Brain Metastasis Treatment & Management

Medical treatments consist of symptomatic and systematic treatments. Other options are surgical treatments, radiation therapy (whole brain radiation, focal beam and stereotactic radiation therapy, eg, radiosurgery), chemotherapy, combined therapies, experimental therapies, and integration therapy. ^[15]

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

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. ^[16] 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 levetiracetam. 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 has started 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 Medscape Reference 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.

The advent in small-molecule tyrosine kinase inhibitors (tyrKi) and monoclonal antibodies has helped transform the management of brain metastasis. Gefitinib and erlotinib, epidermal growth factor receptor (EGFR) tryKis, have shown promising results in treating nonsmall cell lung cancers that metastasize to the brain, especially if they have the EGFR mutation. ^[17] The use of lapatinib in combination with capecitabine is effective in treating HER2 -ositive brain metastasis; similarly, the use of vemurafenib in treating BRAF V600E–positive melanoma that has brain metastasis is also found to be effective. ^[18] It is noteworthy that a recent study at Memorial Sloan-Kettering has shown that the use of sorafenib or sunitinib can lower the incidence of metastasis of renal cell carcinoma to the brain. ^[19]

Monoclonal antibodies such as trastuzumab have been used in treating metastatic breast cancer. The latter, however, is not that effective in crossing the blood-brain barrier and results in relapse within the central nervous system. Ipilimumab, on the other hand, has been found to be effective in treating metastatic melanoma to the brain. ^[20]

Knowing the tumor's molecular signature, using small molecules and monoclonal antibodies in conjunction with radiotherapy (WBRT and/or SRS), has transformed the outcome of managing NSCLC metastatic disease. Osimertinib or Icotinib when offered to patients with EGFR-mutation, and alectinib, brigatinib, or ceritinib, when used for brain metastases with ALK-rearranged, demonstrated therapeutic advantages. A combination of ipilimumab and nivolumab has been used for breast cancer patients regardless of BRAF status or dabrafenib plus trametinib for patients with BRAF-V600E mutation with success. A cocktail of tucatinib, trastuzumab, and capecitabine was effective in breast cancer patients with human EGFR2–positive metastatic tumors. ^[21]

Radiation therapy

Radiation therapy has become a mainstream therapy for brain metastasis. Radiation therapy includes WBRT 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 histological 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.

Hippocampal avoidance (HA), a modification of WBRT, may preserve short-term memory in cancer patients with brain metastases. In a study involving 113 adult cancer patients with a measurable brain metastasis outside a 5-mm margin around the hippocampus, the HA-WBRT group showed a 7% performance decline on a standardized memory test at 4 months, whereas the control group showed a 30% decline. ^[22] At 6 months, the decline averaged 2%.

Brachytherapy is a relatively common modality for prostate and breast cancer treatment, but it is rarely used in brain metastases. This treatment technique involves the implantation of radioactive isotopes during tumor resection for brain metastases. It has a favorable local control rate but suffers significantly from radiation necrosis and swelling; this may change with the recent development and interest in using local intraoperative X-ray radiation within the resection cavity after tumor resection. Unlike true brachytherapy, there is no permanent radiation source remaining in situ. The radiation probe is inserted into the cavity to emit low-energy (50 kV) photons at a high dose rate at the time of surgery. ^[23]

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 conformity 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 15–24 Gy.

Stereotactic radiosurgery (SRS) is a more preferred treatment modality for radio-resistant lesions such as nonsmall cell lung cancer, renal cell carcinoma, and melanoma. It is also more frequently used to treat the resection cavity of brain metastasis, particularly in patients with breast metastatic disease. The latter population of patients has a higher survival potential, thus whole brain radiation or EBRT, with their long-term cognitive adverse effects, make these modalities a less favorable choice.

Despite advances in SRS, rates of in-field recurrence after SRS range from 10 to 25%. High rates of neurologic death have been reported after SRS failure, particularly for recurrences deep in the brain and surgically inaccessible. ^[24] Median survival after radiosurgery is 14.1 months.

Twenty-four percent of patients with brain metastasis from breast cancer have 24-month overall survival. The overall control rate in breast metastasis in the brain is 82-90%. Unfortunately, 47% of the patients have new brain metastasis 11-15 months after initial radiosurgery. This is especially true in melanoma. The median tumor control for most brain metastasis is about 10 months.

The size of metastatic tumors may not change until months after radiation. The lesion may appear to grow slightly immediately after treatment. Treatment can worsen peritumoral edema, which can be controlled with a prolonged course of high-dose steroids. The prophylactic use of anti-inflammatory drugs to reduce edema is still being debated. If cerebral edema becomes symptomatic, then craniotomy and resection is warranted.

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 tumor size, edema, or mass effect with or without frank necrosis. It can be difficult to distinguish from the tumor itself.

In a recent study, the radiation complication rate for stereotactic radiosurgery in treating metastatic brain tumors is estimated to be 6%. It has been shown that the risk of having imaging-documented radiation necrosis is proportional to the volume of nontumor brain tissue exposed to 10 or 12 Gy of radiation. For volume more than 10 cm³ in a single session of radiosurgery, the risk of necrosis is 47% and is about 24% when the volume is less than 10 cm³. ^[25] Fortunately, only 5.8% of the patients are symptomatic.

Collectively, these merging data confirm that radiosurgery is equally effective in treating brain metastasis. Radiosurgery is particularly useful in treating patients with limited systemic disease and higher Karnofsky scores and in patients with life expectancies of more than 6 months. However, radiosurgery is now commonly offered to patients with higher systemic tumor burden when a shorter treatment regimen is more desirable.

Radiosurgery isnow routinely used as the adjuvant therapy in patients who have undergone metastatic brain tumor resection. The effectiveness of this treatment depends on the histology of the tumor.

Indications for surgical resection include the following:

• Solitary lesions larger than 3 cm

• Lesions in noneloquent areas of the brain

• Limited and/or controlled systemic disease

• Karnofsky score greather than 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 less than 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.

Nowadays, with advanced surgical planning tools and robotic-assisted navigation systems, surgeons using a minimal surgical approach can access deep-seated lesions, avoiding critical anatomical structures and fiber tracts previously seen as unresectable. Resecting large tumors alleviates symptoms due to mass effect. The use of stereotactic laser interstitial thermal therapy in recurrent tumor and/or radiation necrosis is becoming popular and with good results, particularly in dealing with associated radiation necrosis.

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. ^[26] 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 larger than 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. ^{[27, 28]}

Read more in 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 single/solitary brain metastasis in patients without prior WBRT

The algorithm for the management of a solitary brain tumor (patient with no or stable systemic disease) is easier than that of a single metastatic tumor. If the solitary lesion is symptomatic and/or in a noneloquent area, then surgical resection is the best option; this provides tissue confirmation and reduces mass effect.

Even then, the use of WBRT or radiosurgery as adjuvant therapy remains controversial. It is a general belief that adjuvant radiotherapy is indicated since the hazard ratios for local recurrence and distance recurrence in patients without WBRT are 3.14 and 2.16 (as compared to 0.58 and 0.42), respectively. However, the use of stereotactic radiosurgery as an adjuvant therapy is gaining momentum. A body of clinical evidence suggests that radiosurgery to the rim of the tumor resection cavity is equally effective in achieving local control. An upcoming NCCTG-N107C study is designed to categorically address this issue.

Radiosurgery has been used effectively in treating multiple lesions as an upfront therapy; therefore, there is no reason to doubt it will not be able to control local diseases around the resection cavity if an adequate marginal dose is achievable; thus, reserve WBRT to be used in distance relapse with multiple lesions, local progression, or in cases in which leptomeningeal spread is suspected. It is also possible to perform re-resection in cases in which local progression is evidenced, as well as in cases in which the differentiation of local recurrence and radiation necrosis is not possible.

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 in Surgical Management of Brain Metastases.