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BRAIN TUMORS

By: Nur Agami

BACKGROUND
Brain tumors may originate from neural elements within the brain, or they may represent spread of distant cancers. Primary brain tumors arise from CNS tissue and account for roughly half of all cases of intracranial neoplasms. The remainder of brain neoplasms are caused by metastatic lesions.

In adults, two thirds of primary brain tumors arise from structures above the tentorium (supratentorial), whereas in children, two thirds of brain tumors arise from structures below the tentorium (infratentorial). Gliomas, metastases, meningiomas, pituitary adenomas, and acoustic neuromas account for 95% of all brain tumors. Classification by tumor cell type is irrelevant to the emergency physician because emergent treatment is the same regardless of the tumor type.

Neoplasms, brain. CT images of several tumor types. Slide courtesy of UMASS Continuing Education Office

Many review articles have been written on brain tumors, and this discussion at times draws from the consensus of these reviews. Glioma has recently been in the news with the diagnosis of this malignant brain tumor in May 2008 in Senator Edward M. Kennedy and his death August 25, 2009.

PATOPHYSIOLOGY
Tumors of the brain produce neurologic manifestations through a number of mechanisms. Small, critically located tumors may damage specific neural pathways traversing the brain. Tumors can invade, infiltrate, or supplant normal parenchymal tissue, disrupting normal function.

Because the brain dwells in the limited volume of the cranial vault, growth of intracranial tumors with accompanying edema may cause increased intracranial pressure. Tumors adjacent to the third and fourth ventricles may impede the flow of cerebrospinal fluid, leading to obstructive hydrocephalus. In addition, tumors generate new blood vessels (ie, angiogenesis), disrupting the normal bloodbrain barrier and promoting edema.

Neoplasms, brain. Colloid cyst of the third ventricle with obstructive hydrocephalus. Image courtesy of Peter Ferrera, MD.

The cumulative effects of tumor invasion, edema, and hydrocephalus may elevate the intracranial pressure (ICP) and impair cerebral perfusion. Intracranial compartmental rise in ICP may provoke shifting or herniation of tissue under the falx cerebri, through the tentorium cerebelli, or through the foramen magnum.

Slow-growing tumors, particularly tumors expanding in the so-called silent areas of the brain, such as the frontal lobe, may be associated with a more insidious clinical course. These tumors tend to be larger at detection. Most primary brain tumors do not metastasize, but if they do metastasize, intracranial spread generally precedes distant dissemination. Metastatic brain tumors from non-CNS primary tumors may be the first sign of malignancy, or they may herald a relapse. Nonetheless, the signs and symptoms of brain metastases simulate those of primary brain tumors. Leptomeningeal infiltration may present with dysfunction of multiple cranial nerves.

FREQUENCY
United States Estimates of the annual incidence rate of primary brain tumors range from 7-19.1 cases per 100,000 population. Metastatic tumors to the brain are more common with more than 200,000 patients per year in the United States with a new diagnosis of intracranial metastases. An increase in the prevalence of HIV infection corresponds to an increase in the occurrence of primary CNS lymphoma. Pituitary adenomas are exceptionally common, and they are frequent incidental findings on autopsy. Autopsy series of patients with systemic cancer show that intracranial metastases are present in 1824% of patients.
International The international incidence is not known, but it is thought to parallel that of the United States.

MORTALITY/MORBIDITY
In the United States in 1999, primary cancers of the central nervous system were the cause of death in approximately 13,100 people. Brain tumors are the second most common cancer in children, comprising 15-25% of all pediatric malignancies. Perhaps no other cancer is as feared as brain tumor since severe disability, including paralysis, seizures, gait disturbances, and impairment of intellectual capacity may occur.

RACE
Differences are seen between ethnic groups within the same country, and a 3-fold difference in incidence has been reported between countries worldwide. Developed countries appear to have the highest rates, but this may reflect better registration systems.

SEX
Meningiomas and pituitary adenomas are slightly more common in women than in men. Males are more likely to be diagnosed with brain tumors than females, with a male-to-female ratio of 1.5:1.

AGE
Tumors in the posterior fossa predominate in preadolescent children, with the incidence of supratentorial tumors increasing from adolescence to adulthood. Low-grade gliomas, such as astrocytomas, are more common in younger people than in older people. High-grade gliomas, such as anaplastic astrocytoma and glioblastoma multiforme, tend to originate in the fourth or fifth decade or beyond. In children, brain tumors are the most prevalent solid tumor, second only to leukemia as a cause of pediatric cancer. The incidence rate of primary CNS neoplasms is 3.6 cases per 100,000 children each year.

HISTORY
Presenting complaints of patients with an intracranial neoplasm tend to be similar for primary brain tumors and intracranial metastases. Manifestations depend on the cause of the symptoms: an increase in ICP, direct compression of essential gray or white matter, shifting of intracranial contents, or secondary cerebral ischemia.

Symptoms may be nonspecific and include headache, altered mental status, ataxia, nausea, vomiting, weakness, and gait disturbance. CNS neoplasms also may manifest as focal seizures, fixed visual changes, speech deficits, or focal sensory abnormalities. The onset of symptoms usually is insidious, but an acute episode may occur with bleeding into the tumor, or when an intraventricular tumor suddenly occludes the third ventricle.

In one study of children with brain tumors, time from symptom onset to diagnosis of a brain tumor was found to be 3.3 months. Head tilt, cranial nerve palsies, endocrine and growth abnormalities and reduced visual acuity were associated with a longer symptom interval. Headache was the number one symptom experienced in more than half of patients.

Although headache is the symptom customarily associated with an intracranial neoplasm, it often is a late complaint. Usually, headache is not an isolated finding. Headache is the worst symptom in only one half of patients. Most headaches in patients with brain tumors are nonspecific and resemble tension-type headaches. A change in any patient's headache pattern may be cause for concern. New onset of headaches in middle-aged or older patients is worrisome.

The location of the headache reliably indicates the side of the head affected, but it does not indicate the precise site of the tumor. Headaches are more common with posterior fossa tumors. Headache is a more frequent symptom of intracranial tumor in pediatric patients. Prevailing inaccurate portrayals of a tumor headache include pain that is worse in the early morning than at other times; vomiting (with or without nausea); and exacerbation with Valsalva maneuvers, bending over, or rising from a recumbent position.

Mental status changes, especially memory loss and decreased alertness, may be subtle clues of a frontal lobe tumor. Complaints may be as mundane as sleeping longer, appearing preoccupied while awake, and apathy. Temporal lobe neoplasms may lead to depersonalization, emotional changes, and behavioral disturbances.

Vision, smell, and other sensory disturbances may be caused by a brain tumor. An acoustic neuroma may present as intermittent (then progressive) hearing loss, disequilibrium, and tinnitus. Symptoms of pediatric posterior fossa tumors include increased irritability, unsteadiness, ataxia, headache, vomiting, and progressive obtundation.

Supratentorial tumors in children are more commonly associated with seizures, hemiparesis, visual field cuts, speech difficulties, and intellectual disturbance. Pituitary adenomas may be divided into 2 broad categories: nonfunctional and hypersecretory. Nonfunctional pituitary adenomas remain asymptomatic until they are large enough to encroach the optic chiasm and disturb normal vision. Most hypersecretory pituitary adenomas secrete prolactin, with affected women noting an amenorrheagalactorrhea syndrome. Men with prolactin pituitary adenomas more commonly complain of headache, visual problems, and impotence.

Seizures, focal or generalized, may be the earliest expression of a brain tumor. A Jacksonian pattern, one in which a focal seizure begins in one extremity and then progresses until it becomes generalized, is distinctive in suggesting a focal structural lesion of the cortex. Depending on the rate of growth of the tumor, seizures may be present for months to years before a brain tumor is diagnosed.

Any middle-aged or elderly patients presenting with a first seizure should have CNS tumor high in the differential diagnosis. Patients with a brain tumor may present with acute neurologic changes mimicking those associated with stroke.

PHYSICAL
No physical finding or pattern of findings unmistakably identifies a patient with a CNS neoplasm. Based on their location, intracranial tumors may produce a focal or generalized deficit, but signs may be lacking (especially if the tumor is confined to the frontal lobe) or even falsely localizing. Papilledema, which is more prevalent with pediatric brain tumors, reflects an increase in ICP of several days or longer. Papilledema usually does not cause visual loss. Not all patients with CNS tumors develop papilledema.

Diplopia may result from displacement or compression of the sixth cranial nerve at the base of the brain. Impaired upward gaze, called Parinaud syndrome, may occur with pineal tumors. Tumors of the occipital lobe specifically may produce homonymous hemianopia or partial visual field deficits. Neoplasms, brain. Occipital lobe glioblastoma with surrounding edema.

Anosmia may occur with frontal lobe tumors. Brainstem and cerebellar tumors induce cranial nerve palsies, ataxia, incoordination, nystagmus, pyramidal signs, and sensory deficits on one or both sides of the body.
Three cranial nerves run through the cerebellopontine angle: facial, cochlear, and vestibular. Masses in these regions may impair the functions of these nerves. Acoustic neuromas most commonly originate from the vestibular nerve (part of cranial nerve VIII).

CAUSES
Although few factors are unequivocally associated with an increased risk of brain cancer, some are consequential. Most CNS neoplasms are thought to arise from individual cell mutations. A prior history of irradiation to the head for reasons other than treatment of the present tumor may increase the chance of primary brain tumor. A few inherited diseases, such as neurofibromatosis, tuberous sclerosis, multiple endocrine neoplasia (type 1), and retinoblastoma, increase the predilection to develop CNS tumors.

The most common tumors originating from the cerebellopontine angle are acoustic neuroma and meningioma. Primary CNS lymphoma is a relatively frequent occurrence in HIV patients. Metastatic tumors reach the brain via hematogenous dissemination through the arterial system. Lung cancer is by far the most common solid tumor disseminating to the brain, followed by breast, melanoma, and colon cancer. Less common sources of metastasis are malignant melanoma, testicular cancer, and renal cell cancer. Prostate, uterine, and ovarian cancers are unlikely sources of brain metastasis.

Primary Brain Tumors


The brain is made up of many different types of cells and tumors that arise from a brain cell type are termed primary brain tumors. Cancers occur when one type of cell transforms and loses its normal characteristics. Once transformed, the cells grow and multiply in abnormal ways. As these abnormal cells grow, they become a mass of cells, or tumor.

Brain tumors that result from this transformation and abnormal growth of brain cells are called primary brain tumors because they originate in the brain. The most common primary brain tumors are gliomas, meningiomas, pituitary adenomas, vestibular schwannomas, primary CNS lymphomas, and primitive neuroectodermal tumors (medulloblastomas).

The term glioma is an expansive one since it includes numerous subtypes, including astrocytomas,oligodendrogliomas,ependymoma s, and choroid plexus papillomas. These primary tumors are named after the part of the brain or the type of brain cell from which they arise

Metastatic Brain Tumors


Metastatic brain tumors are made of cancerous cells that spread through the bloodstream from a tumor located elsewhere in the body. The most common cancers that spread to the brain are those arising from cancers that originate in the lung, breast, and kidney as well as malignant melanoma, a skin cancer.

The cells spread to the brain from another tumor in a process called metastasis. The process metastasis occurs when cancer cells leave the primary cancer tissue and enter either the lymphatic system to reach the blood or the bloodstream directly. These cancer cells eventually reach the brain tissue through the bloodstream where they develop into tumors.

Metastatic brain tumors are the most common type of tumor found in the brain and are much more common than primary brain tumors. Metastatic tumors are usually named after the type of tissue from which the original cancer cells arose (for example, metastatic lung or metastatic breast cancer).

Brain blood flow usually determines where the metastatic cancer cells will lodge in the brain; about 85% locate in the cerebrum (the largest portion of the brain, located in the upper part of the skull cavity). Unfortunately, the majority of metastatic brain tumors occur at more than one site in the brain tissue

Staging of Brain Cancers

WHO histologic grading for CNS tumors Grade I: Lesions with low proliferative potential, a frequently discrete nature, and the possibility of cure following surgical resection alone Juvenile pilocytic astrocytoma, subependymal giant cell astrocytoma Grade II: Lesions that are generally infiltrating and low in mitotic activity but recur; some tumor types tend to progress to higher grades of malignancy Diffuse astrocytoma, oligodendroglioma, oligoastrocytoma Grade III: Lesions with histologic evidence of malignancy, generally in the form of mitotic activity, clearly expressed infiltrative capabilities, and anaplasia Anaplastic astrocytoma, anaplastic oligoastrocytoma, anaplastic oligoastrocytoma Grade IV: Lesions that are mitotically active, necrosis-prone, and generally associated with a rapid preoperative and postoperative evolution of disease

Differential Diagnoses
Encephalitis Epidural Hematoma Stroke, Hemorrhagic Stroke, Ischemic Subdural Hematoma

Laboratory Studies
Patients with cancer are predisposed to medical complications, including bleeding disturbances (hyperviscosity), metabolic disorders (hypercalcemia), and production of excessive hormones (syndrome of inappropriate antidiuretic hormone secretion). With clinical suspicion of cancer, obtain routine laboratory studies on admission, including a CBC, coagulation studies, and analysis of electrolytes and comprehensive metabolic panel.

Procedures
Lumbar puncture is not indicated in the ED in the patient with suspected CNS neoplasms.

Imaging Studies
Obtain neuroimaging studies in patients with symptoms suggestive of an intracranial neoplasm (eg, acute mental status changes; new-onset seizures; focal, motor, or sensory deficits, including gait disturbance; suspicious headache; signs of elevated ICP, such as papilledema). Although some tumors exhibit a characteristic appearance, do not make an unequivocal diagnosis based solely on radiologic findings.

Generally, CT is the imaging modality of choice for the ED physician. Intravenous contrast material assists in tumor identification. Most tumors demonstrate enhancement with contrast material administration. Tumors may appear hypodense, isodense, or hyperdense, or they may have mixed density. Metastases to the brain tend to be multiple, but certain tumors, such as renal cell carcinomas, tend to be solitary metastatic brain lesions.

With increasing availability, MRIs may supplant CTs as the imaging procedures of choice. An MRI is most helpful for identifying tumors in the posterior fossa (including acoustic neuromas), hemorrhagic lesions. It is useful in patients with an allergy to iodinated contrast material or renal insufficiency. Drawbacks to MRI include incompatibility with certain medical equipment, longer imaging times (increased risk of motion artifact), and poor visualization of the subarachnoid space. Neither CT nor MRI can be used to differentiate tumor recurrence from radionecrosis. On plain skull radiographs, large pituitary adenomas are associated with a large sella turcica.

Medical Care
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 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.[7] 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 (610 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.

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 starts the medication.

Management of Seizures

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.

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 newer approach in using convection-enhancing technique to break the BBB has shown some success for local delivery of chemotherapeutic agents.[8] Likewise, local delivery of chemotherapeutic agents using biodegradable matrix has also been tried with promising results.

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 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. A report by Jensen et al advocates the use of gamma knife radiation to the postsurgical resection cavity, as well as other synchronous metastases, in lieu of WBRT.[10] This strategy may provide better postradiation neurocognitive function and may be a good choice for small metastatic lesions (< 3 cm). Adjuvant WBRT following radiosurgery or surgical resection of 1-3 cerebral metastases reduces intracranial relapses and neurological death.[11] However, it does not prolong functional independence.

A report by Jensen et al advocates the use of gamma knife radiation to the postsurgical resection cavity, as well as other synchronous metastases, in lieu of WBRT. This strategy may provide better postradiation neurocognitive function and may be a good choice for small metastatic lesions (< 3 cm). Adjuvant WBRT following radiosurgery or surgical resection of 1-3 cerebral metastases reduces intracranial relapses and neurological death. However, it does not prolong functional independence.

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 clinical 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.

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 highdose 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 more than 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.

Management of recurrent metastasis

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.[12] 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.

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, singleorgan 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.

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