Considerations in the Diagnosis and Management of Brain Metastases

A common complication of systemic cancer is the development of brain metastases—the predominant type of intracranial neoplasm found in adults. Brain metastases are a significant cause of morbidity, typically due to some combination of peritumoral edema, the effect of the tumor mass itself, or the presence of an obstructive hydrocephalus. Any of these conditions can cause an increase in intracranial pressure. Brain lesions may also directly compress adjacent neurons, resulting in focal irritation or neuron destruction.[1] Not surprisingly, they are an important contributing factor to patient mortality.[1-4] While statistical projections have put the number of patient deaths due to brain and other central nervous system neoplasms at approximately 2.4% (13,300 of 564,800) of all cancer deaths,[5] the actual number is likely to be higher because the death of patients with intracranial metastases is often attributed to underlying systemic disease.[1,2,6-8]

The incidence of brain metastases appears to be increasing,[1,6] possibly as a result of earlier and more accurate methods of detection. Other factors that may contribute to this increase are the success of aggressive treatment modalities that prolong survival, the increasing incidence of primary cancers with a propensity to metastasize to the brain (eg, lung and breast cancer), and the overall aging of the population.[1,8-10]

In 1998, it was projected that more than 1.2 million patients in the United States would be newly diagnosed with cancer.[5] Based on projections regarding the frequency of brain metastases stemming from various types of cancer, and using the high end of the projected ranges—48%, 32%, and 21% for patients with skin, lung, and breast cancer, respectively—we calculated that the yearly incidence of new brain metastases would reach more than 107,000 cases in 1998.[1]

The prognosis for untreated brain metastases is poor, with median survival projected to be 2 months or less.[3,11] While techniques for confirming diagnoses have improved substantially in the past decade or so, a review of the literature suggests that up to one-third of patients are asymptomatic, and consequently many of these metastases go undetected. Autopsy studies show that 24% to 31% of patients with cancer develop intracranial metastases,[9,12-14] and the results of several studies suggest that substantially higher percentages of patients have been diagnosed with intracranial metastases postmortem than during their lifetime. Hirsch et al reported that 21% of patients were clinically diagnosed based on signs and symptoms vs 50% at autopsy,[15] and Amer et al reported that 46% were diagnosed clinically vs 75% at autopsy.[16] Although clinical disease progression is expected to continue up to the time of death, making the development of more tumors likely, these findings still serve to underscore the challenge of diagnosing asymptomatic patients.

Once brain metastases have been successfully diagnosed, there are numerous treatment options to be considered, depending on the patient’s profile and underlying disease. Recent advances in technology and therapeutic techniques have expanded the possibilities for the management of brain metastases through the use of chemotherapy, radiation, surgery, and stereotactic radiosurgery, either alone or in combination.

This review addresses the array of considerations the clinician must weigh in the diagnosis and treatment of patients presenting with brain metastases. Emphasis is placed on the need to identify asymptomatic patients at greatest risk for developing brain metastases. In addition, an overview is provided of the advantages and disadvantages of the primary treatment options, with a focus on some of the current, prospective therapeutic approaches and the indications for their use.

Clinical Presentation

Presenting Signs and Symptoms

For cancer patients, the signs and symptoms of neurologic dysfunction are usually the initial indication that underlying disease has metastasized to the brain. Metastases are believed to be primarily disseminated hematogenously, particularly through the arteries.[1,17,18] Typically, tumoral microemboli are distributed in proportion to the relative blood flow to each area of the brain.[18-20] Consequently, 80% to 85% of metastatic tumors are located in the cerebral hemispheres, 10% to 15% in the cerebellum, and 3% to 5% in the brain stem.[14,19,21,22].

The clinical manifestations of intracranial lesions are generally dictated by the location of the metastases. Increased intracranial pressure and mental changes are symptomatic of a frontal metastatic lesion, visual field defects and cortical blindness are indicative of an occipital metastasis, motor weakness suggests a frontoparietal lesion, and a cerebellar metastasis may manifest itself as ataxia or symptoms related to hydrocephalus.[23]

Most neurologic symptoms can be ascribed to increased intracranial pressure (headache, nausea, vomiting, confusion, and lethargy), focal irritation, or destruction of adjacent brain tissue (aphasia, ataxia, visual field defects, hemiparesis, and focal seizures).[1,22,24] A review of six representative studies of patients with brain metastases secondary to a cross section of cancer types showed that the most common presenting symptoms were headache, focal weakness, mental and behavioral disturbances, seizure, ataxia, aphasia, visual field defect, and sensory change.[1]

Headache is the predominant presenting symptom, reported by approximately 50% of all patients with a single intracranial metastasis (40% reporting early morning headaches) and by a larger percentage of patients with multiple metastases.[17] Hemorrhage is also a serious complication, especially with metastases secondary to malignant melanoma, choriocarcinoma, and gestational and testicular cancers.[19] Patients have been reported to present with acute symptoms of stroke secondary to bleeding into a metastatic lesion, embolization of tumor cells, or tumor invasion or compression of an adjacent artery.[9,20]

Leptomeningeal Metastases—Leptomeningeal metastases are a somewhat unique subset of brain metastases. Between 30% and 50% of leptomeningeal metastases are secondary to leukemia, and 8% to 15% are secondary to solid tumors, primarily melanoma, lung cancer, and breast cancer. As with other brain metastases, leptomeningeal metastases typically develop following hematogenous dissemination involving the superficial arachnoid veins, but they may also result from the extension of intracranial metastases into the subarachnoid space or the ventricles. The primary symptoms of leptomeningeal metastases include headache, back pain, nausea/vomiting, paresthesias, and diplopia.[19]

Cancers Associated With Brain Metastases—The three types of cancers with the greatest predisposition for brain metastases are lung cancer (particularly adenocarcinoma and small-cell cancers), breast cancer, and melanoma.[1] Lung cancer is the leading cause of cancer death among men and women in the United States and is the primary site of cancer for 24% to 60% of all patients with metastases.[3,11,14,25-30] Breast cancer, the second most common cause of cancer death among US women and the leading cause of death for US women aged 15 to 54,[5] may be the site of primary disease for 10% to 30% of all brain metastases among women.[3,11,12,14,27,28]

Melanoma is particularly prone to the formation of brain metastases and may account for between 5% and 21% of all patients with brain metastases.[3,11,25,26,31] Table 1 summarizes the most frequently reported symptoms of brain metastases from representative studies in patients with melanoma, lung cancer, and breast cancer.[13,15,16,32-35] The most commonly reported adverse events for this subset of patients are headache, cognitive dysfunction, seizure, motor symptoms, cranial nerve paralysis, cerebellar symptoms, and aphasia.

Treatment Considerations

Corticosteroids, notably dexamethasone(Drug information on dexamethasone) and methylprednisolone(Drug information on methylprednisolone), and anticonvulsants have become standard treatment for the control of peritumoral edema and seizures, respectively.[1,20,21,36] In particular, corticosteroids provide effective palliative therapy for acute symptoms of brain metastases, but they should only be used for symptomatic lesions. Patients should receive the lowest possible effective doses of corticosteroids and anticonvulsants to minimize toxicity, particularly corticosteroids, due to the severity and frequency of associated adverse events such as Cushing’s disease, hypertension, hyperglycemia, and peripheral myopathies.[1,20] Notably, response to acute corticosteroid therapy should be monitored carefully, because it is a useful indicator of a patient’s potential for neurologic recovery following surgical treatment of brain metastases.[37]

Good clinical practice dictates that any patient known to have cancer and presenting with one or more neurologic symptoms should be further evaluated for the presence of brain metastases. However, only about two-thirds of patients with brain metastases are thought to be symptomatic. The majority of patients with no history of cancer and a single brain lesion are symptomatic[21]; thus, most asymptomatic patients are likely to have underlying disease. Many of the newer antineoplastic agents approved for the treatment of melanoma, lung cancer, and breast neoplasms have much better safety profiles and show less neurotoxicity than some of their older counterparts, yet they are still associated with adverse events that could mask common signs and symptoms of brain metastases (Table 2).

For example, paclitaxel(Drug information on paclitaxel) (Taxol) is associated with mild-to-moderate dysfunction of the peripheral nervous system in most patients treated on a weekly basis (severe reactions are reported for patients taking doses over 100 mg/m²). Symptoms of neuropathy usually begin 1 to 3 days after treatment and may last for 3 to 6 months.[38] Although routine diagnostic evaluation of all asymptomatic patients may not be feasible, magnetic resonance imaging (MRI) is being ordered more liberally for patients at risk of developing brain metastases. This at-risk group should include "asymptomatic" patients with primary melanoma, breast cancer, or lung cancer who are currently receiving or have recently been treated with chemotherapeutic agents that may mask the clinical signs and symptoms of brain metastases.

Constrast-Enhanced MRI—Once intracranial metastases are suspected, contrast-enhanced MRI is the best tool for determining whether a brain or leptomeningeal metastasis is present.[24] Compared with computed tomography (CT) and other radiographic techniques, contrast-enhanced MRI is associated with superior sensitivity and specificity in determining the presence of brain metastases and their location and number.[19,21,24] When used with T2-weighted spin-echo sequences, MRI is better equipped to detect even slight edema and to image regions of the brain such as the brain stem, temporal lobe, and cerebellum (which CT scans are unable to depict clearly).[24]

At present, single-dose gadolinium (gadolinium diethylenetriamine pentaacetic acid) is the most commonly used contrast agent,[1] although new agents (eg, gadolinium texaphyrin) and new techniques (eg, pulse sequence software, coil design, and postprocessing capabilities) are under investigation.[39] Despite the tremendous advantages of contrast-enhanced MRI, biopsy remains the most definitive test for differentiating brain metastases from cerebral abscess or a primary brain tumor.[1] It should also be noted that whereas contrast-enhanced MRI has great sensitivity, it does not have comparably high specificity in diagnosing leptomeningeal metastases. Consequently, definitive diagnosis of leptomeningeal metastases requires careful examination of the cerebrospinal fluid, collected ideally from one or more lumbar punctures.[19]