Brain metastases …

Neuro-Oncology

Updated 10.03.2024
Released 04.07.1994
Expires For CME 10.03.2027

Brain metastases

Authors: Guneet Sarai MD, Aashka Sheth

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Editor: Rimas V Lukas MD

Brain metastases

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Introduction

Overview

Metastatic brain tumors arising from systemic cancer affect 150,000 to 200,000 people in the United States each year (144). They are one of the most common neurologic complications of cancer, and their incidence is increasing with improved diagnostic techniques and more effective systemic treatments, leading to longer survival. Brain metastases have a potentially devastating effect on quality of life and patient survival. Developments in the treatment of patients with brain metastases include stereotactic radiosurgery following surgical resection, molecularly targeted agents, and immunotherapy. The authors of this article summarize the clinical features of brain metastases, diagnosis, and treatment strategy in view of the current management guidelines.

Key points

	• Metastasis to the brain parenchyma is the single most frequent neurologic complication of several common neoplasms, including lung cancer, breast cancer, and melanoma.
	• Brain metastases often have a devastating impact on patients' quality of life and are fatal if not controlled.
	• Treatment options for patients with brain metastases include surgical resection, whole-brain radiation therapy, stereotactic radiosurgery, and in some cases chemotherapy, immunotherapy, or molecularly targeted therapy.
	• The management of patients with brain metastases needs to be individualized based on the primary tumor type, number, size, and location of brain metastases, status of the systemic tumor, patients' neurologic and overall performance status, and anticipated duration of survival.

Historical note and terminology

Brain metastases are neoplasms that originate in tissues or organs outside the brain and spread to involve the brain parenchyma. Brain metastases can occur in conjunction with metastases to other parts of the central nervous system, such as the dura or leptomeninges. Metastases to the brain may be single or multiple. The phrase "single brain metastasis" refers to an apparent single cerebral lesion and makes no implication regarding the extent of cancer elsewhere in the body. The phrase "solitary brain metastasis" is used to describe the rare occurrence of a single brain metastasis that is the only known site of metastatic cancer in the body. Synchronous brain metastases are present at the time of the initial systemic tumor diagnosis, whereas metachronous metastases develop later in the course of patients' disease.

Historically, patients with brain metastases had dismal outcomes, and treatment recommendations were limited to those with palliative intent. In 1926 Grant reported the first series of patients given surgical treatment for single brain metastases (69). Radiation therapy for the palliation of brain metastases was introduced in the 1950s. However, it was not until the publication of several prospective studies that demonstrated survival benefit of surgery or stereotactic radiosurgery (SRS) with whole brain radiation (WBRT) that paradigms changed (123; 122; 172). With an evolving understanding of the biology of brain metastases, as well as a more nuanced understanding of subtype specific natural histories, systemic treatment options have also had a significant impact on approaches to treatment for patients with brain metastases.

Clinical manifestations

Presentation and course

• Many patients with brain metastases will manifest neurologic symptoms, the most common being headaches.

Clinical presentation of brain metastases varies depending on many factors, such as primary tumor type, size, location, number of lesions, and intracranial involvement; 60% to 75% of patients with brain metastases present with neurologic symptoms throughout the course of their illness. Symptoms can progress quickly and evolve over a few weeks. Most patients have a combination of "generalized" nonlocalizable symptoms (eg, headache, altered mental status, cognitive impairment) as well as "focal" signs and symptoms determined by the anatomic location. Generalized symptoms occur in patients with mass effect and increased intracranial pressure or in patients with multiple bilateral metastases. Headache is the single most common symptom of brain metastases (25% to 53% of patients), although a minority of patients never develop headache. Approximately 10% to 20% of patients have seizures as a presenting symptom of metastasis, with another 10% to 12% of patients subsequently developing seizures (89). This is a lower seizure incidence than that which is observed with most primary brain tumors. Additionally, other common symptoms include focal neurologic deficits in 20% to 75% of patients, altered mental status in 5% to 60% of patients, ataxia in 15% to 20% of patients, and speech changes in 5% to 20% of patients (90). Brainstem involvement and symptoms are seen in less than 10% of the disease population.

Anywhere from 5% to 10% of patients present with acute neurologic symptoms caused by hemorrhage of, or sudden expansion of, the metastasis. Hemorrhage of a metastasis is particularly common with choriocarcinoma, renal cell carcinoma, and melanoma. Because brain metastases present varied signs and symptoms, their presence should be suspected in all patients with known systemic cancer in whom any new neurologic findings develop (43). As central nervous system imaging is more frequently performed, it is likely that asymptomatic brain metastases are being detected with increasing frequency.

Prognosis and complications

	• For most patients, treatment of brain metastases prevents death due to neurologic causes and overall survival is determined by systemic cancer control.
	• To estimate prognosis for patients with brain metastases and to help guide decisions regarding the appropriate aggressiveness of therapy, prognostication indices have been developed.

Brain metastases are generally associated with a poor prognosis (as are most other manifestations of stage IV cancer), regardless of treatment. Historically, overall median survival is 3 to 8 months among patients who receive some type of anti-tumor treatment for brain metastases (150; 121). Contemporary and population-based analyses from the SEER program have shown a median survival of 12 months or less across most primary sites (153; 154). Patients 65 and older with brain metastases diagnosed at or after primary malignancy have a worse prognosis, with a median survival of 4 months or less. For most patients, treatment of the brain metastases prevents death due to neurologic causes, so the overall survival prognosis becomes largely dependent on control of the systemic cancer. However, uncontrolled or recurrent brain metastases remain the sole or contributing cause of death in a significant proportion of patients with melanoma, non-small cell lung cancer, and breast cancer.

Several key factors play a role in patient outcomes, including age, extent of primary disease control, rate of brain metastases development (brain metastases velocity), presence of extracranial metastases or leptomeningeal disease, performance status (typically measured by the Karnofsky Performance scale), extent of intracranial disease, and histology and molecular characteristics of the primary tumor. To prognosticate more reliably for patients with brain metastases and to help guide decisions regarding the appropriate aggressiveness of therapy, prognostication indices have been developed. These include the recursive partitioning analysis (RPA) score, graded prognostic assessment (GPA), and disease-specific GPA (dsGPA), among others.

In 1997, Gaspar and colleagues reported a recursive partitioning analysis of survival data from more than 1200 patients with brain metastases treated with whole brain radiation in Radiation Therapy Oncology Group (RTOG) protocols. Three RPA classes with significantly different survival were identified (see Table 1). The patient population utilized to create these RPA classes may not reflect the contemporary brain metastases population encountered in oncology and neuro-oncology clinics.

Table 1. Recursive Partitioning Analysis (RPA) Classes for Persons with Brain Metastases

	Class 1	Class 2	Class 3
Karnofsky performance score	> 70	> 70	< 70
Primary (systemic) tumor status	controlled	uncontrolled	uncontrolled
Age in years	< 65	> 65	> 65
Extracranial metastases	none	present	present

Median survival for patients in RPA Classes 1, 2, and 3 was 7.1 months, 4.2 months, and 2.3 months, respectively (61). The predictive value of this RPA classification scheme was validated in a subsequent RTOG study of whole brain radiation therapy (60), as well as in several series of patients treated with stereotactic radiosurgery (34; 137).

U-RPA is the updated RPA in the modern era and remains a valuable tool to estimate the prognosis independent of tumor type. Patients in RPA class 1, 2A, 2B, and 3 who underwent brain-directed treatment had median survival of 28.1, 14.7, 7.6, and 3.3 months, respectively. The median survival for patients in RPA class 3 who received brain-directed treatment (n = 147), comprised of WBRT (n = 79) and SRS (n = 54), was 3.3, 2.9, and 4.1 months, respectively, emphasizing the need to focus on palliative care in RPA class 3 (53).

A newer prognostic scheme for patients with brain metastases eliminates the subjective judgment of "controlled" or "uncontrolled" systemic tumor and incorporates data correlating overall survival with the number of brain metastases. Patients are assigned a subscore for each of four key prognostic factors and then a total graded prognostic assessment (GPA) score ranging from 0.0 to 4.0 (see Table 2).

Table 2. Graded Prognostic Assessment (GPA) for Persons with Brain Metastases

	Score 0.0	Score 0.5	Score 1.0
Age in years	> 60	50 to 60	< 50
Karnofsky performance score	< 70	70 to 80	90 to 100
Number of brain metastases	> 3	2 or 3	1
Extracranial metastases	present	--	absent

Retrospectively applying the GPA to nearly 2000 patients from RTOG studies defined four patient groups with significantly different median survivals (GPA 0.0 to 1.0, 2.6 months; GPA 1.5 to 2.5, 3.8 months; GPA 3.0, 6.9 months; GPA 3.5 to 4.0, 11.0 months) (149). Most patients in these studies had lung cancer. Unfortunately, up to one half of patients with newly diagnosed brain metastases fall into a poor prognostic category (total GPA score 0.0 to 1.0).

The predictive value of the individual prognostic factors in the GPA varies among different primary tumor types, leading to "disease-specific GPA" (150; 151). Molecular markers such as EGFR mutations and ALK rearrangements have been incorporated to create a more specific lung cancer GPA (155). This is similar to the prior incorporation of hormone receptor and HER-2 status in the GPA for breast cancer patients (152). Disease-specific GPA is currently used in several clinical trials for patient eligibility and stratification.

Another method for estimating individual patient prognosis is the use of nomograms (13; 108), which in some studies outperformed the disease-specific GPA. A novel metric called brain metastases velocity (BMV), the annualized rate at which a patient develops new brain metastases, is now being used to predict the likelihood of death due to neurologic causes (54; 111). Patients with low BMV, which is considered less than four metastases per year, would likely benefit from stereotactic radiosurgery in the future. Patients with high BMV, which would be more than 13 metastases per year, have a shorter life expectancy and higher likelihood of having their neurologic disease burden drive mortality (01).

Clinical vignette

A 63-year-old male with a remote history of craniotomy for intracranial infection presented with mid-left chest pain and hemoptysis, with imaging leading to the diagnosis of a lung mass. He underwent left upper lobectomy and lymphadenectomy and was diagnosed with large cell neuroendocrine carcinoma, staged as pT3N0. The patient subsequently received four cycles of adjuvant cisplatin and etoposide. MRI brain was negative for any metastases at that time.

Almost 2 years later, the patient started having headaches. MRI brain was performed and showed three new enhancing intracranial masses. He received stereotactic radiosurgery 25 Gy / 5 Fx to three new enhancing intracranial masses.

The patient ended up getting right retrosigmoid craniotomy for resection of cerebellar mass due to balance issues, and MRI brain showed an increase in size of the metastasis with associated vasogenic edema. The patient then completed four cycles of carboplatin, etoposide, and atezolizumab. The tumor cavity was treated with stereotactic radiosurgery 25 Gy / 5 Fx to the right cerebellar disease/volume and later completed seven cycles of atezolizumab monotherapy.

The patient was on steroids over a long period of time due to the edema associated with brain metastases and was admitted to the hospital with adrenal insufficiency when he suddenly stopped the steroids.

Over the course of a year, he had an increase in the size of frontal brain metastasis and needed resection and fractionated stereotactic radiation therapy with stereotactic radiosurgery to two areas: the resection cavity and an area of recurrence adjacent to the previously treated region in the cerebellum. Both were treated with 30 Gy in five fractions as the latter had shown an increase in the size of the metastases once again.

Systemically, the patient had been stable with no new metastases. Unfortunately, his brain metastases increased over the course of months, and he opted for hospice and passed away shortly after that.

Brain metastases from large-cell neuroendocrine carcinoma (MRI)

T2 FLAIR and T1-post-gadolinium-enhanced MR scan showing three new enhancing brain metastases in right frontal, parietal, and cerebellar areas with associated vasogenic edema. (Contributed by Dr. Guneet Sarai.)

Biological basis

Etiology and pathogenesis

	• Brain metastases are caused by hematogenous spread of circulating tumor cells.
	• There are large differences in the propensity of various neoplasms to metastasize to and thrive in the brain parenchyma.
	• Complex interactions between the primary tumor site, metastatic cells, and the tumor microenvironment are crucial for growth before and after seeding of metastatic cells.
	• Cancer cells metastasizing to the brain are often molecularly distinct from the primary tumor, harboring driver mutations not present in their respective primary tumors. This is termed branched evolution.

Brain metastases are caused by the spread of tumor cells to the brain from tissues located outside the central nervous system. Multiple theories have been postulated for the development of brain metastases.

Most tumor cells reach the brain by hematogenous spread, nearly always via arterial circulation. Within the brain, metastases are most commonly found in the area directly beneath the gray-white junction. The predominance of metastases here is due to a change in the size of blood vessels at this point; the narrowed vessels act as a trap for emboli. Brain metastases also tend to be more common at the terminal "watershed areas" of arterial circulation (the zones on the border of or between the territories of the major cerebral vessels). The distribution of metastases among the large subdivisions of the central nervous system follows roughly the relative weight of and blood flow to each area. Approximately 80% of brain metastases are located in the cerebral hemispheres, 15% in the cerebellum, and 5% in the brainstem.

There are large differences in the propensity of various neoplasms to metastasize to brain parenchyma. The highest prevalence of brain metastases occurs in patients with germ cell tumors, melanoma, and small cell lung carcinoma. Breast carcinoma, non-small cell lung cancers, and renal carcinoma have an intermediate propensity to metastasize to the brain. Among patients with breast carcinoma, a higher risk of developing brain metastases is associated with overexpression of the epidermal growth factor receptor or of the HER2 (ErbB-2) growth factor receptor, or with absent expression of HER2, estrogen receptors, and progesterone receptors ("triple-negative tumors") (85; 41). Additionally, COX2, EGFR ligand HBEGF, and membrane glycosyltransferase ST6GALNAC5 have been implicated in the development of breast cancer metastases (04). Mutations in EGFR and KRAS in non-small cell lung cancer are associated with a high prevalence of brain dissemination in non-small cell lung cancer (173; 113). Copy number changes, such as amplifications in YAP1 and MMP13, may contribute to metastases in lung adenocarcinoma (04). Brain metastases are disproportionately uncommon among patients with carcinoma of the prostate and GI tract. Sarcomas do not commonly spread to the brain, despite their high propensity to metastasize to the lungs.

Studies are elucidating the molecular pathophysiology of brain metastases and the molecular basis for the differences in "neurotropism" among various systemic tumors. To successfully form brain metastases, tumor cells must attach to and penetrate microvessel endothelium, degrade the extracellular matrix, and respond to autocrine and brain-derived survival and growth factors. Complex interactions between the primary tumor site, metastatic cells, and the tumor microenvironment are crucial for growth before and after seeding (171; 129; 24). The role of astrocytes in metastases has been elucidated more recently, and coupling of metastatic cells with astrocytes through gap junctions can promote tumor cell motility invasion and survival through secretion of inflammatory chemokines (32; 04). Immunosuppressive elements of the metastatic microenvironment through tumor associated macrophages and regulatory T cells, also play a key role (88). In addition, cancer cells metastasizing to the brain are often molecularly distinct from the primary tumor, harboring driver mutations absent in their respective primary tumors. Some of these genetic alterations include mutations in CDKN2A, PIK3CA, and PI3K/AKT, loss of PTEN, amplification of ERBB2, and activating proto-oncogene KRAS mutations (18; 04).

Epidemiology

	• Any neoplasm is capable of metastasizing to the brain, although two thirds of all adult patients have lung cancer, breast cancer, or melanoma.
	• There is an increasing incidence of brain metastases as the sole or early site of relapse due to more effective therapies for systemic disease.

The incidence of intracranial malignancies, including brain metastases and leptomeningeal disease, may be on the rise, although this is uncertain as reliable numbers at the national level are not readily available. This possible rise could be due to enhanced screening methods and prolonged survival from advanced therapy. Approximately 60% to 80% of patients who present with brain metastases also have synchronous systemic metastatic disease, with pulmonary involvement being the most frequent, reported in up to 56% of patients with lung cancer of any type (02). Non-small cell lung cancer is the most common subtype of lung cancer associated with brain metastases (159). Small cell lung cancer represents a smaller subset of brain metastases cases but often has a more aggressive disease course, with over 20% of patients having brain metastases at diagnosis and 50% to 80% of patients developing brain metastases throughout their disease progression (159). Brain metastases are reported in 20% of patients with breast cancer, with two thirds of these cases associated with triple negative breast cancer (23).

Brain metastases are associated with increased morbidity and mortality, with about half of patients dying from neurologic disease. Patients with brain metastases diagnosed with primary prostate cancer, bronchoalveolar carcinoma, or breast disease appear to have the longest median survival prognosis (174).

The incidence of leptomeningeal metastasis has been difficult to identify due to challenges in diagnostic work-up. Evidence suggests that 10% of patients with metastatic cancer will develop leptomeningeal metastasis throughout the course of their disease (94).

Prevention

	• Currently, there are no standard prophylactic therapies for the prevention of brain metastases except the use of prophylactic cranial radiation in small cell lung cancer.
	• There are emerging data regarding the use of several molecular agents targeting the alterations driving tumor growth. This has been proven to be effective in the prevention of secondary relapse of solid tumors into the brain (124).

Prevention of brain metastases has mainly been focused on patients with small cell lung cancer, because of the high prevalence of brain metastases after systemic treatment and the high degree of sensitivity of this tumor to radiation. For patients with limited-stage small cell lung carcinoma who achieve a complete remission after initial systemic therapy, the consensus results of several randomized studies indicate that prophylactic whole brain radiation therapy significantly reduces the cumulative incidence of brain metastases (from 50% to 60% to 25% to 30%) and significantly improves overall survival (06; 70; 08). Prophylactic cranial irradiation may also be beneficial for a subset of patients with initially extensive small cell lung carcinoma who have a good response to initial chemotherapy (145). However, prophylactic intracranial radiation increases the risk of neurocognitive decline. Deferring prophylactic whole brain radiation therapy until after completion of induction systemic chemotherapy is believed to reduce the risk of long-term neurotoxicity. The most used dose for prophylactic whole brain radiation therapy is 2500 cGy in 10 daily fractions. WBRT with hippocampal sparing is now being studied to prevent neurocognitive side effects.

Although there has been an increasing incidence of metachronous brain metastases from non-small cell lung cancer with improvements in multimodality treatment of newly diagnosed patients, several studies have shown that prophylactic whole brain radiation for patients with non-small cell lung cancer does not prolong overall patient survival and can have significant neurotoxicity that can impact quality of life (67). Prophylactic whole brain radiation therapy is not currently considered standard care for patients with non-small cell lung cancer.

Several molecular agents, especially EGFR-mutant or ALK-rearranged non-small cell lung cancer inhibitors, HER2-positive breast cancer inhibitors, and BRAF inhibitors for melanoma, are emerging as newer treatment therapies to prevent secondary intracranial relapse. These are discussed in more detail in the Management section.

Differential diagnosis

	• The differential diagnosis in a patient presenting with a solitary of multiple enhancing brain lesions includes primary brain tumors, abscesses, cerebral infarction, hemorrhage, and demyelinating disease.
	• For patients presenting with suspected or proven brain metastases and no previous cancer diagnosis, workup for a systemic cancer should be pursued with a focus on the lungs.

Confusing conditions

The differential diagnosis in a patient presenting with a solitary or multiple enhancing brain lesions includes primary brain tumors, abscesses, cerebral infarction, hemorrhage, parasitic infestation, and demyelinating disease. Contrast-enhanced MRI is usually able to differentiate among these possibilities and the finding of multiple lesions is strongly suggestive of metastases, particularly in a patient with a known diagnosis of cancer. Metastases usually demonstrate contrast enhancement with irregular internal appearances and can cause local vasogenic edema that appears hyperintense on MRI (19). However, not all brain lesions in patients with systemic cancer are metastases. In a study of patients known to have systemic cancer who had single lesions diagnosed by contrast MRI, 11% had lesions other than brain metastases when tissue was obtained (123). Half of the nonmetastatic lesions were primary brain tumors; the other half were infections. The false-positive rate for diagnosis of multiple metastases is unknown but is certainly much less than the 11% quoted for single metastases. Biopsy is the only truly reliable method of establishing the diagnosis, if there is any doubt after contrast-enhanced imaging studies.

Associated or underlying disorders

There are no specific conditions or genetic predisposition syndromes specifically associated with the development of brain metastases from systemic malignancy.

For patients presenting with suspected or proven brain metastases and no previous cancer diagnosis, workup for a systemic cancer should be pursued with a focus on the lungs. If the primary tumor is not bronchogenic, it has probably spread to the lungs before seeding into the arterial circulation and reaching the brain. More than 60% of patients with brain metastases will have a mass demonstrated on chest radiograph. CT scan chest and abdomen-pelvis with contrast is the standard first test ordered (109). Whole-body FDG-PET scanning may reveal a primary tumor that goes undetected by other imaging techniques (87). The practical utility and cost effectiveness of PET scanning in this setting are not clearly known.

Radiation necrosis is the most challenging differential for diagnosing brain metastases. Patients who have had stereotactic radiosurgery to brain metastases can demonstrate an increase in the size of the metastases, leading to more confusion. In such situations, perfusion images, magnetic resonance spectroscopy, and fluorodeoxyglucose and amino acid positron-emission tomography can help. Currently, there is no standardized testing available to distinguish between radiation necrosis and brain metastases. Closer follow-up intervals are recommended by the Response Assessment in Neuro Oncology (RANO) group.

Radiation necrosis (MRI)

T1-post-gadolinium-enhanced MR scan showing left brachium pontis brain metastasis treated with stereotactic radiosurgery. The patient presented with left cranial nerve VI, VII, and VIII palsy and was treated with bevacizumab in...

Diagnostic workup

	• Contrast-enhanced MRI remains the best diagnostic test for brain metastases.
	• Histopathologic analysis of tissue remains the gold standard for diagnosis.

The best diagnostic test for brain metastases is contrast-enhanced MRI, showing more than one lesion in up to 75% of patients. The most used MRI sequences are contrast-enhanced, T1-weighted, and non-contrast FLAIR (162). Findings that favor metastases include multiplicity of lesions, a gray-white junction location, a lesion in the border zone between two major arterial distributions, and a small tumor nidus with a large amount of associated vasogenic edema. Contrast-enhanced MRI is more sensitive than either enhanced CT scanning (including double-dose delayed contrast) or unenhanced MRI in detecting lesions. Up to one third of patients with an apparently single lesion on contrast-enhanced CT have one or more other small lesions when a contrast-enhanced MRI is obtained (138). PET scans may be indicated in settings in which MRI specificity is not high enough, such as distinguishing radiation-induced changes in an active tumor (140).

Multiple brain metastases (MRI)

T2 FLAIR and T1-post-gadolinium-enhanced MR scan showing multiple enhancing brain metastases from non-small cell lung carcinoma with associated vasogenic edema. (Contributed by Dr. Guneet Sarai.)

The number of brain metastases is important for treatment planning (eg, surgical resection or stereotactic radiosurgery) and, to some extent, for prognostic predictions.

Advanced neuroimaging techniques are also being used in clinical evaluation of suspected brain metastases as MR imaging cannot always reliably distinguish a single brain metastasis from an anaplastic glioma or an abscess. MR spectroscopy and MR perfusion may be helpful in this situation. MR spectroscopy provides information on tumoral metabolites and may be useful in attempting to distinguish between neoplastic and non-neoplastic brain lesions, progressive disease, and radiation necrosis (162). Brain metastases are generally well circumscribed, whereas gliomas are often less clearly delineated from the surrounding brain parenchyma. These differences are reflected in the "peritumoral" choline peaks on MR spectroscopy and on cerebral blood volumes (93).

Although neuroimaging can be used to identify brain lesions, it is not specific enough for definitive diagnosis, and histopathologic analysis of tissue remains the gold standard for diagnosis. As a general rule, patients should always have histologic verification of cancer, whether from an extraneural tumor or from the brain lesion itself. For patients with a known cancer diagnosis, biopsy of the brain lesion is usually not necessary. Factors that raise the level of uncertainty for the diagnosis of brain metastases include systemic tumors (eg, prostate carcinoma), which do not often metastasize to the brain parenchyma; a long interval since systemic tumor diagnosis; minimal or no systemic tumor burden; and a single versus multiple brain lesions. Imaging in these circumstances is often not reliable enough to substitute for histologic verification. A role for “liquid biopsy” of cerebrospinal fluid has been suggested as a minimally invasive approach to assess the presence of characteristic genetic alterations of brain metastases (125; 16). This approach, however, still requires validation.

Screening asymptomatic patients for brain metastases in newly diagnosed patients with lung cancer and melanoma has become standard practice. According to the NCCN Guidelines 2024, brain MRI with and without contrast are recommended to screen metastases in patients with stage IV melanoma and stage II, III, and IV non-small cell lung cancer.

Follow-up imaging is recommended every 2 to 3 months for the first 1 to 2 years after initial treatment. If stability is attained in imaging, then the MRI imaging can be slowly spaced out at longer intervals over the next few years. Any symptoms or change in clinical condition should prompt sooner imaging.

Cerebrospinal MRI with or without contrast is considered the gold standard imaging method for the diagnosis of patients with leptomeningeal metastases. Magnetic field strength of 1.5 or 3 T, slice thickness of 1 mm for brain sequences and 3 mm for spinal sequences, and injection of gadolinium before T1-weighted data acquisition should be considered for the best imaging results. Contrast enhancement of cerebellar folia and sulci, basilar cisterns, cranial nerves, and surface of the cauda equina are typical MRI findings for leptomeningeal metastases. Lesions can be either linear or nodular. Post imaging, CSF analysis should be done as abnormalities, such as increasing opening pressure, increased leukocyte count, elevated protein, and decreased glucose, are common findings of leptomeningeal disease (94).

Brain, cervical, and thoracic MR scan showing multiple brain metastases

(Top) T1-post-gadolinium-enhanced MR scan of the brain showing cerebellar folia and VIII cranial nerve enhancement in a patient with non-small cell lung cancer. (Bottom) T1-post-gadolinium-enhanced MR scan of cervical and thora...

Management

• Treatment options for patients with brain metastases include a combination of surgical resection, radiation therapy, systemic medical therapy, and supportive measures, including anticonvulsants and corticosteroids.

Treatment options for patients with brain metastases include a combination of surgical resection, whole brain radiotherapy, stereotactic radiosurgery, systemic medical therapy, and supportive measures, including anticonvulsants and corticosteroids. Several factors must be considered when determining the ideal treatment for each patient, including the primary tumor histology, extent of systemic disease, anticipated survival, neurologic status at diagnosis, and the location, number, and size of metastases. There are several possible measures of treatment efficacy for patients with brain metastases, including improvement in neurologic signs and symptoms, improvement or maintenance of functional performance status, corticosteroid requirements, and radiographic tumor response. Survival after treatment of brain metastases is an easy endpoint to measure but is confounded by the fact that systemic tumor is the cause of death for most patients with brain metastases. Measuring survival is, therefore, more meaningful when the cause of death is determined to be "neurologic" or "non-neurologic." Because brain metastases in most patients arise in the setting of disseminated tumor, the goal of treatment is not necessarily to eradicate the brain lesions. Rather, treatment should be aimed at "controlling" the brain lesions, and at maintaining patients' neurologic function for as long as possible.

Treatment of symptoms is imperative in patients with brain metastases and includes corticosteroids for vasogenic edema and anticonvulsants for seizures.

Corticosteroids for vasogenic edema. Dexamethasone can be given for neurologic symptoms arising from vasogenic edema from brain metastases (166). Asymptomatic brain metastases don't need steroids. Long-term use of corticosteroids has been linked to adrenal insufficiency and numerous other side effects

Anticonvulsants for seizures. Seizures occur in approximately 25% of patients with brain metastases and are presenting symptoms in 10% to 15% of patients. To date, there is no definite evidence that any antiepileptic drug is differentially effective for tumor-related seizures versus epilepsy caused by other structural brain lesions. In addition to their direct side effects, anticonvulsants may cause unfavorable drug interactions with dexamethasone and several chemotherapy agents. For patients taking dexamethasone or receiving chemotherapy agents metabolized by the liver, the nonenzymic-inducing antiepileptic drugs (eg, levetiracetam or lamotrigine) may offer fewer drug interactions than enzyme-inducing drugs (eg, phenytoin or carbamazepine). Valproate may inhibit the hepatic metabolism of some cancer chemotherapy drugs. For patients who do not have seizures at the time of diagnosis of brain metastases, the current (limited) information indicates that prophylactic anticonvulsants do not reduce the incidence of subsequent seizures (63).

Venous thromboembolism. Patients with brain metastases are at increased risk of venous thromboembolism due to lack of mobility and increased risk of thrombus formation in the setting of solid tumor malignancy. There may also be tumor-specific factors that increase the thromboembolism risk.

There are no specific venous thromboembolism management guidelines for patients with brain metastases, and treatment with low molecular weight heparin or direct oral anticoagulant is recommended as in high-grade glioma with no increased risk of intracranial hemorrhage (83).

Radiation necrosis. One of the common side effects of radiating the brain metastases is radiation necrosis. Distinguishing worsening brain metastases from radiation necrosis is a diagnostic dilemma for the neuro-oncologist in the clinic. Symptomatic patients are treated with steroids or bevacizumab infusions (often at a dose of 7.5 mg/kg for a limited number of doses) (91). Side effects of bevacizumab include, but are not limited to, poor wound healing, fatigue, and increased incidence of venous thromboembolism and bleeding. Surgical resection or laser-induced thermal therapy (LITT) treats radiation necrosis as well. Pentoxifylline, hyperbaric oxygen, and vitamin E are some of the less common and not well-established treatments of radiation necrosis (04).

Cognitive decline. Neurocognitive decline has been established as one of the major side effects of brain metastases. Memantine with WBRT and cognitive rehabilitation are some of the methods used to prevent cognitive decline from metastases and radiation treatments over time. Modafinil and methylphenidate have been shown to have no impact on fatigue in patients with brain metastases (04).

Management of brain metastases

Surgical resection and LITT therapy. The role of surgery in the treatment of brain metastases has been well established and is indicated in suspected brain metastases without primary cancer diagnosis and in large symptomatic masses in the brain that need decompression.

Three prospective randomized trials assessed the value of aggressive local management through surgical removal of single brain metastases (123; 165; 112). In each study, patients with a single brain metastasis were treated either with complete surgical resection plus whole brain radiation therapy or with whole brain radiation therapy alone. In the study by Patchell and colleagues, patients in the surgery group had significantly longer overall survival, longer time to recurrence of brain metastases, longer duration of functional independence, and lower risk of death due to neurologic causes (123). Vecht and colleagues also reported improvement in overall survival rates (165).

The value of surgery in the management of patients with multiple metastases is more controversial. In some patients with multiple metastases, there is one lesion that is large or is in a life-threatening location (eg, in the posterior fossa). For these patients, resection of one lesion can improve neurologic function and "buy time" for therapy of the other metastases. Another approach is to resect more than one brain metastasis, either as a single operation or as a stage procedure.

Surgery in the case of multiple brain metastases or in patients with uncontrolled systemic disease has little evidence to support survival. ASCO-SNO-ASTRO guidelines don't suggest any particular method of resection, piece-meal versus en bloc. For most patients with brain metastases, surgical resection is not an option due to the overall number of brain metastases, involvement of deep-seated eloquent areas of the brain, multiple lesions, active systemic disease, or medical comorbidities. Furthermore, surgery alone has been shown to be insufficient in achieving long-term local control (106).

Solitary brain metastasis (MRI)

T2 FLAIR and T1-post-gadolinium-enhanced MR scan of the brain showing solitary metastasis in a patient with breast carcinoma. (Contributed by Dr. Guneet Sarai.)

Novel approaches: laser interstitial therapy (LITT). Stereotactic laser ablation, or laser interstitial therapy, is one of the newer and innovative techniques that has emerged for recurrent brain metastases and radiation necrosis. It involves a small burr hole through which a biopsy is simultaneously obtained, and treatment is delivered using a laser probe. Although there are limitations on lesional size and posttreatment-related edema, this technique allows for the treatment of deep-seated lesions that may not be accessible for resection, as well as previously irradiated areas. A prospective, single-arm, multicenter study involving post-radiation LITT demonstrated 12-week local progression-free survival of 100% versus 54% in patients with necrosis versus recurrent tumor, with side effects mainly related to hemiparesis, headache, and hemorrhage (03). However, newer evidence indicates that bevacizumab is still the treatment of choice to treat radiation necrosis in comparison to LITT or hyperbaric oxygen (167).

Radiation therapy: whole brain radiation. Historically, whole brain radiation therapy was the standard treatment for patients with brain metastases and remains quite common. The use of whole brain radiation therapy is due in large part to a phase III study that showed whole brain radiation therapy following surgical resection reduced the rate of local and distant metastatic recurrence compared to postoperative observation alone (122).

Whole brain radiation therapy is usually given as 3000 to 4000 cGy in 10 to 15 daily fractions. Several randomized studies of altered dose/fractionation regimens have not shown any significant advantage in terms of radiographic response rates, local tumor control rates, or patient outcomes compared with "standard" 3000 cGy in 10 fractions or a biologically equivalent dose. There are surprisingly few good studies looking at the radiographic response of brain metastases to whole brain radiation therapy. Among solid tumors, metastases from breast and small cell lung carcinoma show the highest rate of radiographic response, whereas metastases from melanoma and renal carcinoma may stabilize but do not often shrink after whole brain radiation therapy (120). Other solid tumors show an intermediate radio responsiveness. For any tumor histology, smaller metastases are more likely to regress after whole brain radiation therapy than larger lesions.

Although whole brain radiation therapy is still preferred in patients with numerous brain metastases, leptomeningeal metastasis, or primary histologies prone to micrometastatic disease such as small-cell lung cancer, treatment paradigms are changing as late delayed radiation induced neurotoxicity is being increasingly recognized. Whole brain radiation therapy may cause clinically significant diffuse brain injury. At least one half of patients with brain metastases who survive more than one year after 3000 to 4000 cGy of whole brain radiation therapy develop changes on serial CT or MRI scans, including diffuse cerebral atrophy, ventricular enlargement, and hyperintense T2-weighted or FLAIR signal abnormalities in the hemispheric white matter (42; 142; 116). A small proportion of long-term survivors with brain metastases develop progressive dementia, psychomotor retardation, gait disturbance, and urinary incontinence, appearing 6 to 18 months after whole brain radiation therapy (42; 46). The incidence of "radiation therapy dementia" is not clearly known; a disproportionately high percentage of reported patients received daily dose fractions greater than 300 cGy. The clinical similarity of this syndrome to normal pressure hydrocephalus has led some patients to undergo ventriculoperitoneal cerebrospinal fluid shunting, which can produce partial improvement in some patients. To date, however, there is no reliable way to predict which patients would benefit from a shunt.

Inadequate control or recurrence of brain metastases is a more common cause of deteriorating neurocognitive function than is the toxicity of whole brain radiation, and whole brain radiation remains an important part of treatment for some patients (95). As a result, strategies to minimize long-term neurocognitive deficits include the use of intensity-modulated radiation therapy to deliver "whole-brain" treatment while sparing the hippocampi (66), as well as neuroprotective agents such as memantine given during the course of whole brain radiation therapy and for a total of six months (21). The contemporary NRG cooperative group CC001 randomized phase 3 trial combined both approaches with additive benefit in preventing neurocognitive deterioration (20). In more recent years, radiotherapy has also moved toward more localized techniques such as stereotactic radiosurgery.

With a shifting focus towards the use of stereotactic radiosurgery for the treatment of brain metastases, whole brain radiation is now reserved for patients with good prognosis and ineligible for surgery or stereotactic radiosurgery. Hippocampal avoidance is recommended for such patients, except for metastases in the proximity of the hippocampus or in cases of leptomeningeal disease (139).

Stereotactic radiosurgery. Stereotactic radiosurgery as a monotherapy has become increasingly popular in recent years for patients with limited brain disease as a way to largely spare normal brain. The technique uses a linear accelerator or multiple Cobalt-60 sources ("gamma knife") to deliver a highly focused single dose of radiation (usually 1000 to 2000 cGy) to a circumscribed target. Brain metastases are theoretically well suited for radiosurgery because they are usually roughly spherical and well circumscribed.

Radiosurgery has been administered to many patients in a number of settings: as primary treatment of single metastases instead of surgical resection; as the sole treatment of newly diagnosed single or multiple brain metastases; in combination with whole brain radiation therapy for newly diagnosed metastases; and as treatment of recurrent brain metastases.

For patients with resected brain metastases, radiation therapy (stereotactic radiosurgery or whole brain radiotherapy) is recommended to improve intracranial disease control. For patients whose brain metastasis is planned for resection, preoperative stereotactic radiosurgery is conditionally recommended as a potential alternative to postoperative stereotactic radiosurgery, with the caveat that the quality of evidence is low (139). Numerous retrospective series of stereotactic radiosurgery have reported "local control" rates as high as 75% to 95%, ie, radiographic shrinkage or stabilization of treated lesion(s) for the lifetime of the patient (07; 141; 98). Tumors such as melanoma and renal carcinoma, which are considered "radioresistant," have a better local control rate from radiosurgery than from whole brain radiation (92; 28; 97). Larger metastases generally have lower radiographic control rates than smaller lesions, which is partly related to the ability to safely administer a higher tumor margin dose for metastases smaller than 2cm (27; 28). For patients with multiple metastases, the local control rate is probably related more to the total volume of treated tumor than to the number of metastases (97; 98). In most centers the maximum tumor size for single-fraction radiosurgery is 3 cm. Large retrospective cohort studies have demonstrated excellent local control for tumors less than or equal to 2 cm treated with 2400 to 2600 cGy single-296 fraction stereotactic radiosurgery alone. However, metastases of 2 cm or greater treated with single-fraction stereotactic radiosurgery doses of 1500 to 1800 cGy 297 have been associated with poor local control and multifractionated stereotactic radiosurgery is recommended for tumors 3 cm or greater (37).

For patients with intact brain metastases measuring 3 to 4 cm in diameter, multifractional stereotactic radiosurgery (eg, 2700 cGy in three fractions or 3000 cGy in five fractions) is conditionally recommended. Given the limited evidence, stereotactic radiosurgery for tumor sizes larger than 6 cm is discouraged (139).

The low risk of complications associated with stereotactic radiosurgery and the ability to perform stereotactic radiosurgery on an outpatient basis offers potential cost savings and safety advantages over conventional surgical resection for the treatment of cerebral metastases. Most comparisons of patients with a single, newly diagnosed surgically resectable brain metastasis showed that stereotactic radiosurgery produced local tumor control rates generally equivalent to those seen after surgical resection (07; 130; 131; 118). In one retrospective study, surgical resection yielded better local control and survival than radiosurgery (14). Surgical resection does offer the advantage of immediate debulking and relief of symptoms due to mass effect, and it can deal with metastases too large to be suitable for radiosurgery.

An increasingly utilized approach is a resection of the single brain metastasis and then give stereotactic radiosurgery to the margins of the resection cavity. In several series, this combined treatment resulted in 1-year local control rates of 70% to 90% (82; 35; 106). Local control rates after single-fraction radiosurgery are lower if the resection cavity is large or its margins are indistinct. Hypofractionated radiosurgery can be used for postoperative treatment of a large (eg, greater than 3 cm) resection cavity; however, specific patient selection criteria and treatment dosimetry are not well established.

Several studies have also looked at the efficacy of stereotactic radiosurgery for patients with more than four brain metastases and suggest that stereotactic radiosurgery alone may be a reasonable approach for patients with multiple metastases. A large prospective observational study by Yamamoto and colleagues for patients undergoing stereotactic radiosurgery for 1 to 10 metastases found similar survival outcomes for patients with two to four versus five to 10 metastases (172), and the aggregate volume of lesions being treated may be more important in predicting the efficacy of stereotactic radiosurgery (99). A phase 3 randomized control trial comparing stereotactic radiosurgery versus whole brain radiation in patients with five to 15 intact brain metastases was completed and found in nonmelanoma patients with four to 15 metastases, and stereotactic radiosurgery was associated with reduced cognitive deterioration compared to whole brain radiation without compromising OS (96).

The acute toxicity of radiosurgery includes transient worsening of neurologic deficits and increased peritumoral edema, occurring in approximately 5% of patients within several days after treatment (141; 128). The symptoms improve with corticosteroids. Five percent to 10% of patients develop symptomatic or asymptomatic radiographic worsening (increased contrast enhancement and increased edema) 3 to 6 months after radiosurgery. Most patients subsequently show clinical and radiographic improvement over the subsequent few months. Intratumoral hemorrhage may occur following radiosurgery, particularly with melanoma (28; 97). Delayed symptomatic focal brain necrosis occurs in 2% to 5% of treated patients (141; 127). The incidence of symptomatic radiation necrosis may be higher after treatment of larger versus smaller metastases (15). Symptomatic cyst formation occasionally occurs in long-term survivors after radiosurgery.

The practical difficulty in the patients treated with stereotactic radiosurgery is distinguishing radiation injury from tumor progression or from the common coexistence of necrosis and viable tumor using standard diagnostic MRI scans. Fluorodeoxyglucose-PET scanning (168; 77), MR spectroscopy, or perfusion MRI (74; 114) have fairly good reliability, particularly in cases of “pure” necrosis or “pure” tumor, but all have false positives and false negatives. Biopsy or resection of the lesion is then done if the results from noninvasive diagnostic techniques are still inconclusive.

Brachytherapy. Collagen tile-embedded Cesium 131 brachytherapy is increasingly used for the treatment of brain metastases. It is available as an ongoing clinical trial for use in brain metastases and primary brain tumor treatment after surgical resection. A pilot experience suggested that it provides favorable local control and safety profile in patients with brain metastases that exhibited aggressive growth patterns (44).

Systemic treatment

Chemotherapy. Cytotoxic chemotherapy has generally not been highly successful in treating brain metastases due to several factors: (1) several common sources of brain metastases are not sensitive to currently available agents; (2) many patients who develop brain metastases have already "failed" one or more chemotherapy regimens; (3) subclones of tumor cells that metastasize may be inherently less chemosensitive than the cells in the primary tumor; and (4) the blood-brain barrier may limit penetration of water-soluble agents and macromolecules into brain metastases.

Despite these serious limitations, chemotherapy may have a role in the treatment of selected patients. Some patients with chemosensitive tumors (eg, breast, small cell lung cancer, germ cell tumors) respond to systemic chemotherapy, either as initial therapy for previously untreated brain metastases (55; 30; 71) or for recurrence of brain metastases after prior whole brain radiation therapy (17; 52). For patients with breast cancer, the choice of systemic therapy is often driven by the subtype: with brain metastases from triple negative breast cancer, capecitabine has shown benefit (52), and for estrogen or progesterone receptor positive breast cancer, hormonal therapies are primarily utilized (136; 156; 51). For most patients with germ cell tumors, chemotherapy without cranial irradiation is effective in treating brain metastases, but a small minority of patients have isolated relapse of brain metastases despite eradication of systemic tumor (09). Carboplatin plus pemetrexed has shown modest activity as first-line therapy for brain metastases from lung adenocarcinoma, as well as combinations of vinorelbine, cisplatin, and paclitaxel (133; 39; 11; 45).

Molecular targeted agents. As targeted agents are an important part of standard initial therapy for the management of systemic cancer, the utility of these agents for the treatment of brain metastases has also become increasingly evident. In contemporary practice, they are often employed as the first line of treatment for appropriate patients with brain metastases.

Non-small cell lung cancer brain metastases. Several targeted agents have become first-line standard of care for patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or ROS-1 mutations and have shown significant benefit in CNS disease management. Specifically in epidermal growth factor receptor-mutant non-small cell lung cancer brain metastases, first generation tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have demonstrated response rates of 50% to 80%, overall survival of 15 to 22 months, and increased efficacy with pulsatile high dose administration (26; 78; 143; 86; 72; 169; 79). More recently due to improved CNS penetration, durable response, and efficacy in patients with progression after treatment with first generation tyrosine kinase inhibitors, the second-generation tyrosine kinase inhibitor osimertinib is now considered first-line therapy for patients with EGFR-mutant NSCLC, particularly for those with brain metastases. This is in lieu of the first-line FLAURA study comparing erlotinib and gefitinib to osimertinib, which demonstrated prolonged progression-free and overall survival with osimertinib (132). It can also be considered for the primary prevention of brain metastases compared with first-generation tyrosine kinase inhibitors (115; 148). Osimertinib plus platinum-pemetrexed demonstrated improved CNS efficacy compared with osimertinib monotherapy, including delaying CNS progression, irrespective of baseline CNS metastasis status from the phase III FLAURA2 study (81). Note that amivantamab, a bispecific monoclonal antibody for EGFR exon 20 insertions, has been used, although data relating to intracranial efficacy is lacking (139).

For anaplastic lymphoma kinase (ALK)-positive, anaplastic lymphoma kinase inhibition is a viable option. The first-generation anaplastic lymphoma kinase inhibitor crizotinib has limited blood-brain barrier penetration. For patients with brain metastases, second and third-generation anaplastic lymphoma kinase inhibitors, such as alectinib, brigatinib, ceritinib, and lorlatinib, have shown superior activity even in an anaplastic lymphoma kinase-inhibitor-pretreated patient, with response rates up to 81%, and they are preferred (146; 147; 25; 58). For patients with ROS1 translocations, entrectininb has shown CNS activity in crizotinib-naïve disease with overall response rates of 79% (50). For RET fusion-positive NSCLC, selpercatinib has shown benefit in patients with brain metastases (48; 157). Sotorasib is established treatment for non-small cell lung cancer patients with a KRAS G12c mutation, though patients with symptomatic and untreated brain metastases are excluded. Adagrasib is now studied in clinical trials for patients with brain metastases.

Breast cancer brain metastases. For patients with breast cancer-related brain metastases, treatment is dependent on the presence of HER-2 and hormone receptor expression. The occurrence of isolated brain metastases in patients with HER-2-expressing breast cancer treated with the monoclonal antibody trastuzumab is at least partly due to the inability of trastuzumab to cross the blood-brain barrier. Small molecule inhibitors of the HER-2 tyrosine kinase, such as lapatinib, have shown modest activity against breast cancer brain metastases (101; 158). Cyclin-dependent kinase (CDK) inhibitors specifically targeting CDK4/6 have become an important part of treatment for hormone receptor-positive breast cancer. Abemaciclib, with the highest CNS penetration, has shown promise in the treatment of brain metastases with intracranial benefit of 24% (161).

CNS penetrant chemotherapy-targeted drug combinations and drug conjugates are increasingly showing efficacy in the management of breast cancer-related brain metastases in patients with breast cancer and brain metastases. A phase 2 study of lapatinib plus capecitabine (LANDSCAPE) for previously untreated brain metastases from breast cancer showed a 66% radiographic response rate (10). Although neratinib alone demonstrated limited efficacy, the combination with capecitabine yielded a 49% response rate (56; 57). Similar results have been seen with trastuzumab emtansine (TDM1) in the KAMILLA study, tucatinib/trastuzumab/capecitabine (HER2CLIMB), fam-trastuzumab deruxtecan (DEBBRAH), and sacituzumab govitecan for triple negative breast cancer (ASCENT) (100; 117; 12; 126). In the phase 3 HER2CLIMB study, for patients with HER2-positive breast cancer with brain metastases treated with trastuzumab/capecitabine and the addition of tucantinib, intracranial overall response rates doubled, the risk of intracranial progression or death was reduced by 68%, and the risk of death was reduced by 42% when compared to trastuzumab and capecitabine alone (100; 117).

Melanoma brain metastases. Targeted therapies have also altered the treatment paradigm for metastatic melanoma. Vemurafenib is a signal transduction inhibitor that acts on BRAF kinase and has shown effectiveness in some patients with brain metastases from melanoma (110). Dabrafenib is another BRAF inhibitor that produced an objective radiographic response in one third of melanoma brain metastases in patients whose tumors had the Val600Glu BRAF mutation (103). The combination of dabrafenib and the mitogen-activated protein kinase (MAPK) inhibitor trametinib has yielded improved intracranial response rates, as have combinations of vemurafenib and cobimetinib or encorafenib and binimetinib. Intracranial overall response rates with these agents ranges between 33% to 43%, intracranial disease control rate between 60 and 79%, and mOS between 9.5 and 11.2 months (62; 47; 75). However, duration of response remains a problem (40). Combination with immunotherapy has not shown improved duration of response, and a phase 2 study of atezolizumab, vemurafenib, and cobimetinib (TRILOCET) resulted in an intracranial response rate of 42%, but PFS was five months, and duration of response was seven months (49). In addition, combination of these targeted therapies with stereotactic radiosurgery may have additional benefit (104).

In patients with renal cell carcinoma, the VEGFR tyrosine kinase inhibitor cabozantinib has shown early signs of efficacy in patients with brain metastases with a reported intracranial response rate of 61% (73). There are also reports of radiographic response of brain metastases from renal carcinoma to the oral multikinase inhibitors sorafenib (164) or sunitinib (68). However, only one prospective study, a phase 2 trial of sunitinib in patients with untreated brain metastases, has examined the CNS efficacy of VEGFR tyrosine kinase inhibitors in patients with mRCC. Among 16 evaluable patients, the CNS response rate was 0% and the percentage of patients with stable disease was 31%. The median time to progression was 2.3 months and the median overall survival was 6.3 months (33). In one study of patients with renal carcinoma and brain metastases treated with stereotactic radiosurgery, those who were also treated with a tyrosine-kinase inhibitor, mTOR inhibitor, or bevacizumab had a better rate of local control of the brain lesions compared to patients who did not receive targeted therapy (36).

Immunotherapy. To date, immunotherapy for brain metastases mainly applies to melanoma and non-small cell lung cancer. Immune checkpoint inhibitors targeting CTLA-4 (ipilimumab), PD-1 (nivolumab, ipilimumab), and PD-L1 (atezolizumab), all of which act to augment T-lymphocyte activation, have shown benefit in the treatment of melanoma and non-small cell lung cancer-related brain metastases (105). Disease control rates of melanoma brain metastases with single agent ipilimumab or pembrolizumab have ranged from 10% to 22% with sustained response, and combination therapy has shown even higher response rates near 60% with a marked increase in survival (107; 65; 102; 160). In patients with non-small cell lung cancer treated with single-agent pembrolizumab, intracranial response rates reached 33% and were durable in most patients, with CNS PFS of 10.7 months and mOS of 8.9 months (65; 64). Single agent atezolizumab in patients with asymptomatic treated non-small cell lung cancer brain metastases was associated with improved survival when compared to traditional chemotherapy (59). It is not yet clear how ipilimumab should be integrated into the overall treatment strategy of patients with brain metastases, and exploration of combined regimens of radiation therapy and immunotherapy have been pursued and are suggestive of a synergistic benefit (05; 119). Alternative approaches include treatment with autologous tumor-infiltrating lymphocytes engineered to express a T-lymphocyte receptor that recognizes a melanocytic differentiation antigen has also caused regression of brain metastases in some patients with melanoma brain metastases (76). The FDA approved lifileucel, tumor-infiltrating lymphocytes, for the treatment of melanoma based on a study that included stage IV melanoma patients with increased progression-free survival who received tumor-infiltrating lymphocytes compared to ipilimumab (134).

Recurrent brain metastases. A difficult and frequently encountered clinical problem is the treatment of recurrent brain metastases. The reappearance of brain metastases is often complicated by the fact that many of these patients also have extensive systemic disease. In general, the same types of treatment used for newly diagnosed brain metastases are also available for recurrent tumors. However, the type of previous therapy often limits the therapeutic options available at recurrence.

Surgical resection of recurrent brain metastases is an option for selected patients with a single site of brain recurrence, limited systemic disease, and a fairly good performance status. This includes patients who received prior resection, whole brain radiation, or radiosurgery (163; 84).

For patients with recurrence of brain metastases after whole brain radiation therapy, the amount of additional radiation therapy that can be given safely is usually 1500 to 2500 cGy. Repeat courses of whole brain radiation therapy can improve or stabilize neurologic function in a significant proportion of patients (170; 135). Reirradiation may be somewhat more beneficial in the subset of patients who showed an initial favorable response to radiation therapy and who remain in good general condition when cerebral recurrence develops (38). Systemic tumor status is the main determinant of survival for these patients.

Several series of patients with recurrent brain metastases following whole-brain radiation and subsequent radiosurgery have shown high rates of local control over the patients' lifetimes (31; 29; 22). Longer overall survival is correlated with good performance status, "controlled" primary tumor, a single brain metastasis versus multiple metastases, and the total volume of brain lesions treated with radiosurgery (22). Despite control of the treated lesions, patients may die of leptomeningeal dissemination or "polyfocal intraparenchymal" metastases (31; 127).

Follow-up. There is no set standard for the follow-up of brain metastases after treatment. Clearly, MRI or CT scans are indicated at any time after therapy where patients develop new neurologic symptoms. How frequently asymptomatic patients need follow-up scans is controversial. For patients treated with surgery, a contrast MRI scan should be performed within five days after surgery to detect residual disease. This is especially important if consideration is being made to forgo postoperative whole brain radiation therapy. A reasonable schedule of follow-up scanning would be to get a scan 2 to 3 months after completion of last therapy (either whole brain radiation therapy, surgery, or radiosurgery), and then about every 2 to 3 months for the first year following treatment. The length of time between scans can then be gradually stretched out so that asymptomatic patients are scanned only once per year.

Outcomes

Median survival for patients with brain metastases varies widely for patients with non-small cell lung, breast, melanoma, gastrointestinal, and renal cancers (see Prognosis and complications). Outcomes are largely dependent on a number of variables that include age, functional status, extent of systemic and CNS disease, CNS disease velocity, and molecular profiling. Improved radiation techniques and developments in targeted therapies and immunotherapies for patients with non-small cell lung cancer, breast cancer, and melanoma have dramatically transformed the treatment and survival of patients with brain metastases. As patients live longer with CNS metastatic disease, however, in addition to side effects such radiation necrosis discussed earlier, cognitive impairment as a direct effect of metastatic disease as well as an effect of therapy remains a challenge. Up to 30% of patients with cancer exhibit cognitive impairment prior to treatment, 75% might have measurable cognitive impairment during treatment, and 35% of cancer survivors will continue to exhibit cognitive difficulties in the months to years that follow treatment (80).

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All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Guneet Sarai MD

Dr. Sarai of the University of Louisville has no relevant financial relationships to disclose.
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Aashka Sheth

Dr. Sheth of the University of Louisville has no relevant financial relationships to disclose.
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Editor

Rimas V Lukas MD

Dr. Lukas of Northwestern University Feinberg School of Medicine received honorariums from Novartis and Novocure for speaking engagements, honorariums from Cardinal Health, Novocure, and Merck for advisory board membership, and research support from BMS as principal investigator.
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Former Authors

Roy Patchell MD
Edward J Dropcho MD
Mariza Daras MD

Patient Profile

Age range of presentation: 1 month to 65+ years
Sex preponderance: male=female
Heredity: none
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Secondary malignant neoplasm of brain and cerebral meninges: C79.3
ICD-11: Malignant neoplasm metastasis in brain: 2D50

Malignant neoplasm metastasis in meninges: 2D51
ICD-O: Neoplasm, malignant: M-8000/3

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Brain metastases

Differential Diagnosis

primary brain tumors
abscesses
cerebral infarcts
hemorrhages
demyelinating disease
- infections

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Clinical Categories

Neuro-Oncology

Web References

Clinical Trials

NIH: Metastatic Brain Tumors

Brain metastases

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Table 1. Recursive Partitioning Analysis (RPA) Classes for Persons with Brain Metastases

Table 2. Graded Prognostic Assessment (GPA) for Persons with Brain Metastases

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Management of brain metastases

Systemic treatment

Outcomes

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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