investment and cost, and have the potential to cause fatigue, memory impairment, and neurological injury due to inflammation. Furthermore, radiation treatment may delay hospice enrollment (if that is a goal) (3). While cancer-directed radiation may increase lifespan, offer some preservation of cognitive function, and relieve headache pain, vision loss, and seizures, it is important to determine whether this time spent in treatment and monitoring aligns with the patient’s preferences. Furthermore, prognosis is variable among those with brain metastases and may range from 2-47 months depending on the malignancy type and treatment options (1). Consultation with specialists (particularly radiation oncology and neuro-oncology), often is recommended to gauge this complicated benefit versus harm ratio. In general, radiation-based therapy is most beneficial for patients with a prognosis of at least several months.

Treatment modalities and considerations: Discussion of an individual case in a multidisciplinary tumor board is a common and efficient way to identify optimal treatment modalities that are patient specific. Generally, this includes the input of clinicians from various specialties including radiation oncology, radiology, neurosurgery, medical oncology, neuro-oncology, etc.These recommendations are then shared with the patient or surrogate and a shared decision-making model is utilized. Three main types of radiation-based treatment modalities exist, and sometimes a combination of these modalities is pursued.

1. SRS involves targeted, high-dose radiation to brain tumors while aiming to spare normal tissue. It is a highly precise procedure requiring head fixation (with pins) and mild/moderate sedation for a 30–45-minute period. It is usually performed by the neurosurgery and radiation oncology team together in one or more sessions, depending on the size of the tumor and treatment plan. SRS is the treatment of choice for patients with a few metastatic lesions (e.g., <10), higher prognostic scores, and lower tumor burden. There is growing evidence to suggest that even in some patients with >10 lesions, SRS can offer comparable overall survival to WBRT with fewer neurocognitive adverse effects. However, treatment with SRS alone is also associated with higher rates of new brain metastases and greater need for re-treatment (4-6). Inflammation-based treatment-related side effects include headaches, dizziness, seizures, or other focal neurological symptoms.
2. WBRT is a type of external radiation delivered to the whole brain usually over the course of 1-3 weeks (course varies depending on tumor type, patient tolerance, and treatment fractionation). It is most often completed over many sessions as an outpatient procedure without sedation (since it does not require precise targeting, head fixation). While WBRT is associated with greater adverse effects (more fatigue, hair loss, greater risk of cognitive decline) than SRS, it offers a broader area of intracranial tumor control and may be indicated in patients for whom SRS is not an option. This includes those with leptomeningeal disease, heavy metastatic burden, and/or a prognosis that is anticipated to be measured in months (2). Several studies show that patients with a better initial prognosis who received WBRT plus SRS later on in their illness course had improved survival compared to those who received WBRT alone. There is mixed evidence on the benefit of WBRT plus SRS when compared to SRS alone (7).  This suggests that when appropriate, SRS may be the most effective standalone treatment (7).
3. HA-WBRT: When anatomically feasible, HA-WBRT has emerged to limit neurocognitive decline from radiation-induced hippocampal atrophy and stem cell injury (8-10). However, because cognitive decline in patients with expected lifespan <4 months is largely attributed to disease progression and other factors, HA-WBRT may not provide additional benefit to these patients (10). 

Cost: While most insurance providers cover the cost of WBRT and SRS for brain metastases, cost can still be a limiting factor for many patients. Additionally, hospice programs may be unable to assume the cost of these therapies. SRS and HA-WBRT, being more specialized procedures, typically cost more than WBRT, and SRS may have additional costs associated with the potential need for salvage therapy.

Management of neurotoxicity: The neurocognitive effects of radiation, especially WBRT, have been linked to hippocampal stem cell injury and alterations in the relative levels of NMDA and GABA. The NMDA-antagonist memantine (usual daily dose of 20 mg) has been shown to be effective in preserving patient-reported cognition, executive function, and episodic memory without significant changes in survival (11-13). It is usually started within three days of WBRT or HA-WBRT initiation and taken for up to 24 weeks. Its use has not yet been studied in patients undergoing SRS (11).

References 

1. Sperduto PW, Mesko S, Li J, et al. Survival in Patients With Brain Metastases: Summary Report on the Updated Diagnosis-Specific Graded Prognostic Assessment and Definition of the Eligibility Quotient. J Clin Oncol. 2020;38(32):3773-3784.
2. Arora RD, Agarwal MS, Maani EV, Cascella M. Palliative Radiation Therapy For Brain Metastases. In: StatPearls. Treasure Island (FL): StatPearls Publishing; February 11, 2022. Tsao MN, Xu W, Wong RK, et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev. 2018;1(1):CD003869. 
3. Meyers DS. Palliative Radiation Therapy for the Hospice Patient: Nuances of Care and Reimbursement. J Oncol Pract. 2015;11(1):e87-e88.
4. Robin TP, Rusthoven CG. Strategies to Preserve Cognition in Patients With Brain Metastases: A Review. Front Oncol. 2018;8:415.
5. Yamamoto M, Serizawa T, Shuto T, Akabane A, Higuchi Y, Kawagishi J, et al.. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol. 2014;15:387–95.
6. Yamamoto M, Serizawa T, Higuchi Y, Sato Y, Kawagishi J, Yamanaka K, et al. A Multi-institutional prospective observational study of stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901 Study Update): irradiation-related complications and long-term maintenance of mini-mental state examination scores. Int J Radiat Oncol Biol Phys. 2017;99:31–40.
7. Khan M, Lin J, Liao G, et al. Whole Brain Radiation Therapy Plus Stereotactic Radiosurgery in the Treatment of Brain Metastases Leading to Improved Survival in Patients With Favorable Prognostic Factors. Front Oncol. 2019;9:205.
8. Mulvenna P, Nankivell M, Barton R, et al. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet. 2016;388(10055):2004-2014. 
9. Venur VA, Chukwueke UN, Lee EQ. Advances in Management of Brain and Leptomeningeal Metastases. Curr Neurol Neurosci Rep. 2020;20(7):26.
10. 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. 
11. Brown PD, Pugh S, Laack NN, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol. 2013;15(10):1429-1437. 
12. Chilukuri S, Burela N. Memantine for Prevention of Brain Irradiation-Induced Cognitive Toxicity: A Tale of an Underappreciated and Underused Intervention. JCO Glob Oncol. 2020;6:1384-1388. 
13. Yang WC, Chen YF, Yang CC, et al. Hippocampal avoidance whole-brain radiotherapy without memantine in preserving neurocognitive function for brain metastases: a phase II blinded randomized trial [published correction appears in Neuro Oncol. 2021 Aug 07]. Neuro Oncol. 2021;23(3):478-486. 

Authors’ Affiliations: David Geffen School of Medicine, Los Angeles, CA; University of California, Los Angeles Medical Center, Los Angeles, CA; Pacific Neuroscience Institute, Los Angeles, CA; Providence Saint John’s Health Center, Los Angeles, CA

Conflicts of Interest: None to report

Version History:  First electronically published in February 2023; originally edited by Lara India MD and Sean Marks MD