Clinical Manifestations, Diagnosis, and Management of Patients with Brain

Metastases

Bita Fakhri, MD, MPH05/20/2015

Question to Med Consult

• 68M w/lung adenoCA and multiple new hemorrhagic brain mets. Please advise on medical management of brain mets.

• Scheduled for metastasectomy (pre-op management)• Loaded with Dexamethasone 10 mg (x1) followed by 6 mg q6h• Keppra loaded followed by keppra 1000 mg bid (no hx of seizure)• SQH 5000 IU q8h

Introduction

• Brain metastases are the most common intracranial tumors in adults

• accounting for significantly more than one-half of brain tumors.

• The incidence of brain metastases may be increasing, due to both improved detection of small metastases by MRI and better control of extracerebral disease resulting from improved systemic therapy

Primary Tumors in Adults

• Lung — 16 to 20 percent• Melanoma — 7 percent• Renal cell cancer — 7 to 10 percent• Breast cancer — 5 percent• Colorectal cancer — 1 to 2 percent

Increasing Incidence with Advances in Systemic Therapy• Breast cancer — particularly high in those with lung metastases and those with highly-

proliferative, hormone receptor-negative tumors that are positive for HER2 overexpression.

I. tumor biology – HER2-positive breast cancers have a higher propensity for metastases to sites such as lung and brain

II. lack of trastuzumab penetration into the central nervous system, owing to its high molecular weight

• Colorectal cancer — longer survival seen with newer systemic therapies. Compared to the era when 5-fluorouracil was the primary agent for metastatic disease, median survival has increased markedly with the introduction of oxaliplatin, irinotecan, and biologics.

• Non-small cell lung cancer —improved diagnosis of brain metastases with newer imaging modalities.

Pathogenesis

• Cerebral hemispheres — approximately 80 percent• Cerebellum — 15 percent• Brainstem — 5 percent

Clinical Manifestations

• Headache• Focal neurologic dysfunction• Cognitive dysfunction• Seizures• Stroke

Differential Diagnosis

• Primary brain tumors• Infectious processes• Progressive multifocal leukoencephalopathy• Demyelination• Paraneoplastic phenomena• Cerebral infarction or bleeding• Effects of treatment such as radiation necrosis

Imaging Studies

• Contrast-enhanced MRI is the preferred imaging study for the diagnosis of brain metastases

• Radiographic features that can help differentiate brain metastases from other CNS lesions include:

I. The presence of multiple lesions

II. Localization at the junction of the grey and white matter

III. Circumscribed margins

IV. Large amounts of vasogenic edema compared to the size of the lesion

Radiographic Features that Can Help Differentiate Brain Metastases from Other CNS Lesions

Radiographic Features that Can Help Differentiate Brain Metastases from Other CNS Lesions

Overveiw of Management

• Specific treatments directed against the brain metastases• The management or prevention of complications (eg, seizures,

cerebral edema, prevention of deep venous thrombosis)• Treatment of systemic malignancy if appropriate

Prognostic Classification

• The median survival of patients who receive supportive care and are treated only with corticosteroids is approximately one to two months.

• The use of whole brain radiation therapy in large series increased the average survival to three to six months.

Recursive Partitioning Analysis (RPA)

• The key parameters that determine survival after the diagnosis of brain metastases are:

i. Performance statusii. The extent of extracranial diseaseiii. Ageiv. Primary diagnosis

Recursive Partitioning Analysis (RPA)

Recursive Partitioning Analysis

Class I Class II Class III

• Karnofsky performance score 70 or higher

• Age < 65• Controlled primary tumor• Without extracranial metastases Median survival was 7.1 months. These patients are considered to have a favorable prognosis.

• Karnofsky performance score 70 or higher

• Age > 65• Uncontrolled primary tumor• Other extracranial metastases

Median survival in this group was 4.2 months.

• Karnofsky performance score less than 70

Median survival of 2.3 months. This group is considered to have a poor prognosis.

Management of Brain mets based on RPA• In patients being managed as having a favorable prognosis, treatment

focuses on the eradication or control of the brain metastases. These approaches include surgical resection and various forms of radiation therapy (eg, whole brain, stereotactic radiosurgery).

• In those patients considered to have a poor prognosis, treatment focuses on control of symptoms caused by the brain metastases, as well as maintenance of neurologic function to as great an extent as possible.

Symptom Management

• Control of peritumoral edema and increased intracranial pressure with corticosteroids

• Treatment and prevention of seizures• Management and prevention of venous thromboembolic disease

Control of Vasogenic Edema

• Dexamethasone is the standard agent:• its relative lack of mineralocorticoid activity reduces the potential for fluid retention. • dexamethasone may be associated with a lower risk of infection and cognitive

impairment compared to other glucocorticoids

• Dose and schedule — • Dexamethasone regimen consists of a 10 mg loading dose, followed by 4 mg four

times per day or 8 mg twice daily. • Although dexamethasone is typically administered in four divided daily doses, its

biological half-life is sufficiently long to allow twice daily dosing and this approach is often used for maintenance therapy

Treatment and Prevention of Seizures

• For patients who have experienced one or more seizures associated with a primary or metastatic brain tumor, we recommend initial treatment with a single agent antiepileptic drug (AED) (Grade 1A)

• For patients without a history of seizures and who have not undergone a neurosurgical procedure, we recommend NOT using prophylactic AEDs (Grade 1B)

Management and Prevention of Venous Thromboembolic Disease

• Treatment of venous thromboembolism

• Anticoagulation in all patients with brain tumors and venous thromboembolism (VTE) except those that have a high rate of intracranial hemorrhage (ie, metastases from melanoma, choriocarcinoma, thyroid carcinoma, and renal cell carcinoma)

• VTE in low-grade glioma and benign tumors should be treated for three to six months. Long-term anticoagulation is recommended for malignant gliomas.

• We suggest LMW heparin rather than warfarin for anticoagulation

Management and Prevention of Venous Thromboembolic Disease

• Prophylaxis of VTE• Although patients with primary or metastatic brain tumors are at relatively high

risk for the development of VTE, we suggest that these patients not be anticoagulated, except in the postoperative period (Grade 2B).

• In patients undergoing surgery, use pneumatic compression stockings combined with postoperative LMW heparin or unfractionated heparin beginning 12 to 24 hours after surgery and continuing until ambulation is resumed.

Question to Med Consult

• 68M w/lung adenoCA and multiple new hemorrhagic brain mets. Please advise on medical management of brain mets.

• Scheduled for metastasectomy (pre-op management)• Please refer to our RCRI assessment and pre-op eval • Loaded with Dexamethasone 10 mg (x1) followed by 6 mg q6h• Please continue dexamethasone 4 mg q6h• Keppra loaded followed by keppra 1000 mg bid (no hx of seizure)• Given lack of history of primary seizure disorder and no hx of seizure secondary to brain

mets, there is no indication for prophylactic antiepileptic treatment. We would highly appreciate neuro input on this topic as well.

• SQH 5000 IU q8h• Please discontinue SQH and consider sequential compression device for DVT PPX

References

1. Posner JB. Management of brain metastases. Rev Neurol (Paris) 1992; 148:477.

2. Sawaya R, Bindal RK. Metastatic brain tumors. In: Brain Tumors, Kaye AH, Laws ER (Eds),

Churchill Livingstone, Edinburgh 1995. p.923.

3. Graus F, Walker RW, Allen JC. Brain metastases in children. J Pediatr 1983; 103:558.

4. Wen PY, Loeffler JS. Management of brain metastases. Oncology (Williston Park) 1999; 13:941.

5. Johnson JD, Young B. Demographics of brain metastasis. Neurosurg Clin N Am 1996; 7:337.

6. Loeffler JS, Patchell RA, Sawaya R. Metastatic brain cancer. In: Cancer: Principles and Practice of

Oncology, Davita VT, Hellman S, Rosenberg SA (Eds), JP Lippincott, Philadelphia 1997. p.2523.

7. Posner JB. Neurologic Complications of Cancer, FA Davis, Philadelphia 1995.