Overview of Brain Metastasis (BM) and Treatment Modalities

Central nervous system (CNS) metastases include both parenchyma brain metastases and leptomeningeal disease.

With improvements in the survival of patients with systemic cancers and the development of screening brain MRI in the metastatic setting, the incidence of CNS metastases, specifically intracranial metastases (brain metastases and leptomeningeal disease) has increased.

Approximately 2% to 12% of patients with brain metastases may have leptomeningeal disease at initial presentation.

Up to 37% of patients with brain metastases may develop leptomeningeal disease during their clinical course.

Brain metastases are approximately 10 times more common than primary malignant brain tumors.

Any primary cancer can result in CNS metastasis.

Lung cancer (small cell and non–small cell), breast cancer, and melanoma are highest potential for intracranial metastasis (both parenchymal and leptomeningeal).

In this overview, we will discuss about parenchymal brain metastasis (BM) only.

1.EPIDEMIOLOGY

Metastatic tumors are most common mass lesions in brain! (> 50% of total brain tumors in adults but only 6% of pediatric brain tumors).

Incidence is 11 / 100,000 population / year (probably underestimate due to underdiagnosis and inaccurate reporting)
Incidence varies with age: incidence < 1/100,000 in age younger than 25 and incidence > 30/100,000 for age > 60
60% patients are 50-70 years of age

No gender difference for occurrence of CNS metastasis (male ≈ female).

During autopsy:

brain metastases occur in 15-33% of patients who die of systemic cancer (30% adults, 6–10% children)
only 1/3 of these are diagnosed during life
leptomeningeal metastases in 4–15% of solid tumors
dural metastases in 8–9%
direct intracranial extension from local primary tumors – rare
spinal epidural metastases in 5–10% (much more frequent than spinal leptomeningeal or intramedullary metastases)

20% of cancer deaths are due to brain metastasis.

Any type of cancer can metastasize to the brain.

The 3 commonest primary tumors associated with brain metastases are lung (40–50%), breast (15–25%) and malignant melanomas (5–20%).

Fig.1: Primary cancer sites with corresponding frequencies of causing brain metastases

2.RISK FACTORS

Tumor site, molecular subtype of primary tumors, patients age (advanced age), geographic location and ethnicity are important factors that influence the risk of distant brain metastases among cancer patients.

Some tumors have very high propensity to metastasize to the brain whereas other tumors rarely spread to the brain.

3.EPIPATHOPHYSIOLOGY

The blood-brain barrier (BBB) protects the brain from the effect of chemicals in the blood circulatory system.

Metastasis of cancer cells is a multifaceted process and to establish metastasis, tumor cells must have the following events by stages:

Fig.2: Brain metastasis events

Different tumors metastasize preferentially to different organs.

Tumor cells can survive in environments of low oxygen tension and when tumor colony increases in volume by > 2-3 times, it induces angiogenesis (by angiopoietin 2, vascular endothelial growth factor).

Two longstanding theories on the metastatic spread of cancer are the “seed and soil” hypothesis and mechanical theory.

1. Metastatic development was a consequence of particular tumor cells (‘seeds’) finding a suitable environment (‘soil’) in order to develop and grow. (Seed and soil theory)
2. Circulatory patterns between the primary tumor and specific secondary organs are sufficient to explain the majority of organ-specific metastatic spread (Mechanical theory)

Relationship between tumor molecular, epigenetic, genetic factors and that of secondary site all contribute to the metastasis of specific tumors to the brain.

4.PRIMARY SOURCES

(A). IN ADULTS

Mainly hematogenous spread from systemic cancers (only few primary high-grade brain tumors metastasize to other parts of neuroaxis)

Virtually all systemic cancers have capacity for brain metastasis!

1. Lung (35-50%)

Small-cell carcinomas (20% lung cancers) account for 50% brain metastases from lung cancer.
In patients with newly diagnosed non-small cell lung cancer (NSCLC), 30-50% will develop brain metastases.
80% lung cancer patients who survive > 2 years have brain metastases.
Interval between diagnosis of primary lung cancer and brain metastases is ≈ 4 months.
Prophylactic cranial irradiation reduces 2-year cumulative incidence of brain metastases in patients with small-cell carcinoma from 47 to10%.

2. Breast (13-20%)

Main source of metastatic disease in women!
Interval between diagnosis of primary breast cancer and brain metastasis is ≈ 3 years.

3. Melanoma (9-11%)

4. GU tract (7-11%) (21% kidney, 46% testes, 5% cervix, 5% ovary)

Prostate carcinoma rarely metastasizes to brain! (but frequently to spine)

5. Sarcoma (3-10%)

6. GI tract (3-9%) (3% colon, 2% pancreatic)

7. Head and neck cancer (6%)

8. Neuroblastoma (5%)

9. Lymphoma, mainly non-Hodgkin (1%)

10% cases have no identifiable primary source (most often adenocarcinomas or squamous cell carcinomas).

11% of solid cancer mass lesions in patients with cancer are not metastases!

Dural metastases – common from prostate, breast, lung, hematologic tumors.

Leptomeningeal metastasis – common from lung and breast cancer, melanoma, hematopoietic tumors.

Table 1: Cumulative incidence of brain metastasis with interval after diagnosis of primary tumor

(B). IN CHILDREN

leukemia > lymphomas > osteogenic sarcomas > rhabdomyosarcomas > Ewing sarcoma

GERM-CELL TUMORS are common in adolescents and young adults aged 15-21
years.

5.BRIEF PATHOLOGY

(A). Number of tumors:

1 tumor – single tumor (25-50% cases) (up to 50% of patients have only 1 metastasis but only 50% of those are surgical candidates in terms of extracranial disease)
2-3 tumors – oligometastases
4-8 tumors – diffuse multifocal disease
≥ 9 tumors – miliary disease

Very few are solitary

Melanoma is most likely to be associated with multiple metastases than other tumor types.
Bronchogenic carcinomas tend to outgrow their blood supply and become necrotic.
Breast carcinoma deposits may also cavitate but are more frequently solid.

In majority cases edema is substantial (for unclear reasons, some metastases produce almost no edema).

Calcification is unusual in untreated tumors (except for metastases from primary osseous tumors)

Some metastases hemorrhage spontaneously (esp. melanoma, thyroid carcinoma, renal cell carcinoma, choriocarcinoma).

Proliferation is variable and often higher than in primary neoplasm.

(B). Locations

85% in cerebrum (metastases prefer anatomical arterial “watershed areas” and gray matter-white matter junction, where end arteries penetrate into brain, narrow and branch into arterioles)
15-18% in cerebellum (esp. colorectal, renal, pelvic tumors)
3-5% in brainstem

Occasionally, metastatic CNS tumors seed along walls of ventricles or are located in pituitary gland, choroid plexus, or pre-existing lesion like meningioma.

6.CLINICAL FEATURES

The clinical manifestation of metastatic brain lesions have variable signs and symptoms those are influenced by the region of the brain involved as well as the extent of peritumoral edema.

There is a need for high index of suspicion among cancer patients.

Neurologic presentations of brain metastases can be divided into two categories:

Generalized neurologic symptoms
Focal neurologic symptoms.

(A) Generalized neurologic symptoms

They are due to increased intracranial pressure.

Headache

Headache is a common presenting complaint among 32% – 54% of cancer patients who are diagnosed with brain metastasis.
71% of brain neoplasms are associated with tension type headache.
Headache associated with increased ICP typically worsens in the morning and is aggravated with coughing, carotid massage, or Valsalva maneuver.
Multiple brain lesions and localization in the posterior cranial fossa are associated with more frequent headaches.

Increased intracranial pressure (ICP)

The skull bone provides a fixed space that accommodates a person’s brain tissue and associated meninges, CSF, and vasculature.
The presence of a lesion that is increasing size increases the ICP in this fixed space.
As a result, there are symptoms that occur due to increased ICP such as altered level of consciousness (confusion), headache, nausea, vomiting and visual disturbance in the form of blurred vision or diplopia.
Vomiting is more common with children than adults.

Seizure

Seizures are potential life-threatening complications of brain metastases.
Seizures are a presenting symptom in 15 to 40% of patients.
Metastatic tumors are less likely to induce seizures than primary brain tumors.
The risk of developing a seizure is influenced by the tumor type, the location, and its proximity to the cortical gray-matter.
Prophylactic antiseizure medications are not recommended for routine use in patients with brain metastases who have not undergone surgical resection and who are otherwise seizure free.
Its routine use in the post craniotomy setting for seizure-free patients with brain metastases is not recommended either.

Stroke

Stroke is a presenting symptom in 10% of patients.
Hemorrhagic strokes can occur from metastatic brain lesions with intratumor bleeding, vascular invasion, or embolization of tumor cells.
Cancers such as malignant melanoma, choriocarcinoma, thyroid and renal carcinoma are associated with stroke presentation.

Altered level of consciousness

It can be seen in 35% (in some literature up to 75%) of patients.
Disruption and inactivation of the intricate network of the RAS (the reticular activating system) decreases the release of neurotransmitters (serotonin, histamine, norepinephrine, and nitric oxide) needed for arousal and wakefulness.
This results in altered level of consciousness manifested by inattentiveness, drowsiness, decreased cognition, memory impairment, confusion and even hallucinations.

(B) Focal neurological symptoms

Focal neurological symptoms may manifest on the side of the body opposite to the location of the lesion in the brain.

Metastatic brain lesions are usually located in cerebral cortex (80%), cerebellum (15%) and brainstem (5%).

Focal symptoms are directly dependent on the localization of metastatic lesions in the lobes of the brain.

Most common symptoms are frontal symptoms (such as disinhibition, decreased attention, loss of executive function), memory impairment, cognitive decline, paresis, ataxia, visual complaints, sensory disturbances, and speech abnormalities.

7.DIAGNOSIS WORKUP

(A) Blood studies
1. CBC
2. Electrolyte panel
3. Coagulation screen
4. Liver function panel
5. Specific cancer serum markers:

CEA, PSA, CA125, CA153, AFP, HCG, LDH.
anti-Yo antibody in cerebellar degeneration
anti-Hu antibody in limbic encephalopathy
anti-Ri antibody in opsoclonus and ataxia

(B) Search for systemic cancer
1. Stool guaiac
2. Gynecologic / pelvic examination (incl. testicles)
3. Skin and thyroid examination.
4. Chest radiography and CT chest and/or abdomen-pelvis

for any mass lesion in brain, specifically in patients without history of systemic cancer; if negative → chest CT; if negative → CT of abdomen-pelvis

5. Mammogram
6. Whole-body FDG PET/CT
7. Bone scan

If primary tumor is not quickly revealed by evaluation, pathologic diagnosis of single brain tumor needs to be found by resection or, if unresectable, by biopsy.

CT with contrast

Can be used in situations in which MRI is contraindicated such as implanted pacemaker, metal fragment or metallic implants.
Many are invisible (isodense) → underestimation.
Some deposits are spontaneously dense (esp. malignant melanoma).
The overall sensitivity of CT for brain metastases is low, particularly with non-contrast CT, the only evidence of brain metastases is hypodensities corresponding to cerebral edema.
Contrast-enhanced CT improves this sensitivity but does not match that of MRI.

MRI with gadolinium (Gd)

The imaging modality of choice for brain metastasis.
Gd-based contrast leaks into parenchyma in areas with BBB breakdown, and the paramagnetic properties of Gd generate hyperintense signal on T1 weighted images.
Cerebral edema usually appears as perilesional T2 or fluid-attenuated inversion recovery (FLAIR) hyperintensity, and this edema is often out of proportion to the actual lesion size.

Fig. 3: Solitary brain mets and ring enhancement and perilesional edema

Fig. 4-A: nonenhanced MRI scan appears almost normal

Fig.4-B: contrast-enhanced MRI shows miliary metastatic lesions with no significant surrounding edema

PET

FDG PET has poor sensitivity (27%) for BM detection.
[18F] fluoroethyl)-L-tyrosine (FET) PET – sensitivity 90% to detect larger (> 1 cm in diameter) BM; however, detection of lesions with < 1 cm diameter is considerably inferior to that of MRI.
The advanced imaging techniques can potentially help distinguish tumor progression from treatment-related effects caused by radiation or immunotherapy.

(D) CSF analysis

Cytological examination in leptomeningeal metastases reveals malignant cells in initial CSF sample in 50%, 90% when CSF sampling is repeated in adequate volumes (10 mL).

(E) Biopsy

Tissue diagnosis should be performed in cases of uncertain etiology.

8.THERAPEUTIC APPROACHES

Treatment for intracranial metastases is multimodality and involving surgery, radiation, and/or medical therapy.

The approach to treatment is two goals:

prolong survival in the setting of typically non-curable disease
preserve quality of life by preventing new neurologic deficits or delaying further neurologic deterioration.

Tumor-directed treatment is typically achieved through three primary modalities: surgery, radiation, and medical therapy.

(A) Systemic Anti-cancer Pharmacotherapy

It depends on systemic disease, tumor type, and stage.
Most tumors that metastasize to brain are not chemosensitive. (most sensitive -small cell lung cancer and seminomas)
Development of brain metastases while patients are undergoing systemic chemotherapy indicates that the BBB makes the brain a sanctuary from many chemotherapeutic agents.
Chemotherapy role is limited to multiple brain metastases or active systemic cancer reasonably likely to respond to chemotherapy.
In most cases, 2-3 agents are used in combination and in conjunction with whole-brain radiation therapy (WBRT).

(B)Symptomatic medical therapy

Glucocorticoids

It decreases perilesional edema and reduces the permeability of the blood brain barrier.
Dexamethasone is the most commonly used.
Dexamethasone has a biological half-life of more than 30 hours with minimal mineralocorticoid effect as compared to hydrocortisone, prednisone,cortisone, and methylprednisolone.
Steroids are metabolized in the liver in a cytochrome P450-dependent manner therefore a p450 inducer affects the bioavailability of the medication when combined use with anti-seizure medications such as phenytoin carbamazepine and phenobarbital.
Steroids can be stopped without tapering down for a short period of time.
Prolonged steroid administration lasting for weeks or months requires tapering over a longer period of time to avoid steroid withdraw.
Effects of long-term use of steroids include osteoporosis, steroid-induced diabetes, myopathy, thromboembolic event, psychiatric disorders, and immunosuppression.
Patients on glucocorticoids may experience symptoms of gastric irritation and proton pump inhibitors (PPI)are started to counter this effect.
For asymptomatic brain metastases without mass effect insufficient evidence to use steroids.

Antiseizure medications (ASM)

Seizure prophylaxis is not necessary if there is no history of seizure.
They are administered only to patients at high risk for seizure.
ASM should be started (routinely) before radiation therapy / surgery.
Incidence of postoperative seizures – 18-24%
Most commonly used drugs are LEVETIRACETAM, PHENYTOIN, CARBAMAZEPINE, VALPROIC ACID.

(C) Radiotherapy (RTx)

Different types of cancers have different sensitivities to radiation.

Small cell lung cancer and germ cell tumors are very sensitive to radiation whereas lung and breast cancers are only moderately sensitive to radiation. Malignant melanoma and renal cell carcinoma are less sensitive to radiation.

Whole brain radiation Therapy (WBRT)

It involves irradiating the entire brain and is considered to be a standard of care in select patients with diffuse brain metastasis (≥5 brain metastases).
It is also considered for patients in whom surgery or stereotactic radiosurgery (SRS) is not recommended for various reasons.
It has the advantage of simplicity of delivery and the ability to treat both local and distant intracranial disease.
There is no consensus on the optimal dose and fractionation schedule for WBRT, despite multiple studies to determine the optimal delivery.
Acute adverse effects of WBRT include skin erythema, alopecia, fatigue, serous otitis and an altered sense of smell and taste.
Late-onset adverse effects of WBRT are cognitive decline, memory loss, confusion, and leukoencephalopathy.
Strategies to lessen neurocognitive decline from WBRT include the use of Memantine (a non-competitive NMDA receptor antagonist that retains activated NMDA receptors in an open-channel state causing preservation of long-term potentiation) and hippocampal avoidance (HA-WBRT).

Stereotactic radiosurgery (SRS)

It is a minimally invasive treatment option in the management of brain metastases with similarly high efficacy for both radiosensitive and radioresistant tumors.
SRS is a preferred option mainly because of the limited area irradiated.
It is limited by its small therapeutic ratio in lesions ≥ 4cm and/or tumor localization in the brainstem.
This limitation is solved with the use of fractionated SRS given in 3–7 fractions which typically results in a good therapeutic ratio with high local control rates (75–85%) and lower toxicity rates for large lesions.
SRS can be used alone or as a combined modality with WBRT or surgery. SRS has demonstrated superior local tumor control and functional autonomy for patients with brain metastases when combined with WBRT compared with WBRT alone.
Postoperative SRS is an alternative to WBRT for patients who undergo resection of brain metastases, with a reduced risk of neurocognitive decline.

(D) Surgical management

Patients with single metastatic lesions can benefit more from treatment with surgical resection plus radiotherapy compared to radiotherapy alone.
This benefit includes incidence of fewer recurrences, better quality of life and longer overall survival time.
Surgery offers rapid and effective symptom control for patients with large tumors or those associated with significant peritumoral edema or mass effect.
Microsurgical resection of metastatic brain lesions is effective in relieving brainstem compression and reducing peritumoral edema as well as decreasing ICP caused by “mass effect” of the gross tumor in the brain parenchyma.
Surgical resection of metastatic brain lesions is associated with a morbidity rate of 2–10%.
The commonest complications are postoperative hemorrhage (2.7%), pulmonary embolism (2.2%), CSF leakage (0.8%) and cardiovascular accident (0.6%) Permanent neurological complications range from 6% to 11%. These events are associated more with tumors in eloquent areas of the brain.
Advanced age > 65 years is not associated with significantly higher morbidity rate for patients who undergo brain microsurgery.

(E)Immunotherapy (IT)

ITs are the types of cancer treatments that utilize components of the immune system made by the body itself or developed in a laboratory to boost our immune system that help to identify and kill cancer cells.
The four major ITs currently used in BM include:
- 1.Immune checkpoint inhibitors (ICIs)
  - ICIs block the binding of checkpoint proteins with their partner proteins, thus allowing cytotoxic T-cells to induce tumor celldeath.
- 2.Adoptive cellular immunotherapy.
  - It involves isolating immune cells from a patient and either expanding their numbers or using gene therapy to enhance their cancer-fighting abilities.
- 3.Treatment vaccines
  - Vaccines employ the use of tumor-associated antigens that are present at low levels or not present in healthy cells to prime the immune system to recognize and react to those antigens to target and kill cancer cells.
- 4.Oncolytic virus therapy
  - This directly injects the virus into a tumor where it can then infect both normal adjacent tissue and cancerous cells, but only normal cells can kill the virus, whereas as cancer cells are unable to do so, causing the tumor cell death.
Conclusion

BM is a heterogeneous group of diseases with increasing prevalence.

The three most common cancers associated with brain metastasis are lung cancer, breast cancer and malignant melanoma.

Control of extracranial malignant disease is an important survival factor in the management of these patients.

The therapeutic decision for each patient must be individualized and a multi-disciplinary approach applied.

References:

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3.Horbinski C, Nabors LB, Portnow J, et al. 2023. “NCCN Guidelines® Insights: central nervous system cancers, version 2.2022.” J Natl Compr Canc Netw;21(1):12-20.
4.KocherM, Soffietti R, Abacioglu U, et al. 2011 “Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study.” J Clin Oncol;29(2):134-141.
5.Lamba N, Wen PY, Aizer AA. Epidemiology of brain metastases and leptomeningeal disease. Neuro Oncol 2021;23(9):1447-1456
6.Le Rhun E, Guckenberger M, Smits M, et al. EANO-ESMO clinical practice guidelines for diagnosis, treatment, and follow-up of patients with brain metastasis from solid tumours. Ann Oncol 2021;32(11):1332-1347.
7.Mahajan A, Ahmed S, McAleer MF, et al. Postoperative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol 2017;18(8):1040-1048.
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Author Information

Thar Thar Oo
MBBS, MD, MPH, FAAN
Senior Consultant Neurologist