Brain metastases represent the most common intracranial malignancy. The management of brain metastases is often complex, multidisciplinary, and highly individualized. In this review, the role of radiotherapy in the management of brain metastases is considered from a historical perspective, in the context of other treatment modalities, and with regard to different radiotherapy techniques. Data regarding coordination of systemic therapy with radiotherapy is reviewed, outlining historical findings and a paucity of data in the context of novel systemic cytotoxic and biologic therapies with whole brain radiotherapy and stereotactic radiosurgery. Controversial aspects of patient management are considered, including multifactorial patient, tumor, and treatment factors that inform treatment recommendations for individual patients. Current clinical controversies and research endeavors are reviewed as they relate to maximization of therapeutic efficacy, minimization of toxicity, and optimization of quality of life. General evidence-based approaches to management of brain metastases are considered and published guidelines are addressed in this review.
Brain metastases represent the most common intracranial malignancy in adults and are reported to develop in 10% to 40% of patients with a known extracranial primary malignancy.1
While the exact incidence is uncertain, present estimates suggest that approximately 180,000 patients in the United States are diagnosed with brain metastases annually.1–3
With advances in systemic therapies and the potential increased longevity of cancer patients, the absolute incidence of brain metastases may increase, as may survival following therapeutic intervention for brain metastases. Thus, more than ever before, therapeutic strategies are urgently needed that offer effective, durable control of brain metastases with a favorable toxicity profile.
Whole Brain Radiotherapy
The management of brain metastases has evolved over the past several decades but has continued to rely on radiotherapy and neurosurgical resection as the predominant treatment modalities. Most systemic therapies including chemotherapy have demonstrated poor penetration of the blood brain barrier and have had limited efficacy against brain metastases. As such, whole brain radiotherapy (WBRT) has been the classic treatment for brain metastases for decades, and includes irradiation of the entire cerebrum, cerebellum, and brainstem.
The techniques utilized in the delivery of WBRT are generally straightforward but beyond the scope of this review. For the purposes of this review, the treatment may be thought of as one lateral x-ray delivered from the patient’s left and one lateral x-ray delivered from the patient’s right. Throughout the 1960s to 1980s several studies evaluating different WBRT dosing and fractionation schemes were performed.4–10
In recent decades, most institutions have used WBRT regimens involving between 5 and 20 daily fractions of radiotherapy treatment, with 10 fractions being the most common. Landmark randomized controlled trials in the 1990s evaluated the role of WBRT, surgery, and various combinations of WBRT and surgery for patients with a single brain metastasis.11–13
For patients treated with WBRT, the addition of neurosurgical resection to WBRT in patients with a single brain metastasis resulted in decreased rates of local recurrence (20% recurrence with WBRT and surgery vs 52% recurrence with WBRT and no surgery) and improved overall survival (OS; 40 weeks with surgery vs 15 weeks with WBRT alone).13
Multiple studies suggest the survival benefit is most pronounced in young patients with a single brain metastasis, good performance status, and absent/controlled extracranial disease.14,15
Of note, one study evaluating the role of surgery in patients with a Karnofsky Performance Score (KPS) of 50% or greater and one cerebral metastasis undergoing WBRT failed to show a survival benefit to the addition of surgery.16
Additional factors influencing recommendation for surgical resection include the rapidity of onset of symptoms, size of a metastasis, location (eloquent vs non-eloquent location), number of metastases, and whether a histopathologic diagnosis has previously been established. In a study evaluating the role of WBRT following upfront neurosurgical intervention for patients with a single brain metastasis, the addition of WBRT resulted in no increase in OS but did demonstrate decreased rates of local failure (10% with WBRT and surgery vs 46% with surgery alone) and decreased rates of any intracranial failure (18% with WBRT and surgery vs 70% with surgery alone).12
While no OS benefit was appreciated, the addition of WBRT to surgery reduced the rate of neurologic death in patients with a single brain metastasis (14% with surgery and WBRT vs 44% with surgery alone).12