Overview of brain metastases

INTRODUCTION — Brain metastases are an increasingly important cause of morbidity and mortality in cancer patients, occurring in approximately 10 to 30 percent of adults and 6 to 10 percent of children with cancer. It is estimated that each year in the United States there are between 98,000 and 170,000 new cases of brain metastases. This number may be increasing due to the ability of magnetic resonance imaging (MRI) to detect small metastases and prolonged survival due to improvement in systemic therapy.

Brain metastases are the most common form of intracranial tumor accounting for significantly more than one-half of brain tumors in the adult. Because of advances in the diagnosis and management of this condition, most patients receive effective palliation and the majority do not die from the metastases.

ETIOLOGY — In adults, the major primary tumors responsible for brain metastases are predominantly carcinomas. In children, the most common sources of brain metastases are sarcomas, neuroblastoma, and germ cell tumors.The majority of patients have multiple metastases

The most common causes of brain metastases in adults with their approximate frequency are:

  bullet Lung — 50 percent
  bullet Breast — 15 to 20 percent
  bullet Unknown primary — 10 percent
  bullet Melanoma — 10 percent
  bullet Colon and rectum — 5 percent

However, for all of these tumors (with the exception of lung cancer, and possible breast cancer, see below), brain metastases are relatively uncommon. This was illustrated in two separate reports. One, from the Metropolitan Detroit Cancer Surveillance System, studied the incidence of brain metastases in patients diagnosed with single primary lung, melanoma, breast, renal cell and colorectal cancer between 1973 and 2001, while the second was a Dutch series of 2724 patients with colorectal, breast, kidney, lung cancer, or melanoma diagnosed between 1986 and 1995, In both studies, the cumulative incidence of brain metastases was remarkably similar:

  bullet Lung — 16 and 20 percent
  bullet Melanoma — 7 percent in both series
  bullet Renal cell cancer — 7 and 10 percent
  bullet Breast cancer — 5 percent in both series
  bullet Colorectal cancer — 1 and 2 percent

Certain other tumors almost never metastasize to the brain. These include carcinomas of the prostate, esophagus, and oropharynx and non-melanoma skin cancers.

There is some evidence that the incidence of brain metastases among women with breast cancer is increasing, and is particularly high in those with lung metastases and hormone receptor-negative tumors. In one series, 15 of 50 patients (30 percent) presenting with lung metastases as the first site of relapse subsequently developed brain metastases during follow-up. One possible explanation is the selective destruction of non-brain metastases by newer chemotherapy regimens, allowing the later development of brain metastases.

The incidence of brain metastases in patients with metastatic colorectal cancer and stage III non-small cell lung cancer also appears to be increasing, possibly as a result of more effective treatment of systemic disease

Intracranial distribution — The most common mechanism of metastasis to the brain is by hematogenous spread. These metastases are usually located directly beneath the gray-white junction where blood vessels decrease in diameter and act as a trap for clumps of tumor cells. Brain metastases also tend to be more common at the terminal "watershed areas" of arterial circulation. The distribution of metastases roughly follows the relative weight of and blood flow to each area.

  bullet Cerebral hemispheres — approximately 80 percent
  bullet Cerebellum — 15 percent
  bullet Brain stem — 5 percent

For unclear reasons, possibly due to cell surface properties of metastatic cells and endothelial characteristics within the circulation of the CNS, there are differences between various primary tumors in terms of sites of predilection for metastasis within the brain. Pelvic (prostate and uterus) and gastrointestinal tumors have a predilection to metastasize to the posterior fossa, while metastases of small cell carcinoma of the lung are equally distributed in all regions of the brain.

CLINICAL MANIFESTATIONS — It is estimated that more than two-thirds of patients with cerebral metastases experience neurologic symptoms during the course of their illness. The clinical features are extremely variable, and the presence of brain metastases should be suspected in any cancer patient who develops new neurologic symptoms. In one study of 815 patients with systemic cancer and neurologic symptoms (back pain, altered mental status, or headache), 45 percent had metastatic involvement of the nervous system and 16 percent had brain metastases.

The majority of patients with metastatic disease present with progressive neurologic dysfunction resulting from a gradually expanding tumor mass and the associated edema; rarely, symptoms are due to the development of obstructive hydrocephalus.

Approximately 10 to 20 percent of patients present acutely with seizures, while another 5 to 10 percent present acutely due to strokes caused by embolization of tumor cells, invasion or compression of an artery by tumor, or hemorrhage into a metastasis. Melanoma, choriocarcinoma, and thyroid and renal carcinoma have a particular propensity to bleed.

The clinical presentation of brain metastases is similar to that of other brain tumors and includes headaches, focal neurologic dysfunction, cognitive dysfunction, and seizures.

  bullet Headaches occur in approximately 40 to 50 percent of patients with brain metastases. The frequency is increased in patients with multiple metastases or posterior fossa metastases. The headaches are usually dull, nonthrobbing, and often indistinguishable from tension headaches. They are usually on the same side as the tumor, although they can be diffuse. Characteristics of increased intracranial pressure, such as early morning headaches or headaches exacerbated by coughing, bending, and straining, are present in less than one-half of patients with brain metastases and headaches.

The headaches may be associated with nausea, vomiting, and transient visual disturbances. Papilledema is present in less than 10 percent of patients at the time of presentation.

  bullet Focal neurologic dysfunction is the presenting symptom of 20 to 40 percent of patients. Hemiparesis is the most common complaint but the precise symptom varies with the location of the metastases.

  bullet Cognitive dysfunction, including memory problems and mood or personality changes, is the presenting problem in 30 to 35 percent of patients. In patients with known malignancy who develop altered mental status, metabolic encephalopathy is a much more common cause than metastatic disease.

  bullet New onset of seizures is the presenting symptom in 10 to 20 percent of patients. Seizures in patients with brain metastases generally indicate supratentorial disease.

DIAGNOSIS — Brain metastases must be distinguished from primary brain tumors, abscesses, progressive multifocal leukoencephalopathy, demyelination, cerebral infarction or bleeding, and effects of treatment such as radiation necrosis. Imaging studies provide useful information but, in many cases, brain biopsy is necessary for definitive diagnosis. Other important diagnostic issues include determination of single versus multiple metastases and evaluation of the patient without a known primary tumor.

Imaging studies — Although computerized tomographic (CT) scans detect the majority of brain metastases the best diagnostic test is contrast-enhanced MRI . This test is more sensitive than enhanced CT scanning or nonenhanced MRI in detecting lesions in patients suspected of having cerebral metastases, and in differentiating metastases from other central nervous system (CNS) lesions. In one report of 23 patients, for example, contrast-enhanced MR demonstrated more than 67 definite or typical parenchymal metastases compared to more than 40 with T2-weighted MR, and only 37 with double-dose contrast-enhanced CT.

Radiographic features that help differentiate brain metastases from other CNS lesions include the presence of multiple lesions (which helps distinguish metastases from gliomas or other primary tumors), localization of the lesion at the grey-white junction, more circumscribed margins, and relatively large amounts of vasogenic edema compared to the size of the lesion.

Experimental techniques such as magnetization transfer (MT) and triple dose gadolinium imaging have further improved lesion detection with MRI. In one study of 52 patients, for example, MT imaging showed more metastases than gradient-echo T1-weighted images in 23 percent of patients. Newer modalities such as echo planar imaging, spectroscopy, PET, and SPECT, also may prove to be useful. They are mainly used to differentiate tumor from radiation necrosis and not for the initial diagnosis of brain metastases.

Brain biopsy — Biopsy should be performed whenever the diagnosis of brain metastases is in doubt, since this is the only reliable method for establishing the diagnosis. In one study, the initial diagnosis of single brain metastasis was changed in six of 54 patients (11 percent) after the lesion was biopsied. These six patients had primary brain tumors or infectious or inflammatory processes. The false-positive rate for the diagnosis of multiple metastases is undoubtedly significantly less than the 11 percent for single metastases.

Breast cancer patients with a single dural-based lesion pose a particular diagnostic dilemma, since the incidence of meningiomas is increased in patients with breast cancer. Imaging studies are often inconclusive, and biopsy or surgical resection of the lesion is required to establish the diagnosis.

Single versus multiple metastases — It is important to differentiate patients with single or solitary metastases from those with multiple brain metastases since the subsequent treatment will be different.

The term single brain metastasis refers to a single cerebral lesion, and no implication is made regarding the extent of extracranial disease. In contrast, the term solitary brain metastasis describes the occurrence of a single brain metastasis that is the only known site of metastatic disease.

At the time of neurologic diagnosis, as many as 50 percent of patients have a single brain metastasis on CT scan. However, studies using more sensitive MRI suggest that the true frequency of single metastases is lower, accounting for only one-third to one-fourth of patients with cerebral metastases. Metastases from breast, colon, and renal cell carcinoma are often single, while lung cancer and malignant melanoma have a greater tendency to produce multiple metastases.

Brain metastases without a known primary tumor — In the majority of patients (80 percent), brain metastases develop after the diagnosis of systemic cancer (metachronous presentation). However, in some patients, brain metastases may be diagnosed before the primary tumor is found (precocious presentation) or at the same time (synchronous presentation).

For patients who present with brain metastases without a known primary tumor, the lung should be the focus of the evaluation. Over 60 percent of such patients have a lung primary or pulmonary metastases from a primary tumor located elsewhere. Other frequent sites include malignant melanoma, and colon cancer, while the primary remains unknown in approximately 25 to 30 percent of cases.

The history and physical examination demonstrate the site of origin in one-third to one-quarter of patients. In the others, a chest radiograph should be the first imaging test obtained. If the chest radiograph is nondiagnostic, a chest CT scan should be performed since this significantly increases the likelihood of detecting a lung tumor. One study, for example, evaluated 31 patients who presented with brain metastasis without a known primary and subsequently were determined to have primary lung cancer by CT scan; chest radiographs were positive in only 19 (59 percent). These patients should also have a CT scan of the abdomen and pelvis and a bone scan to determine the extent of metastatic disease.

SYMPTOMATIC THERAPY — The median survival of patients with untreated brain metastases is approximately one month. The addition of steroids increases survival to two months, while whole brain radiation therapy further improves survival to three to six months. Patients with single brain metastases and limited extracranial disease who are treated with surgery and whole brain radiation therapy have a longer median survival of approximately 10 to 16 months.

The management of patients with brain metastases can be divided into symptomatic and definitive therapy.

  bullet Symptomatic therapy includes corticosteroids for peritumoral edema, anticonvulsants for control of seizures, and anticoagulants or inferior vena cava (IVC) filters for the management of venous thromboembolic disease.

  bullet Definitive therapy includes treatments such as surgery, radiotherapy and chemotherapy that are directed at eradicating the tumor itself. These approaches are discussed elsewhere.

Increased intracranial pressure — Dexamethasone has remained the standard treatment for peritumoral edema since its introduction in 1961. It acts, at least in part, by reducing the permeability of tumor capillaries, and is indicated in any patient with symptomatic cerebral edema.

  Dosing of corticosteroids — Dexamethasone is preferred to other corticosteroids since it has relatively little mineralocorticoid activity which reduces the potential for fluid retention and hypokalemia. In addition, dexamethasone may be associated with a lower risk of infection and cognitive impairment.

The usual dexamethasone regimen consists of a loading dose of 10 mg followed by a maintenance dose of 4 mg four times per day. There is some evidence that lower doses may be as effective. One double-blind, randomized study evaluated the effects of different doses of dexamethasone on Karnofsky score in 89 patients with CT-proven brain metastasis. Administration of 4 mg or 8 mg dexamethasone per day resulted in the same degree of improvement as 16 mg/day after one week of therapy. Toxicity was dose-dependent and, during a four-week period, occurred more frequently in patients receiving 16 mg/day.

Most patients improve symptomatically within 24 to 72 hours; however, neuroimaging studies may not show a reduction in the amount of edema for up to one week. In general, headaches tend to respond better than focal deficits. If 16 mg of dexamethasone is insufficient, the dose can be increased up to 100 mg/day.

It is the clinical condition of the patient rather than the amount of edema on MRI that determines the steroid dose. We use lower doses in patients with a small amount of edema and few symptoms. The dose is usually tapered after irradiation, although the taper may begin earlier in patients with little peritumoral edema.

  Side effects and complications of corticosteroids — Corticosteroids are associated with a number of well known side effects including myopathy, weight gain, fluid retention, hyperglycemia, insomnia, gastritis, and immunosuppression. The frequency of these complications can be reduced by using the lowest possible dose of corticosteroids.

Patients with cancer may be at increased risk for steroid myopathy, largely because of the high steroid doses that are given. In one prospective study, for example, nine of 15 (60 percent) adult cancer patients developed clinically detectable proximal muscle weakness, all but one within 15 days. Ten of these patients, including two of the six without proximal muscle weakness, developed respiratory dysfunction due presumably to involvement of the respiratory muscles. The muscle weakness partially or completely resolved within three months after cessation of corticosteroid therapy.

Patients with brain tumors who are treated with corticosteroids are also at increased risk of Pneumocystis carinii infection. In one retrospective study, histologically confirmed Pneumocystis carinii pneumonia developed in 10 of 587 patients (1.7 percent) presenting for treatment of brain tumor. The median duration of dexamethasone therapy at the onset of symptoms of infection was three months. This complication should be prevented with the use of trimethoprim-sulfamethoxazole or other prophylaxis, particularly in patients over 50 years of age

Seizures — Seizures are the presenting symptom in approximately 10 to 20 percent of patients with brain metastases and occur at some stage of the illness in another 10 to 20 percent of patients. Patients with brain metastases who develop seizures should be treated with standard anticonvulsants. In order to minimize toxicity, the lowest effective dose of medication should be used and polytherapy avoided whenever possible.. Electroencephalography may be useful if the diagnosis of seizures is in doubt but is not routinely needed for patients who give a clear history of seizures or do not have symptoms suggestive of seizures.

  Anticonvulsant drug rash — In addition to the usual complications of anticonvulsants, brain tumor patients experience an increased incidence of drug rashes and a small percentage develop Stevens-Johnson syndrome. It has been suggested that the combination of phenytoin, cranial irradiation, and the gradual reduction of concomitant steroids are associated with the development of erythema multiforme and/or Stevens-Johnson syndrome.

The actual incidence of these complications is uncertain. In one series of 289 patients receiving cranial irradiation for brain tumor, mild, morbilliform rashes occurred in 18 percent of exposures to anticonvulsants and in 22 percent of exposures to phenytoin. One patient developed erythema multiforme. However, most of the rashes occurred before the initiation of radiation therapy. Stevens-Johnson syndrome has also been described in brain tumor patients receiving carbamazepine.

  Anticonvulsant drug interactions — Anticonvulsants have clinically significant interactions with other drugs commonly used in patients with brain metastases because they induce hepatic microsomal enzymes. As an example, phenytoin increases the hepatic metabolism of dexamethasone, reducing its half-life and bioavailability. Anticonvulsants also may increase the metabolism of certain chemotherapeutic agents such as taxol. On the other hand, dexamethasone and a number of chemotherapeutic agents commonly used in cancer patients interact with phenytoin, causing a reduction in serum phenytoin concentrations and potentially leading to breakthrough seizures.

  Prophylactic anticonvulsant therapy — Because the risk of seizures in patients with brain metastases who do not present with seizures is very low, prophylactic anticonvulsant therapy is usually not indicated. A meta-analysis of randomized clinical trials addressing this issue concluded that there was no statistical evidence showing a significant benefit of prophylactic treatment with anticonvulsant therapy. In a review of prophylactic anticonvulsants for patients with primary or metastatic brain tumors from the Quality Standards Subcommittee of the American Academy of Neurology, the panel recommended that prophylactic anticonvulsants should not be used routinely in patients with newly diagnosed brain tumors or metastases.

Possible exceptions to this approach are patients with brain metastases in areas of high epileptogenicity (eg, motor cortex), melanoma metastases or both brain metastases and leptomeningeal metastases. These patients have a higher seizure risk and may benefit from prophylactic anticonvulsant therapy.

Venous thromboembolic disease — Malignancy is frequently associated with a hypercoagulable state, with tissue factor and cancer procoagulant being major factors promoting thrombus formation.. Venous thromboembolic disease is common in patients with brain metastases, occurring in approximately 20 percent of cases.

Treatment options include anticoagulation and the placement of inferior vena cava (IVC) filters. These patients are often perceived to be at increased risk of intracranial hemorrhage with anticoagulation because of the vascularity of the tumors and anecdotal case reports of hemorrhage. As a result, most patients with brain metastases and venous thromboembolic disease have been managed with IVC filtration devices rather than systemic anticoagulation.

However, this may not be the optimum approach since there is a high rate of complications with filtration devices in these patients. As an example,in a retrospective series of 42 patients with intracranial malignancy and venous thromboembolism who received IVC filters, the complication rate was 62 percent. Twelve percent developed pulmonary embolism and 57 percent developed IVC or filter thrombosis, recurrent deep venous thrombosis, or postphlebitic syndrome.

In addition to the high risk of complications with IVC filters, there is increasing evidence suggesting that the risk of intracranial hemorrhage may not be significantly increased in patients with primary or secondary brain tumors who are anticoagulated outside the immediate postoperative period. In one series, only three of 42 patients treated with anticoagulation developed serious CNS complications. In two of the three, devastating CNS hemorrhage occurred in the setting of supratherapeutic anticoagulation.

  Recommendation — We believe that the current data suggest that anticoagulation with warfarin may be more effective than IVC filter placement and is acceptably safe when the prothrombin time is maintained within the therapeutic range. This is particularly applicable in patients with brain metastases from breast cancer, which generally do not hemorrhage.