Innovation in the Management of Brain Metastases
Innovation in the Management of Brain Metastases
ABSTRACT: Metastatic lesions to the brain occur commonly in oncology patients and portend a very poor outcome, as they often occur in the setting of progressive systemic metastatic disease and can result in neurologic deterioration that may preclude therapy. Therapy of patients with brain metastases requires a combination of measures to achieve local control at the site of metastasis (e.g., with surgical resection or radiosurgery) and to reduce the subsequent risk of recurrences elsewhere in the brain (e.g., with whole-brain radiation). Successful therapy of extracranial systemic metastases is required for optimal outcomes. Clinical trials are currently underway to define the optimal role of whole-brain radiation and radiosurgery in different subsets of patients. Novel therapies to enhance radiation responsiveness are also under investigation. In the current review, we discuss recent developments in the management of patients with brain metastases.
The development of brain metastases is an unfortunate and common complication in oncology patients. Data from several studies suggest that up to 40% of patients with certain metastatic cancers (eg, lung cancer) may develop brain metastases over their lifetime. Even this relatively high figure is probably an underestimate, as these lesions may remain asymptomatic, to be detected only on autopsy; may be misdiagnosed since they present with atypical findings (eg, with hemorrhage); and often occur in terminally ill patients, in whom a thorough diagnostic evaluation may not be desired or tolerated. Even when brain metastases are suspected, the detection rate may depend on the availability of appropriate imaging technology.
Patients with brain metastases have a very poor prognosis—the median survival of untreated patients is approximately 1 month. Death can be attributed to neurologic complications in around half of all patients, and to progression of systemic metastases in the rest. Since brain metastases result in a significant degree of morbidity and mortality, therapy of this complication assumes importance in the overall care of the patient. The status of systemic metastases—their presence and rate of progression—is an important prognostic factor. Therefore, therapy directed toward extracranial metastases is also an essential component of treatment.
The exact population incidence of brain metastases is unknown, and the studies done to assess this issue are fraught with methodologic issues that make identification of time trends difficult. The annual population incidence of central nervous system (CNS) metastases in Iceland was found to be 2.8 per 100,000 in a survey conducted in the 1950s to 1960s. A more recent population-based survey (from 1972) suggested an annual incidence of 11.1 per 100,000. Other studies from autopsy series suggest that up to 25% of all oncology patients will have developed brain metastases at the time of their death.[2,3] One-third of these were clinically silent antemortem. Several investigators have speculated that brain metastases have become an increasingly common problem in oncology patients due to improvements in diagnostic techniques as well as improvements in survival as a result of better therapies. Due to the high prevalence of this problem, it is critical for the practicing oncologist to become aware of the issues involved in managing this complication.
The most common primary solid tumors that are responsible for brain metastases are lung cancer (50%-60%), breast cancer (10%-15%), melanoma and renal cell cancer (5%-10% each), with a variety of other malignancies (eg, gastrointestinal cancers) producing the rest.[4-6] Patients with certain hematologic malignancies (eg, subtypes of non-Hodgkin's lymphoma) have an extraordinarily high (> 25%) lifetime risk of brain involvement; further discussion of the management of these hematologic malignancies is outside the scope of this review. Certain commonly occurring cancers (eg, colon cancer) uncommonly metastasize to the brain, whereas some less prevalent cancers (eg, melanoma and renal cell cancer) seem to present with brain metastases relatively commonly. These observations would support the hypothesis that metastases to the brain are caused by specific receptor-ligand interactions between tumor cells and the cerebral vasculature, rather than the effect of tumor emboli randomly lodging in narrow cerebral arterioles.
Patients with brain metastases typically present with signs of focal neurologic dysfunction. These symptoms include seizures and focal motor or sensory deficits. The diagnosis requires use of imaging studies (magnetic resonance imaging [MRI] is the most sensitive method) and possibly a pathologic confirmation (surgical biopsy or resection), and infrequently involves the need to sample the cerebrospinal fluid (Figure 1).
The extent of the diagnostic work-up required depends on the clinical situation. For example, invasive procedures may not be required in a patient with known cancer with widespread metastases who presents with neurologic deficits and has characteristic imaging findings. Several clinical prognostic factors have been identified in this patient group that result in poor outcomes; the best validated of these are advanced age, poor performance status, lack of response to steroid therapy, and concurrent progression of extracranial metastases.[9,10] Therapeutic decisions require an understanding of an individual patient's baseline prognosis, especially so that futile therapy can be avoided for patients with a very poor prognosis.
General Therapeutic Considerations
The treatment of patients with brain metastases is almost always administered with palliative intent, given the small likelihood of achieving long-term survival. The realistic goals of therapy for most patients with brain metastases are to improve symptoms and quality of life. Some of the interventions discussed below have been demonstrated to moderately prolong survival in selected patient subsets.
Appropriate management of brain metastases requires a multidisciplinary approach, with input from several medical and ancillary specialties such as radiology, radiation and medical oncology, neurosurgery, neurology, psychiatry, and physical therapy. Optimal supportive care represents the minimum therapy required for all patients. Therapy directed toward the brain metastases (radiation and surgery) should be offered only to selected patients—the best candidates for such therapy are younger patients with a good baseline prognostic status (good performance status) and limited and/or well-controlled extracranial metastatic disease (Figure 2).
Palliative therapy directed at the brain metastases can result in high rates of response and symptomatic improvement (usually > 90%), with a significant reduction in the risk of disease recurrence in the brain, prolongation of the duration that patients can remain functional neurologically, and in a small fraction of patients (usually 1%-2%), long-term disease control.[12-15] Successful treatment of systemic metastases is essential for optimal long-term cancer-related outcomes and should be offered in conjunction with therapy directed at the brain metastases. The availability of systemic therapy options and the likelihood of response to such therapy depends on the nature of the primary tumor (eg, patients with metastatic breast cancer are more likely to have effective treatment options for systemic metastases than are those with metastatic melanoma).
Optimal supportive care of a patient with brain metastases involves the use of steroids for cerebral edema (which occurs in almost all patients) and anticonvulsants for those who develop seizures (which occur in 20% to 30% of patients). Corticosteroids play a central role in the treatment of brain metastases. The benefits of steroid therapy occur rapidly, with a decrease in cerebral edema documented to occur within a few hours of therapy. Approximatley two-thirds of patients will notice a significant improvement in their performance status with steroid therapy.
The most common steroid used is dexamethasone—the choice of this particular agent is empiric, and other corticosteroids can be used effectively in this situation as well. The usual practice is to begin therapy with a total daily dose of 12 to 24 mg of dexamethasone (eg, 4 to 6 mg orally, every 6 hours), and to taper the dose as tolerated. Steroids have multiple adverse effects, of which weight gain, psychosis, infection risk, long-term steroid dependence, and gastrointestinal bleeding are most troubling in this patient population. Once definitive therapy (eg, radiation) for the metastases is delivered, the steroid dose should be reduced as rapidly as tolerated in order to avoid these toxicities.
Patients who present with or develop seizures require therapy with anticonvulsant drugs to control symptoms. No comparative studies have tested which of the available agents (eg, phenytoin, phenobarbital) is the most effective in this patient population. Newer anticonvulsants (eg, levetiracetam [Keppra]) are being used more commonly, as they have fewer adverse effects and do not interfere with cytochrome p450-induced drug metabolism (which may be a consideration in some patients). However, these newer agents are significantly more expensive than the standard drugs. Although medical therapy with these agents effectively reduces the frequency of subsequent seizures, prophylaxis with anticonvulsant drugs (in those who have not suffered from seizures) does not seem to be effective and has the disadvantage of exposing patients to their adverse effects.