Brain Metastases

Published on 09/04/2015 by admin

Filed under Hematology, Oncology and Palliative Medicine

Last modified 09/04/2015

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13 Brain Metastases

Presentation and Diagnosis

Patients with brain metastases may present with the classical features of a brain tumor. In the presence of multiple lesions, the presentation may be with a nonspecific global deficit and confusional state or epilepsy. Although cognitive impairment is common, detected in up to 65% of patients,2 it requires detailed neuropsychological testing. Any patient with known malignant disease presenting with any features indicating an intracranial problem requires imaging with CT, or preferably MRI, with and without contrast.

Brain metastases are typically isodense or hyperdense on CT and isointense or hyperintense on MRI, usually with surrounding low density assumed to represent edema. Most brain metastases enhance with intravenous contrast. The difficulty in differential diagnosis arises in the presence of hemorrhage into the lesion, which does not allow for visualization of the underlying tumor. While the majority of brain metastases lie within the brain parenchyma, they may occasionally mimic tumors such as meningioma or acoustic neuroma. It may not be possible to distinguish the two diagnoses on imaging alone, particularly as patients with disseminated malignancy may have coexisting benign tumors. The imaging diagnosis is also difficult in patients presenting with a single intracranial lesion in the absence of systemic disease; the differential diagnosis includes other enhancing single lesions, such as high-grade gliomas.

The need for a histological confirmation of metastatic disease in the brain is summarized in an algorithm (Figure 13-1). In the presence of known systemic malignancy and metastatic disease, there is no indication for biopsy of intracranial lesions unless there is a high index of suspicion for an alternative diagnosis such as an atypical infection. In patients presenting with lesions in the brain, without previous history of primary malignancy, histological confirmation of diagnosis is generally required, preferably from an extracranial site.

The management of brain metastases is influenced by the extent and activity of systemic disease; this information would be part of the routine workup of a patient with known malignant disease and should be available prior to a decision on treatment. In patients with presumed solitary brain metastases, any decision on local treatment should only be made after confirmation of the solitary nature of the tumor by MRI.

Medical Management

The aim of treatment of brain metastases is palliation, to improve neurological deficit and quality of life and to prolong survival. Mass effect and neurological deficit assumed to be due to surrounding edema are appropriately treated with corticosteroids. Oral dexamethasone is generally employed as the drug of choice and can be administered in a single daily dose. The tendency has been to recommend a large loading dose followed by reduced daily doses, although it is not clear whether this approach leads to a faster improvement in function. The only regimen subject to a randomized trial is the administration of low-dose dexamethasone (4 mg daily) in comparison to high-dose dexamethasone (12 mg daily). The improvement in function at one week was the same regardless of dose. Patients receiving higher doses experienced more severe side effects,5 which suggests that 4 mg dexamethasone given in a single daily dose is sufficient and should only be increased in the absence of response after 2 or 3 days. In patients with clinical features of increased intracranial pressure, higher loading doses are recommended. After a clinical benefit has been achieved, the dose should be gradually titrated down to the lowest necessary to maintain improvement in symptoms. It is also important to reduce and discontinue corticosteroids after definitive treatment, to avoid cushingoid side effects.

In patients presenting with brain metastases detected on routine imaging who have no or minimal symptoms, corticosteroids should not be automatically administered. Corticosteroids are also not recommended as a prophylactic treatment prior to cranial irradiation or chemotherapy. Prolonged use may, theoretically, alter the uptake of water-soluble chemotherapeutic agents due to alteration in the blood brain barrier (BBB), although the clinical relevance is not clear. The principal reason for withholding corticosteroids in patients with minimal or no symptoms is to avoid disabling proximal myopathy and other steroid-induced side effects.

The management of seizures in patients with brain metastases should be along the lines of management of epilepsy in patients with any brain tumor. There is no evidence for benefit of prophylactic anticonvulsants.6 If chemotherapy is part of the management (see below), it is preferable to avoid enzyme-inducing anticonvulsants that increase the metabolism of taxanes, anthracyclines, vinca alkaloids and small molecular tyrosine kinase inhibitors, leading to lower effective doses. Lamotrigine is a reasonable first choice as it does not induce liver enzymes.

Specific Treatment Modalities

RADIOTHERAPY

Whole brain irradiation has been the mainstay of treatment of patients with brain metastases. Only one randomized trial compared supportive care (corticosteroids alone) with whole brain radiotherapy (WBRT); it showed a small improvement in median survival in patients receiving WBRT.12 Subsequent randomized studies examining the role of WBRT compared different dose fractionation schedules to identify the most effective regimen. None have shown benefit for more intensive treatment employing higher doses, given either as daily fractionation or as accelerated radiotherapy using multiple treatments per day. A UK study comparing 30 Gy in 10 fractions with 12 Gy in two fractions had shown a survival benefit for longer fractionation in favorable-prognosis patients,13 and one or two fraction regimens are rarely employed. The preferred WBRT for patients with multiple brain metastases is 20 Gy in 5 fractions, or 30 Gy in 10 fractions. WBRT improves neurological function in over half of patients with a deficit, although part of the improvement may be due to corticosteroids.

It is generally accepted that patients with good performance status and reasonable prognosis may benefit from WBRT both in terms of survival and neurological function/QoL. However, the value of radiotherapy in patients with marked disability and poor performance status is questioned,14 and at present it is not clear whether WBRT is appropriate. Randomized trials currently underway examine survival and quality of life benefits of WBRT in patients with multiple brain metastases and poor prognosis.

Patients with brain metastases from chemosensitive tumors are appropriately treated with primary chemotherapy, as discussed later in this chapter. Because of presumed residual microscopic disease following the completion of chemotherapy, patients are usually offered consolidation WBRT, although randomized studies assessing the additional value of irradiation are not available.

In diseases with a high incidence of intracranial dissemination of disease, brain irradiation may be used as prophylaxis, similar to the use of craniospinal irradiation in acute lymphatic leukemia in childhood. Prophylactic cranial irradiation (PCI) improves intracranial tumor control and survival in patients with limited and advanced-stage small cell lung cancer who achieve good remission with chemotherapy15,16; however, the magnitude of gain in life expectancy is not large and neurocognitive deficits in long-term survivors are of concern. So far there is not enough evidence to support PCI in patients with other solid tumors.

RADIOTHERAPY AND RADIOSENSITIZERS

A number of radiation sensitizers have been tested in addition to radiotherapy with the aim of improving disease control in the brain as well as survival. Electron-affinic sensitizers (metronidazole, misonidazole)17,18 and sensitizers of proliferating cells (BUdr)19 have not demonstrated benefit in randomized studies. The addition of radiation sensitizers motexafin gadolinium, which is preferentially taken up by enhancing lesions,20 and efaproxiral do not improve survival or disease control.

RADIOSURGERY

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