Brain metastases: An update on the multi-disciplinary approach of clinical management

Abstract

Importance: Brain metastasis (BM) is the most common malignant intracranial neoplasm in adults with over 100,000 new cases annually in the United States and outnumbering primary brain tumors 10:1.

Observations: The incidence of BM in adult cancer patients ranges from 10-40%, and is increasing with improved surveillance, effective systemic therapy, and an aging population. The overall prognosis of cancer patients is largely dependent on the presence or absence of brain metastasis, and therefore, a timely and accurate diagnosis is crucial for improving long-term outcomes, especially in the current era of significantly improved systemic therapy for many common cancers. BM should be suspected in any cancer patient who develops new neurological deficits or behavioral abnormalities. Gadolinium enhanced MRI is the preferred imaging technique and BM must be distinguished from other pathologies. Large, symptomatic lesion(s) in patients with good functional status are best treated with surgery and stereotactic radiosurgery (SRS). Due to neurocognitive side effects and improved overall survival of cancer patients, whole brain radiotherapy (WBRT) is reserved as salvage therapy for patients with multiple lesions or as palliation. Newer approaches including multi-lesion stereotactic surgery, targeted therapy, and immunotherapy are also being investigated to improve outcomes while preserving quality of life.

Conclusion: With the significant advancements in the systemic treatment for cancer patients, addressing BM effectively is critical for overall survival. In addition to patient's performance status, therapeutic approach should be based on the type of primary tumor and associated molecular profile as well as the size, number, and location of metastatic lesion(s).

Keywords: Brain metastasis; Cancer; Chemotherapy; Lung cancer; Neurosurgery; Radiation.

Figure 1:

Current epidemiology of brain metastasis by cancer type among patients from the Surveillance, Epidemiology, and End Results (SEER) program described at the time of diagnosis of systemic malignancy [6]. Patients were all diagnosed with non-hematologic malignancies originating outside the CNS between 2010–2013. Only the top six cancer types with highest incidence of brain metastasis were included in this summary. Data includes (A) incidence of BM within the cohort, (B) likelihood of BM if diagnosed with metastatic disease, and (C) median survival of these BM patients in months (Figure adapted from the SEER data [6]) (D) summary of top symptoms and (E) key molecular prognostic factors [41, 43, 281]. GI = gastrointestinal; NSCLC = Non-small cell lung cancer; SCLC = Small cell lung cancer; IQR = Interquartile range; EGFR = Epidermal growth factor receptor; ALK = Anaplastic lymphoma kinase; BRAF = B-Raf proto-oncogene; ER = Estrogen receptor; PR = Progesterone receptor; HER-2 = human epidermal growth factor receptor 2.

Figure 2:. Brain metastasis pathophysiology.

(A) Metastasis is a complex, multistage process that begins when cancer cells acquire genetic mutations resulting in invasion, intravasation, circulation, intracranial arrest, and colonization [14]. Once a primary tumor metastasizes, cancer cells spread hematogenously and thus distribute similarly to regional blood flow of the brain – 80% hemispheres, 15% cerebellum, and 5% brainstem. Among 16 major cancer types studied, lung, breast, and melanoma were the most likely to metastasize to the brain and carried a relative risk >1 [15]. In order to arrest in the central nervous system, metastatic cells must penetrate the blood brain barrier (BBB), which is a neurovascular unit formed by unique cerebral endothelial cells joined together by intercellular tight junctions. Along with pericytes, astrocytes, neurons, and microglia, it controls the exchange of substances between the CNS and periphery to maintain the delicate environment required for neuronal function [16]. (B) Cancers with a high propensity to metastasize to the brain have developed mechanisms to increase BBB permeability and disrupt endothelial function [–21]. Within the tumor microenvironment, glial cells such as astrocytes and microglia boost tumor survival and proliferation through immune suppression [–27].

Figure 3.

Treatment algorithm for symptomatic cancer patients with potential brain metastasis.