Considerations in the Diagnosis and Management of Brain Metastases

September 1, 2001

Brain metastases are a common complication of systemic cancer and a significant cause of morbidity. For patients whose brain metastases remain untreated, the prognosis is poor. The advent of contrast-enhanced magnetic

Dr. Sawaya’s review provides a comprehensive overview andexcellent summary of current knowledge on an important topic. Brain metastasesfar outnumber primary brain tumors; their diagnosis and treatment arebread-and-butter for both medical and neurosurgical oncologists. Additionally,unlike primary brain tumors, a definable at-risk population exists for brainmetastases, making prevention a potentially achievable goal.

Diagnosis

As Dr. Sawaya points out, however, many brain metastases are asymptomatic.Diagnosis and treatment before symptoms develop are important. When brainimaging is included in a "staging" work-up, magnetic resonance imaging(MRI) with and without gadolinium should be used rather than computed tomography(CT) because of its greater sensitivity. Most asymptomatic metastases are lessthan 1 cm in diameter, and many are only a few millimeters in size. Although MRIwith "triple-dose" gadolinium is considered by some to be even moresensitive than standard contrast imaging, we have used standard contrast MRIwith careful attention to the imaging sequences that highlight edema aroundsmall metastases. The fluid-attenuated inversion recovery (FLAIR) sequence isprobably best for this purpose.

When a metastasis has a ring-enhancing appearance with surrounding edema,brain abscess is an important differential consideration. The characteristicbright appearance of abscesses on diffusion-weighted imaging is helpful in thisregard, because the necrotic centers of most ring-enhancing metastases will showlow or intermediate signal intensity.

We find that most brain metastases can be confidently diagnosed withoutobtaining tissue. In some situations, such as a single brain lesion with noknown systemic cancer or with a chest primary of unknown histology that cannotbe biopsied without thoracotomy, biopsy of a brain metastasis is necessary fordiagnosis. Interstitial brachytherapy can be performed at the same sitting inthis situation, using a probe introduced stereotactically into the center of thetumor to deliver in a few minutes a therapeutic single-fraction treatmentequivalent to radiosurgery.[1]

Medical Treatment

As Dr. Sawaya notes, corticosteroids are indicated for most patients withbrain metastases, especially those with neurologic symptoms. An exception occurswhen brain lymphoma is a diagnostic consideration, because even a brief courseof steroid treatment can cause complete regression of these lesions, thusthwarting biopsy.

Anticonvulsants are no longer considered effective prophylaxis againstseizures in patients with brain metastases, and their use should be restrictedto those who have actually had seizures.[2] It is not widely appreciated amongmedical oncologists that common anticonvulsants such as phenytoin andphenobarbital can have a dramatic effect on the pharmacokinetics of standardchemotherapeutic agents that are metabolized by the P450 hepatic enzyme system.Such interactions may complicate treatment of extracranial disease in thispopulation. For example, the dose of paclitaxel (Taxol) in a phase II trial inrecurrent malignant glioma was 330 mg/m² for patients using P450-inducing anticonvulsants, compared with 210mg/m² for those not using such agents.[3] When use of an anticonvulsant isnecessary in a cancer patient, valproate may be preferable because it is not aP450 inducer.

Surgical or Radiosurgical Treatment

At present, three major controversies surround the treatment of brainmetastases: surgery vs radiosurgery, surgery/radiosurgery alone vs withwhole-brain radiotherapy, and appropriate use of surgery/radiosurgery inpatients with multiple metastases.

Most studies comparing surgery and radiosurgery have shown little differencein survival or local failure rate, and the two modalities seem nearly equivalentfor most purposes. Radiosurgery is less invasive, and we prefer it for mostsingle metastases. Surgery relieves symptomatic edema more quickly and ispreferred (for accessible lesions) when steroid-resistant symptoms aredebilitating. Whenever possible, surgery is performed under a local anestheticto shorten both inpatient and outpatient recovery time.[4]

Randomized evidence favoring whole-brain radiotherapy after surgical excisionof a single metastasis is now available, as Dr. Sawaya indicates. This evidence,however, may not be generalizable to every situation. For example, in patientswith total excisions of single metastases from radioresistant primary lesionssuch as melanoma or sarcoma, the role of whole-brain irradiation is less clear.Withholding whole-brain irradiation and using surgery or radiosurgeryaggressively as needed for salvage of local or regional failure may be moreappropriate for some of these patients. Randomized trials limited to thesehistologies would be valuable.

To further complicate the situation, implantable wafers that graduallyrelease carmustine (Gliadel) into the brain parenchyma surrounding a resectioncavity are being evaluated in early-stage clinical trials. This strategy couldpotentially replace cranial irradiation in a defined subset of patients for whomlocal rather than regional failure was the primary consideration, usingaggressive focal salvage treatments as necessary. For now, the use of suchwafers after metastasis resections should be carefully limited to the setting ofprospective clinical protocols.

Aggressive local treatment (surgery or radiosurgery) has an undefined role inpatients with multiple metastases. Although one small randomized trial showedmarkedly improved local control and a trend toward improved survival afterradiosurgical treatment of two to four metastases,[5] a preliminary report fromthe much larger RTOG 9508 trial, also randomized, showed no survival benefit forpatients with two or three metastases.[6] There are no randomized trials ofsurgical excision in patients with more than one brain metastasis, although theM. D. Anderson experience quoted by Dr. Sawaya does confirm a long mediansurvival in a carefully selected group of patients.

Prevention

In most medical situations, prevention is usually preferred to treatment. Forbrain metastases, the prophylactic modality—whole-brain radiotherapy—carriesa risk of dementia and other neurologic dysfunction that seems prohibitivelyhigh to some patients and physicians. The actual magnitude of this risk is amatter for debate and clearly needs further study. However, the survival benefitassociated with prophylactic cranial irradiation for small-cell lung cancerpatients who are in complete remission has now been established by ameta-analysis of randomized trials.[7] There is current interest in usingprophylactic cranial irradiation in other settings as well, such as locallyadvanced (stage IIIa/IIIb) non-small-cell lung cancer.[8] Better definition ofthe group at high risk for postradiation dementia, and for brain metastasis innon-small-cell lung cancer, may identify a target population that wouldclearly benefit from prophylactic cranial irradiation.

Another advance that may foster wider use of prophylactic cranial irradiationwould be effective prevention or treatment of the neurologic sequelae. Atpresent, there are no pharmacologic agents known to prevent the effects ofradiation on normal brain parenchyma, and no effective radiosensitizers are yetknown that would permit the use of smaller overall doses while preservingefficacy. Use of smaller radiation fractions may help prevent postradiationdementia, but the practice lengthens treatment time.

Once symptoms occur, there is little that can be done to prevent theirprogression. Cerebrospinal fluid shunting can provide temporary palliation insome patients, especially when gait disorder and incontinence are thepredominant symptoms.

References:

1. Cosgrove GR, Hochberg FH, Zervas NT, et al: Interstitial irradiation ofbrain tumors, using a miniature radiosurgery device: Initial experience.Neurosurgery 40:518-523, 1997.

2. Glantz MJ, Cole BF, Forsyth PA, et al: Practice parameter: Anticonvulsantprophylaxis in patients with newly diagnosed brain tumors. Report of the QualityStandards Subcommittee of the American Academy of Neurology. Neurology54:1886-1893, 2000.

3. Chang SM, Kuhn JG, Robins HI, et al: A phase II study of paclitaxel inpatients with recurrent malignant glioma using different doses depending uponthe concomitant use of anticonvulsants: A North American Brain Tumor Consortiumreport. Cancer 91:417-422, 2001.

4. Taylor MD, Bernstein M: Awake craniotomy with brain mapping as the routinesurgical approach to treating patients with supratentorial intraaxial tumors: Aprospective trial of 200 cases. J Neurosurg 90:35-41, 1999.

5. Kondziolka D, Patel A, Lunsford LD, et al: Stereotactic radiosurgery pluswhole brain radiotherapy vs radiotherapy alone for patients with multiple brainmetastases. Int J Radiat Oncol Biol Phys 45:427-434, 1999.

6. Andrews DW, Scott C, Sperduto P, et al: Preliminary analysis of RTOG 9508:A phase III prospective randomized trial comparing whole brain irradiation alonevs whole brain irradiation plus stereotactic radiosurgery for patients with twoor three brain metastases (abstract). Neurosurgery 47:520, 2000.

7. Auperin A, Arriagada R, Pignon JP, et al: Prophylactic cranial irradiationfor patients with small-cell lung cancer in complete remission. ProphylacticCranial Irradiation Overview Collaborative Group. N Engl J Med 341:476-484,1999.

8. Stuschke M, Eberhardt W, Pottgen C, et al: Prophylactic cranialirradiation in locally advanced non-small-cell lung cancer after multimodalitytreatment: Long-term follow-up and investigations of late neuropsychologiceffects. J Clin Oncol 17:2700-2709, 1999.