eMedicine Specialties > Neurology > Neuro-oncology

Brain Metastasis: Treatment & Medication

Author: Victor Tse, MD, PhD, Assistant Professor, Department of Neurosurgery, Stanford University Medical Center, Santa Clara Valley Medical Center
Contributor Information and Disclosures

Updated: Jan 28, 2008

Treatment

Medical treatments consist of symptomatic and systematic treatments. Other options are surgical treatments, radiation therapy (whole brain radiation, focal beam and stereotactic radiation therapy such as radiosurgery), chemotherapy, combined therapies, experimental therapies, and integration therapy.

Integration therapy is a multidiscipline approach with joint therapy of behavioral modification/coping, nutritional counseling, alternative medicine (herbal), in addition to physical and occupational therapy. Integration therapy has become more accessible to most health care providers in the past few years. It was once looked upon as therapy that was in the fringe of pseudo-sciences; it is now an important element in major cancer centers. It serves as a resource and reference center to most of the cancer patients.

Medical Care

Medical management of metastatic diseases has mainly focused on the treatment of cerebral edema, headache, and seizure. Headache and cerebral edema are interrelated and are discussed as such.

• Management of headache and edema
  • Causes of headache are cerebral edema with increased intracranial pressure and meningeal irritation secondary to infiltration of cancer cells. Other causes, such as hydrocephalus and hemorrhage, require surgical intervention.
  • The diagnosis is normally confirmed with radiographic studies.
  • Hydrocephalus is uncommon in metastatic disease. In most cases, carcinomatosis meningitis is the cause. In rare cases, obstruction of the aqueduct of Sylvan or the fourth ventricle is the cause.
  • Shunting of the ventricle is the treatment of choice. The most common concern with this maneuver is the possibility of systemic seeding of tumor cells into the peritoneal cavity.
  • Cerebral edema of metastatic disease is mainly vasogenic. Brain swelling causes a secondary insult to the surrounding healthy brain, which may worsen cognitive function and/or motor and sensory deficits. If severe, it compromises cerebral perfusion and results in cerebral infarction.
    • Dexamethasone is the treatment of choice. It has the least mineralocorticoid effect of all steroids and is less likely than other steroids to be associated with infection or cognitive dysfunction. It does not increase the risk of myopathy.
    • Common adverse effects are psychotic reaction (5%), GI bleed (less than 1%), and glucose intolerance (19%).
    • The frequency of steroid complications depends on the duration of treatment (>3 wk increases risk). It is also associated with hypoalbuminemia, which increases the risk of adverse effects associated with steroid treatment.
    • The optimal dosage of dexamethasone vasogenic edema is 4 mg given intravenously or orally every 6 hours after a loading dose of 10 mg.
    • Symptoms improve in 70-80% of patients within 48 hours of the start of treatment. High doses of steroid (6-10 mg q6h) may improve functional scores (70 vs 54) after 7-10 days of treatment. However, this trend is reversed after 3-4 weeks. Most physicians advocate an initial dose of 16 mg/day, which is tapered after 4-28 days. Adverse effects of steroids include GI bleeding, an increased rate of opportunistic infection, diabetes, and myopathy. In patients with cancer, one must be aware of the catabolic effect of steroids and provide nutritional supplements as needed.
• Management of seizures
  • The frequency of seizures in patients with metastatic brain tumor is 30-40%. One half of patients who have seizures present with them.
  • The type of seizure guides treatment. Prophylactic treatment for seizure is not necessary in patients with no history of seizure.
  • The most commonly used drug is phenytoin, especially for patients with generalized motor seizures. Valproate has also been used, as have newer medications, such as kappa. Phenytoin should be started before radiation therapy. The incidence of allergic reaction increases if it is started after radiation. An allergic reaction can be acute or delayed; it commonly appears within 3-6 weeks after the patient's starting the medication.
  • Status epilepticus occurs infrequently in patients with metastasis, but it is associated with a high mortality rate (6-35%). Status epilepticus should be considered the cause in patients with a prolong postictal state or in stuporous or comatose patients whose imaging study does not show significant mass effect of edema. Status epilepticus should be treated aggressively. Ativan or Diazepam is the common medication. Propofol infusion has also been used.
  • See the following eMedicine articles for more information about the diagnosis and treatment of seizures: Complex Partial Seizures and Status Epilepticus.
• Chemotherapy
  • Medical treatment directed at cancer cells that have seeded into the brain is ineffective. The failure of chemical therapy has always been attributed to an intact BBB and the acquisition of drug resistance by the cancer cells. Most tumors that metastasize to the brain are not chemosensitive, though small-cell lung cancer, breast cancer, and lymphoma respond to chemotherapy. Hence, management and treatment depend on the systemic disease, the tumor type, and the stage of the disease.
  • A variety of chemotherapeutic agents have been used to treat brain metastasis from lung, breast, and melanoma, including cisplatin, cyclophosphamide, etoposide, teniposide, mitomycin, irinotecan, vinorelbine, etoposide, ifosfamide, temozolomide, fluorouracil (5FU), and prednisone.
  • In most cases, 2-3 of these agents are used in combination and in conjunction with whole-brain radiation therapy (WBRT). The outcome with this approach is not promising. The mean survival for chemotherapy alone for small-cell lung and breast cancer and melanoma is about 3.2-8 months. Survival with the combination of chemotherapy and WBRT is about 3.5-13 months.
  • Chemotherapy can have a remission rate of above 10%, a partial-response rate of about 40%, and a local-control rate of about 9%.
  • Temozolomide has recently been used as a single agent to treat brain metastasis from breast cancer. The result is encouraging. Complete remission was achieved in 36% of patients, and an additional 58% had a partial response.
• Radiation therapy
  • Radiation therapy has become a mainstream therapy for brain metastasis. Radiation therapy includes WBRT, multiplanar fractionated radiation, and stereotactic radiosurgery.
  • For decades, WBRT has been advocated for patients with multiple lesions. WBRT is also advocated for patients with a low Karnofsky score or a life expectancy of <3 months. Effectiveness of this treatment depends on the histologic type of the tumor. Small-cell lung tumor and germ-cell tumors are highly susceptible to radiation, other types of lung cancer and breast cancers are less sensitive, and melanoma and renal-cell carcinoma are not sensitive at all.
  • Regarding the effectiveness of radiation therapy, the Radiation Therapy Oncology Group (RTOG) has recommended a treatment schedule of 30 Gy delivered in 10 fractions over 2 weeks. With this treatment, median survival is 3-6 months depending on number of lesions, their radiosensitivity, and the status of systemic disease. Disadvantages are short- and long-term adverse effects. Besides hair loss, headache, nausea, otitis media, and cerebral edema, patients may have increased somnolence. After 6 months, patients may have evidence of radiation necrosis, leukoencephalopathy, and/or dementia.
• Stereotactic radiosurgery
  • This modality makes use of multiple, well-collimated beams converging on a small lesion with a steep dose gradient at the edge of the beam. This configuration allows a high dose of radiation to be delivered to the target in a single fraction without causing excessive radiation damage to surrounding healthy brain. Several lesions can theoretically be treated on a single clinic visit. As the number of lesions increase, the overlapping of fields exceeds tolerance of healthy brain to radiation injury. For lesions 1-3 cm, the median dose is 17-18 Gy.
  • Median survival after radiosurgery is 11 months. The size of metastatic tumors may not change until months afterward. The lesion may appear to grow immediately after treatment. Treatment can worsen peritumoral edema, which can be controlled with a prolonged course of a high-dose steroid.
  • The prophylactic use of anti-inflammatory drugs to reduce edema is still being debated.
  • Acute reactions due to edema occur within 2 weeks in 7-10% of patients. These reactions include headache, nausea, vomiting, worsening of preexisting neurological deficits, and seizure. Radiation necrosis happens later, 6 months after treatment in 4% of patients. It can manifest as a transient increase in tumoral size, edema, or mass effect with or without frank necrosis. It can be difficult to distinguish from the tumor.
  • Emerging data has suggested multiplanar focal radiation and radiosurgery can be equally effective. These modalities have been offered to patients with low Karnofsky scores and to patients with life expectancies of 3 months. They are also used as adjuvant therapies in patients who have undergone metastatic brain-tumor resection. The effectiveness of this treatment depends on the histology of the tumor.

Surgical Care

• Indications for surgical resection include the following:
  • Solitary lesions > 3 cm
  • Lesions in noneloquent areas of the brain
  • Limited and/or controlled systemic disease
  • Karnofsky score >70
  • One symptomatic lesion with multiple asymptomatic lesions (The symptomatic lesion should be resected, and remaining lesions should be treated with radiotherapy.)
• The surgical morbidity rate is about 10%, and the mortality rate is <5%. The outcome of resection can be improved by applying intraoperative navigation and monitoring with cortical mapping; this allows for aggressive resection, even in eloquent regions.
• Contraindications to surgery include a radiosensitive tumor (eg, small-cell lung tumor), patient life expectancy <3 months (WBRT indicated), and multiple lesions. However, Bindal et al recently indicated that patients who underwent resection of multiple lesions fared better than patients with multiple lesions who did not undergo surgery.⁵ Morbidity and mortality rates are essentially the same as those in patients with a solitary lesion.
• Surgical resection versus radiosurgery
  • Surgical resection is considered standard care for solitary metastases > 3 cm and in noneloquent areas of the brain.
  • Surgical resection is superior to radiosurgery, with a median survival nearly twice that of radiosurgery. About 13% of surgically treated patients have local recurrence, whereas 39% of patients treated with radiosurgery have local progression of disease.
  • Cho and Auchter reported that combined therapies (eg, resection plus radiosurgery or radiosurgery plus WBRT) yield outcomes better than those of WBRT alone.^6,7
  • Read more on Stereotactic Radiosurgery in the Management of Brain Metastasis.
• Multimodality therapy
  • In 2 prospective randomized trials, surgical resection plus WBRT was more effective than WBRT alone in controlling disease. The combination had a median survival of 8-16 months and 7-15% local recurrence rates. The role of adjunctive WBRT after surgery for a solitary lesion is controversial.
  • Postoperative WBRT reduces the recurrence rate but does not affect overall survival.
  • In 1 comparison of radiosurgery plus WBRT versus WBRT alone in patients with multiple metastases (2-4 tumors, <25-mm total diameter), combined therapy was most effective in controlling disease and that it had a survival advantage (median time to local failure of 36 vs 6 mo).
  • WBRT after surgery or radiosurgery is controversial. Local control is best with a combined approach, but functional scores and overall survival were not clearly different.
  • The growing trend is to postpone WBRT until recurrence and to use fractionated stereotactic radiotherapy with radiosensitizers (eg, gadolinium texaphyrin, RSR13).
• Management of recurrent metastasis
  • The local recurrence rate of brain metastasis is relatively high. It can be as high as 85% in patients undergoing craniotomy without WBRT. For patients given radiation therapy and stereotactic radiosurgery, the relapse rate can be as much as 67%.
  • The recurrence rate of brain metastasis is related to the duration of survival, which in turn mostly depends on the nature and the course of the systemic disease.
  • Treatment outcomes for patients with brain metastases who live 24 months or longer after initial treatment include primary tumor control, single-organ metastasis, and a long latency period between primary treatment and recurrence.
  • The management paradigm for recurrent brain metastasis is highly controversial.
• Management of brain metastasis with unknown primary diseases
  • Metastatic cancer of an unknown primary lesion accounts for 3-5% of all cancers, and makes it the seventh most common malignancy. About 15% of brain metastasis is included in this category.
  • Metastasis without a primary lesion is considered present when a complete history, physical examination (including breast and pelvic examination in female patients and prostate and testicular examination in male patients), standard laboratory investigations, and histologic examination fail to confirm systemic disease before any form of treatment is given. In this situation, the likelihood of identifying the primary disease is about 30-82%.
  • The general belief is that the primary lesion has become involuted or that the phenotype and/or genotype of the tumor suggest metastatic potency instead of a slow local expansion of the tumor.
  • This designation creates uncertainty regarding treatment and an assumption of a poor prognosis. In fact, this condition represents a subgroup of cancers with widely divergent prognoses.
  • Serum markers, such as cancer antigen (CA)15.3 for breast tumor, CA19.9 for pancreatic tumors, and CA125 for ovarian cancers have helped to focus the search of the primary disease and have empirically guided treatment.
  • Brain metastases of unknown primary origin are often adenocarcinomas or squamous cell carcinomas (31% and 9%, respectively). A search for occult head and neck cancer frequently reveals the origin of the systemic disease. Nevertheless, in 42% of cases, the origin remains unclear after extensive investigation.
  • The median survival of patients with brain metastasis without a primary cancer is about 6 months; those with solitary lesions have a better prognosis.
  • Surgery in combination of WBRT is the most common mode of therapy. Chemotherapy is infrequently used when serum markers and histological clues indicate the most likely source of the disease.

Read more on Surgical Management of Brain Metastases.

Medication

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Corticosteroids

These agents reduce edema around tumor, frequently leading to symptomatic and objective improvement.

Dexamethasone (Decadron, AK-Dex, Alba-Dex, Dexone, Baldex)

Postulated mechanisms of action of corticosteroids in brain tumors include reduction in vascular permeability, cytotoxic effects on tumors, inhibition of tumor formation, and decreased CSF production.

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