By Michael A. Badruddoja, MD

Metastatic brain tumors are the most common type of brain tumor. They arise from neoplasms that originate from sites other than the brain. In accordance with the most common types of systemic neoplasms in adults, the most common type of metastatic brain tumors are those that arise from lung cancers and breast carcinomas. Other types of systemic neoplasms that can spread to the brain include renal cell carcinoma, malignant melanoma and gastrointestinal. Eight-five percent of metastatic brain tumors arise from one of these five solid tumor types ( Figure 1 ).

There are nearly two million people diagnosed with cancer per year, and 100,000 of these people will have their tumors spread to the brain or spine. Approximately 40% of patients with lung cancer (adenocarcinoma, small-cell carcinoma, squamous cell carcinoma, large cell carcinoma) will have their disease spread from lung to brain. Similarly, nearly 20% of patients with breast carcinoma will have their neoplasms spread to the brain. In contrast, almost 50% of patients with melanoma will have disease spread to the central nervous system.

Although most patients will already have the diagnosis of a systemic neoplasm when a brain metastasis is diagnosed, nearly 15% of patients will have an initial neurologic complaint prompting brain imaging with further medical assessment to define a systemic neoplasm. The common symptoms (in order of frequency) that patients can experience include: headache, focal weakness, cognitive changes, gait abnormalities, sensory abnormalities (including numbness, tingling), language abnormalities and vision changes.

Headaches occurring in the setting of a space-occupying lesion (i.e., a brain metastases) are related either to compression of or stretching of vessels or meninges (the linings of the brain) or to compression or occlusion of the ventricles or foramen that connect the ventricles, thereby impeding the flow of cerebral spinal fluid though the brain and spine. Nearly 50% of patients will present headaches related to their brain metastasis.

Weakness related to a metastatic brain lesion is the result of compression of the motor tracts or the motor cortex, causing dysfunction of the cells in the motor cortex or interruption of the connections of the motor neurons to the neurons within the spinal cord.

Approximately 20% of patients with brain metastases will have a seizure as their initial symptom. Seizures are the result of abnormal spontaneous electrical activity from neurons on the cortical surface of the brain. Seizures can be categorized as either generalized, complex partial or simple partial. A simple partial seizure usually is manifested by transient twitching or sensory abnormality (numbness or tingling, or smell sensation). A complex partial seizure can be manifested similarly as a transient motor or sensory symptom, but in addition there is an altered level of conscious (i.e., confusion). Simple and complex partial seizures represent focal areas of spontaneous electrical activity that remain in a limited area of brain. A generalized seizure may also manifest itself as a simple partial seizure and complex partial seizure but with further spread of abnormal activity that encompasses the entire brain. Generalized seizures are manifested as profound alterations in consciousness accompanied by transient stiffening or stiffening and flexion of the limb(s) or body.

Nearly a third of patients with brain metastases will present with cognitive changes and an additional 20% will experience language abnormalities. Both of the symptoms represent lesions located within specific areas of the brain. Considering that the frontal lobe is important to cognition and higher executive functioning, patients with brain lesions including brain metastases may present with attentional, emotional or memory disturbances. Quite often a family member will include language abnormalities as an example of memory complaints, "John forgets the name of our dog." In actuality the patient may have a language abnormality. Any lesion including a brain metastasis located within the inferior frontal or posterior temporal dominant hemisphere can cause a language abnormality. Only 10% of patients with a brain metastasis will present with a language abnormality.

Treatment for brain metastasis has largely relied on surgical resection, radiation therapy and more recently chemotherapy or therapy directed at relevant intracellular targets. There are also novel approaches to deliver chemotherapy directly into the tumor cavity at the time of surgery or agents that can be administered to increase the delivery of chemotherapy by pharmacologically manipulating the blood-brain tumor barrier to increase the concentration of chemotherapy in the metastatic brain tumor.

Neurosurgical intervention has played an important role in the management of patients with brain metastases for centuries. Although it was initially held that neurosurgical intervention may not have altered the outcomes for patients with metastatic brain lesions, with the advent of neurosurgical navigation systems and advances in techniques, some patients do have an improvement in survival associated with neurosurgical extirpation of these neoplasms. Most patients will already have the diagnosis of a systemic tumor once the tumor has spread to the brain. Once the tumor has spread to the brain some patients will not undergo surgical intervention if there are multiple tumors. There are important patient and tumor characteristics that assist the neurosurgeon in making the determination of whether a patient is an appropriate neurosurgical candidate. Patients will usually undergo a surgical resection of a single lesion if the lesion is located in an accessible part of the brain (i.e., the tumor is not located in the deep subcortical grey matter or brain stem); if the patient has a KPS of > 60% ( Table 1 ); if the patient has limited or controlled systemic disease; and if the lesion is greater than 3 cm. There are several benefits to surgical removal of a metastatic lesion: 1) there is immediate relief of brain compression; 2) the tissue diagnosis is confirmed; and 3) surgery is therapeutic for lesions that are too large to be treated with radiosurgery (i.e. >3 cm). There are three prospective studies that have evaluated the survival benefit of surgical removal of a single metastatic lesion followed by whole brain radiation therapy ( Table 2 ).

Since the first case of whole-brain radiation was reported in 1954 by Chao et al radiation therapy has been an important method of treating single and multiple metastatic brain lesions. Radiation can either be delivered to the entire brain (whole brain radiation therapy -WBRT), or external beam radiation can be delivered by multiple coplanar beams delivered in a single fraction to a small target volume - radiosurgery (RS). Various schedules of WBRT have been evaluated by the Radiation Therapy Oncology Group (RTOG). Based on their findings, a dose of 30 Gy in 10 fractions results in similar control rates as longer, higher-dose schedules.

These two methods of delivering radiation are typically used for slightly different patient populations, although there are studies evaluating the combination of these two techniques in various clinical settings. Typically, WBRT is reserved for patients that have multi-focal metastatic disease. A major benefit to WBRT is that this form of radiation is able to target microscopic areas of tumor cells. In contrast, WBRT also has the disadvantage of delivering radiation to normal brain tissue. The early side effects associated with WBRT include alopecia (hair-loss), nausea, vomiting, headache and otitis media. The late side effects that can be seen include symptomatic necrosis, leukoencephalopathy and radiation-induced dementia. Radiosurgery is usually reserved for patients that have a limited number of metastatic lesions that are also limited in size (< 3 cm). The side effects associated with the use of RS is symptomatic vasogenic edema and necrosis, which could both require administration of steroids. Histology is also an important factor in evaluating outcomes in patients with metastatic brain tumors. Typically, lung and breast malignancies tend to be more radiosensitive than melanoma and renal cell carcinoma.

There are three retrospective studies that compare the control rates of patients that either received RS or conventional surgery (Auchter et al 1996; Bindal et al 1996; Cho et al 1998). Auchter et al retrospectively evaluated 122 patients with a single metastatic lesion that received RS+WBRT compared to two historical controls that received surgery+WBRT. The median survival of patients who received RS+WBRT was 56 weeks compared to a median survival of two historical controls of 40 weeks and 43 weeks that received surgery+WBRT. Local recurrence and death due to CNS progression were similar. This group concluded that RS+WBRT may be more appropriate in this patient population as compared to surgery+WBRT. Two other studies produced differing conclusions. Bindal et al 1996 matched 31 patient that received RS with 62 patients that underwent conventional surgery. The median survival of patients who received RS was 30 weeks, while those patients who received conventional surgery had twice the median survival (65.6 weeks). Cho et al 1999 reviewed their experience with 225 patients who received either WBRT, surgery+WBRT or RS+WBRT. The survival of patients who received either surgery or RS + WBRT was the same, although both groups had longer median survival than patients who received WBRT alone. This group favored RS over surgery based on its cost-effectiveness.

More recently, Yu et al (2005) are currently using radiosurgery in a setting that is novel. They are conducting a phase I study to evaluate the toxicity of an intracranial dendritic cell vaccine for patients with primary brain tumors. Patients with CNS neoplasms < 3cm receive radiosurgery to induce tumor injury and tumor antigen exposure prior to resection. The vaccine is then administered directly into the resection cavity. A phase II study for patients with brain tumors to evaluate the efficacy of intracranially administered vaccine using radiosurgery to induce tumor antigen exposure will soon be open.

There are significant potential advantages to the use of chemotherapy for the treatment of brain tumors, including metastatic brain tumors. The use of chemotherapy is a global therapy unlike surgery, which achieves immediate local control but does not eradicate microscopic cells that result in local failure. The use of chemotherapy for the treatment of CNS metastatic disease is controversial. Regimens that have activity against the primary tumor prior to it spreading to the brain subsequently have limited activity once the tumor has spread to the CNS. There are two main factors that are relevant to the lack of efficacy of chemotherapy in the treatment of primary and metastatic lesion(s) to the CNS: 1) the blood-brain tumor barrier (BTB) significantly limits the ability of chemotherapy from entering tumor in the brain and 2) acquired resistance to chemotherapy.

The BTB poses a significant obstacle for the treatment of metastatic brain tumors. The BTB represents a specialized structure that lines the CNS vasculature. The CNS vasculature is lined by specialized endothelial cells attached by tight junctions, encased by a basement membrane and lined by astrocytic foot processes. This structure tightly regulates the entrance of molecules into the CNS based on solubility in lipids, size (molecular weight) and charge. Most chemotherapeutic agents are too large to readily pass through the BTB. Although metastatic brain lesion(s) "enhance" on post-contrast images indicating alteration in the permeability of the cerebral vasculature and BTB, alterations in BTB permeability are very limited. Enhancing areas represent areas of necrosis not necessarily in areas where tumor cells are actively multiplying. There are several methods that have been evaluated to improve chemotherapy delivery for the treatment of brain tumors. Trials evaluating the toxicity and efficacy of chemotherapy impregnated wafer and pharmacologic disruption of the BTB (Black et al 2005) are currently ongoing or will soon begin accrual. Pharmacologic disruption of the BTB in particular has several important advantages over other methods of blood-brain barrier disruption. The identification and characterization of an important pathway that results in transient blood-brain tumor permeability has been identified (Ningaraj et al 2002). Activation of the bradykinin-2 receptor system by bradykinin or a bradykinin analog, labradimil transiently alters the permeability of the BTB. Bartus et al (2001) reported a phase I/II study carried out in Western Europe that attempted to determine the maximum dose and efficacy of labradimil in combination with carboplatin in patients with CNS metastatic non-small cell and small cell lung carcinoma. There was a dose response relationship for patients with non-small cell lung carcinoma. Fifteen percent of the patients who received moderate doses of labradimil with their carboplatin had greater than 50% shrinkage of their CNS tumors. In contrast, nearly half of the patients who received high doses of labradimil with carboplatin had a > 50% shrinkage of the brain tumor. Pharmacologic disruption of the BTB is a noninvasive method of improving chemotherapy delivery to brain tumor, and chemotherapy is delivered only to the tumor, thereby limiting the exposure of normal brain to chemotherapy.

Metastatic brain cancer is a serious and relatively common event in patients diagnosed with solid tumors. The presentation of a patient with a metastatic brain tumor may be subtle in a patient already diagnosed with a systemic malignancy, or the patient may present with a neurologic complaint prompting brain imaging and only further medical intervention uncovers a systemic neoplasm. For selected patients, surgery is an important option. Radiation therapy either as focal therapy for local disease or whole-brain radiation for patients with multi-focal disease represents an additional important therapeutic option. Chemotherapy for the treatment of metastatic brain tumors may also be an important option for patients, and improving the delivery of active chemotherapies across the BTB continues to be evaluated.

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