A common complication of systemic cancer is the development of brain metastasesthe predominant type of intracranial neoplasm found
in adults. Brain metastases are a significant cause of morbidity, typically due
to some combination of peritumoral edema, the effect of the tumor mass itself,
or the presence of an obstructive hydrocephalus. Any of these conditions can
cause an increase in intracranial pressure. Brain lesions may also directly
compress adjacent neurons, resulting in focal irritation or neuron
destruction. Not surprisingly, they are an important contributing factor to
patient mortality.[1-4] While statistical projections have put the number of
patient deaths due to brain and other central nervous system neoplasms at
approximately 2.4% (13,300 of 564,800) of all cancer deaths, the actual
number is likely to be higher because the death of patients with intracranial
metastases is often attributed to underlying systemic disease.[1,2,6-8]
The incidence of brain metastases appears to be increasing,[1,6] possibly as
a result of earlier and more accurate methods of detection. Other factors that
may contribute to this increase are the success of aggressive treatment
modalities that prolong survival, the increasing incidence of primary cancers
with a propensity to metastasize to the brain (eg, lung and breast cancer), and
the overall aging of the population.[1,8-10]
In 1998, it was projected that more than 1.2 million patients in the United
States would be newly diagnosed with cancer. Based on projections regarding
the frequency of brain metastases stemming from various types of cancer, and
using the high end of the projected ranges48%, 32%, and 21% for patients with
skin, lung, and breast cancer, respectivelywe calculated that the yearly
incidence of new brain metastases would reach more than 107,000 cases in
The prognosis for untreated brain metastases is poor, with median survival
projected to be 2 months or less.[3,11] While techniques for confirming
diagnoses have improved substantially in the past decade or so, a review of the
literature suggests that up to one-third of patients are asymptomatic, and
consequently many of these metastases go undetected. Autopsy studies show that
24% to 31% of patients with cancer develop intracranial metastases,[9,12-14] and
the results of several studies suggest that substantially higher percentages of
patients have been diagnosed with intracranial metastases postmortem than during
their lifetime. Hirsch et al reported that 21% of patients were clinically
diagnosed based on signs and symptoms vs 50% at autopsy, and Amer et al
reported that 46% were diagnosed clinically vs 75% at autopsy. Although
clinical disease progression is expected to continue up to the time of death,
making the development of more tumors likely, these findings still serve to
underscore the challenge of diagnosing asymptomatic patients.
Once brain metastases have been successfully diagnosed, there are numerous
treatment options to be considered, depending on the patient’s profile and
underlying disease. Recent advances in technology and therapeutic techniques
have expanded the possibilities for the management of brain metastases through
the use of chemotherapy, radiation, surgery, and stereotactic radiosurgery,
either alone or in combination.
This review addresses the array of considerations the clinician must weigh in
the diagnosis and treatment of patients presenting with brain metastases.
Emphasis is placed on the need to identify asymptomatic patients at greatest
risk for developing brain metastases. In addition, an overview is provided of
the advantages and disadvantages of the primary treatment options, with a focus
on some of the current, prospective therapeutic approaches and the indications
for their use.
Presenting Signs and Symptoms
For cancer patients, the signs and symptoms of neurologic dysfunction are
usually the initial indication that underlying disease has metastasized to the
brain. Metastases are believed to be primarily disseminated hematogenously,
particularly through the arteries.[1,17,18] Typically, tumoral microemboli are
distributed in proportion to the relative blood flow to each area of the
brain.[18-20] Consequently, 80% to 85% of metastatic tumors are located in the
cerebral hemispheres, 10% to 15% in the cerebellum, and 3% to 5% in the brain
The clinical manifestations of intracranial lesions are generally dictated by
the location of the metastases. Increased intracranial pressure and mental
changes are symptomatic of a frontal metastatic lesion, visual field defects and
cortical blindness are indicative of an occipital metastasis, motor weakness
suggests a frontoparietal lesion, and a cerebellar metastasis may manifest
itself as ataxia or symptoms related to hydrocephalus.
Most neurologic symptoms can be ascribed to increased intracranial pressure
(headache, nausea, vomiting, confusion, and lethargy), focal irritation, or
destruction of adjacent brain tissue (aphasia, ataxia, visual field defects,
hemiparesis, and focal seizures).[1,22,24] A review of six representative
studies of patients with brain metastases secondary to a cross section of cancer
types showed that the most common presenting symptoms were headache, focal
weakness, mental and behavioral disturbances, seizure, ataxia, aphasia, visual
field defect, and sensory change.
Headache is the predominant presenting symptom, reported by approximately 50%
of all patients with a single intracranial metastasis (40% reporting early
morning headaches) and by a larger percentage of patients with multiple
metastases. Hemorrhage is also a serious complication, especially with
metastases secondary to malignant melanoma, choriocarcinoma, and gestational and
testicular cancers. Patients have been reported to present with acute
symptoms of stroke secondary to bleeding into a metastatic lesion, embolization
of tumor cells, or tumor invasion or compression of an adjacent artery.[9,20]
Leptomeningeal MetastasesLeptomeningeal metastases are a somewhat
unique subset of brain metastases. Between 30% and 50% of leptomeningeal
metastases are secondary to leukemia, and 8% to 15% are secondary to solid
tumors, primarily melanoma, lung cancer, and breast cancer. As with other brain
metastases, leptomeningeal metastases typically develop following hematogenous
dissemination involving the superficial arachnoid veins, but they may also
result from the extension of intracranial metastases into the subarachnoid space
or the ventricles. The primary symptoms of leptomeningeal metastases include
headache, back pain, nausea/vomiting, paresthesias, and diplopia.
Cancers Associated With Brain MetastasesThe three types of cancers with
the greatest predisposition for brain metastases are lung cancer (particularly
adenocarcinoma and small-cell cancers), breast cancer, and melanoma. Lung
cancer is the leading cause of cancer death among men and women in the United
States and is the primary site of cancer for 24% to 60% of all patients with
metastases.[3,11,14,25-30] Breast cancer, the second most common cause of cancer
death among US women and the leading cause of death for US women aged 15 to
54, may be the site of primary disease for 10% to 30% of all brain metastases among
Melanoma is particularly prone to the formation of brain metastases and may
account for between 5% and 21% of all patients with brain
metastases.[3,11,25,26,31] Table 1 summarizes the most frequently reported
symptoms of brain metastases from representative studies in patients with
melanoma, lung cancer, and breast cancer.[13,15,16,32-35] The most commonly
reported adverse events for this subset of patients are headache, cognitive
dysfunction, seizure, motor symptoms, cranial nerve paralysis, cerebellar
symptoms, and aphasia.
Corticosteroids, notably dexamethasone and methylprednisolone, and
anticonvulsants have become standard treatment for the control of peritumoral
edema and seizures, respectively.[1,20,21,36] In particular, corticosteroids
provide effective palliative therapy for acute symptoms of brain metastases, but
they should only be used for symptomatic lesions. Patients should receive the
lowest possible effective doses of corticosteroids and anticonvulsants to
minimize toxicity, particularly corticosteroids, due to the severity and
frequency of associated adverse events such as Cushing’s disease,
hypertension, hyperglycemia, and peripheral myopathies.[1,20] Notably, response
to acute corticosteroid therapy should be monitored carefully, because it is a
useful indicator of a patient’s potential for neurologic recovery following
surgical treatment of brain metastases.
Good clinical practice dictates that any patient known to have cancer and
presenting with one or more neurologic symptoms should be further evaluated for
the presence of brain metastases. However, only about two-thirds of patients
with brain metastases are thought to be symptomatic. The majority of patients
with no history of cancer and a single brain lesion are symptomatic; thus,
most asymptomatic patients are likely to have underlying disease. Many of the
newer antineoplastic agents approved for the treatment of melanoma, lung cancer,
and breast neoplasms have much better safety profiles and show less
neurotoxicity than some of their older counterparts, yet they are still
associated with adverse events that could mask common signs and symptoms of
brain metastases (Table 2).
For example, paclitaxel (Taxol) is associated with mild-to-moderate
dysfunction of the peripheral nervous system in most patients treated on a
weekly basis (severe reactions are reported for patients taking doses over
100 mg/m²). Symptoms of neuropathy usually begin 1 to 3 days after
treatment and may last for 3 to 6 months. Although routine diagnostic
evaluation of all asymptomatic patients may not be feasible, magnetic resonance
imaging (MRI) is being ordered more liberally for patients at risk of developing
brain metastases. This at-risk group should include "asymptomatic"
patients with primary melanoma, breast cancer, or lung cancer who are currently
receiving or have recently been treated with chemotherapeutic agents that may
mask the clinical signs and symptoms of brain metastases.
Constrast-Enhanced MRIOnce intracranial metastases are suspected,
contrast-enhanced MRI is the best tool for determining whether a brain or leptomeningeal metastasis is
present. Compared with computed tomography (CT) and other radiographic
techniques, contrast-enhanced MRI is associated with superior sensitivity and
specificity in determining the presence of brain metastases and their location
and number.[19,21,24] When used with T2-weighted spin-echo sequences, MRI is
better equipped to detect even slight edema and to image regions of the brain
such as the brain stem, temporal lobe, and cerebellum (which CT scans are unable
to depict clearly).
At present, single-dose gadolinium (gadolinium diethylenetriamine pentaacetic
acid) is the most commonly used contrast agent, although new agents (eg,
gadolinium texaphyrin) and new techniques (eg, pulse sequence software, coil
design, and postprocessing capabilities) are under investigation. Despite
the tremendous advantages of contrast-enhanced MRI, biopsy remains the most
definitive test for differentiating brain metastases from cerebral abscess or a
primary brain tumor. It should also be noted that whereas contrast-enhanced
MRI has great sensitivity, it does not have comparably high specificity in
diagnosing leptomeningeal metastases. Consequently, definitive diagnosis of
leptomeningeal metastases requires careful examination of the cerebrospinal
fluid, collected ideally from one or more lumbar punctures.
1. Sawaya R, Bindal RK, Lang FF, et al: Metastatic brain tumors, in Kaye AH,
Laws ER Jr (eds): Brain Tumors: An Encyclopedic Approach, pp 3-30. Edinburgh,
2. Bindal AK, Bindal RK, Hess KR, et al: Surgery vs radiosurgery in the
treatment of brain metastasis. J Neurosurg 84:748-754, 1996.
3. Markesbery WR, Brooks WH, Gupta GD, et al: Treatment for patients with
cerebral metastases. Arch Neurol 35:754-756, 1978.
4. Galicich JH, Arbit E: Metastatic brain tumors, in Youmans JR (ed):
Neurological Surgery, 3rd ed, pp 3204-3222. Philadelphia, WB Saunders, 1990.
5. Landis SH, Murray T, Bolden S, et al: Cancer statistics, 1998. CA Cancer J
Clin 48:6-29, 1998.
6. Posner JB, Chernik NL: Intracranial metastases from systemic cancer. Adv
Neurol 19:579-592, 1978.
7. Patchell RA, Tibbs PA, Walsh JW, et al: A randomized trial of surgery in
the treatment of single metastases to the brain. N Engl J Med 322:494-500, 1990.
8. Bindal RK, Sawaya R, Leavens ME, et al: Surgical treatment of multiple
brain metastases. J Neurosurg 79:210-216, 1993.
9. Posner JB: Neurologic Complications of Cancer, pp 3-7, 77-110, 204-209,
729. Philadelphia, FA Davis, 1995.
10. Galicich JH, Sundaresan N, Thaler HT: Surgical treatment of single brain
metastasis: Evaluation of results by computerized tomography scanning. J
Neurosurg 53:63-67, 1980.
11. Lang EF, Slater J: Metastatic brain tumors: Results of surgical and
nonsurgical treatment. Surg Clin North Am 44:865-872, 1964.
12. Posner JB, Chernik NL: Intracranial metastases from systemic cancer. Adv
Neurol 19:579-592, 1978.
13. Tsukada Y, Fouad A, Pickren JW, et al: Central nervous system metastasis
from breast carcinoma: Autopsy study. Cancer 52:2349-2354, 1983.
14. Takakura K, Sano K, Hojo S, et al: Metastatic Tumors of the Central
Nervous System, pp 7, 28-29. New York, Igaku-Shoin, 1982.
15. Hirsch FR, Paulson OB, Hansen HH, et al: Intracranial metastases in
small-cell carcinoma of the lung: Correlation of clinical and autopsy findings.
Cancer 50:2433-2437, 1982.
16. Amer MH, Al-Sarraf M, Baker LH, et al: Malignant melanoma and central
nervous system metastases: Incidence, diagnosis, treatment and survival. Cancer
17. Patchell RA: Brain metastases. Neurol Clin 9:817-824, 1991.
18. Delattre JY, Krol G, Thaler HT, et al: Distribution of brain metastases.
Arch Neurol 45:741-744, 1988.
19. Sawaya R, Ligon BL, Flowers A, et al: Management of metastatic brain
tumors: A review. Neurosurgery Quarterly 4(3):140-157, 1994.
20. Wen PY, Loeffler JS: Management of brain metastases. Oncology
21. Lang FF, Wildrick DM, Sawaya R: Metastatic brain tumors, in Bernstein M,
Berger MS (eds): Neuro-Oncology: The Essentials, pp 329-337. New York, Thieme,
22. Kaye AH: Malignant brain tumors, in Little JR, Awad IA (eds): Reoperative
Neurosurgery pp 49-76. Baltimore, Williams & Wilkins, 1992.
23. Bentson JR, Steckel RJ, Kagan AR: Diagnostic imaging in clinical cancer
management: Brain metastases. Invest Radiol 23:335-341, 1988.
24. Sawaya R, Ligon BL, Bindal RK: Educational review: Management of
metastatic brain tumors. Ann Surg Oncol 1(2):169-178, 1994.
25. Le Chevalier T, Smith FP, Caille P, et al: Sites of primary malignancies
in patients presenting with cerebral metastases: A review of 120 cases. Cancer
26. Sundaresan N, Galicich JH: Surgical treatment of brain metastases:
Clinical and computerized tomography evaluation of the results of treatment.
Cancer 55:1382-1388, 1985.
27. Baker AB: Metastatic tumors of the nervous system. Arch Pathol Lab Med
28. Baker GS, Kernohan JW, Kiefer EJ: Metastatic tumors of the brain. Surg
Clin North Am 31:1143-1145, 1951.
29. Chang DB, Yang PC, Luh KT, et al: Late survival of non-small-cell lung
cancer patients with brain metastases: Influence of treatment. Chest
30. MacGee EE: Surgical treatment of cerebral metastases from lung cancer.
The effect on quality and duration of survival. J Neurosurg 35:416-420, 1971.
31. Chason JL, Walker FB, Landers JW: Metastatic carcinoma in the central
nervous system and dorsal root ganglia. A prospective autopsy study. Cancer
32. Wronski M, Arbit E, Burt M, et al: Survival after surgical treatment of
brain metastases from lung cancer. A follow-up study of 231 patients treated
between 1976 and 1991. J Neurosurg 83:605-616, 1995.
33. Read RC, Boop WC, Yoder G, et al: Management of non-small-cell lung
carcinoma with solitary brain metastasis. J Thorac Cardiovasc Surg 98:884-891,
34. Choi KN, Withers HR, Rotman M: Intracranial metastases from melanoma:
Clinical features and treatment by accelerated fractionation. Cancer 56:1-9,
35. Retsas S, Gershuny AR: Central nervous system involvement in malignant
melanomas. Cancer 61:1926-1934, 1988.
36. Posner JB: Management of central nervous system metastases. Semin Oncol
37. Lang FF, Sawaya R: Surgical treatment of metastatic brain tumors. Semin
Surg Oncol 14:53-63, 1998.
38. Available at: www.cp.gsm.com. Clinical Pharmacology 2000: Paclitaxel
monograph, adverse reactions. Revised May 31, 2000.
39. Available at: www.ClinicalTrials.gov. Accessed July 10, 2001.
40. Aronson SM, Garcia JH, Aronson BE: Metastatic neoplasms of the brain:
Their frequency in relation to age. Cancer 17:558-563, 1964.
41. Winston KR, Walsh JW, Fischer EG: Results of operative treatment of
intracranial metastatic tumors. Cancer 45:2639-2645, 1980.
42. Vecht CJ, Haaxma-Reiche H, Noordijk EM, et al: Treatment of single brain
metastasis: Radiotherapy alone or combined with neurosurgery? Ann Neurol
43. Noordijk EM, Vecht CJ, Haaxma-Reiche H, et al: The choice of treatment of
single brain metastasis should be based on extracranial tumor activity and age.
Int J Radiat Oncol Biol Phys 29:711-717, 1994.
44. Pieper DR, Hess KR, Sawaya RE: Role of surgery in the treatment of brain
metastases in patients with breast cancer. Ann Surg Oncol 4(6):481-490, 1997.
45. Bindal RK, Sawaya R, Leavens ME, et al: Reoperation for recurrent
metastatic brain tumors. J Neurosurg 83:600-604, 1995.
46. Auchter RM, Lamond JP, Alexander E III, et al: A multiinstitutional
outcome and prognostic factor analysis of radiosurgery for resectable single
brain metastasis. Int J Radiat Oncol Biol Phys 35(1):27-35, 1996.
47. Wronski M, Maor MH, Davis BJ, et al: External radiation of brain
metastases from renal carcinoma: A retrospective study of 119 patients from the
M.D. Anderson Cancer Center. Int J Radiat Oncol Biol Phys 37(4):753-759, 1997.
48. Bindal RK, Sawaya RE, Leavens ME, et al: Sarcoma metastatic to the brain:
Results of surgical treatment. Neurosurgery 35(2):185-191, 1994.
49. Haar F, Patterson RH: Surgery for metastatic intracranial neoplasm.
Cancer 30:1241-1245, 1972.
50. Patchell RA, Posner JB: Neurologic complications of systemic cancer.
Neurol Clin 3:729-750, 1985.
51. Galluzzi S, Payne PM: Brain metastases from primary bronchial carcinoma:
A statistical study of 741 necropsies. Br J Cancer 10:408-414, 1956.
52. Lang FF, Sawaya R: Current controversies in the surgical management of
cerebral metastases. Perspect Neurol Surg 7:55-70, 1997.
53. Lang FF, Sawaya R: Surgical management of cerebral metastases. Neurosurg
Clin N Am 7(3):459-483, 1996.
54. Breneman JC, Sawaya R: Cerebral radiation necrosis, in Barrow D (ed):
Perspectives in Neurological Surgery, pp 127-140. St Louis, Quality Medical
55. Hazle JD, Jackson EF, Schomer DF, et al: Dynamic imaging of intracranial
lesions using fast spin-echo imaging: Differentiation of brain tumors and
treatment effects. J Magn Reson Imaging 7:1084-1093, 1997.
56. Burt M, Wronski M, Arbit E, et al: Resection of brain metastases from non-small-cell
lung carcinoma. Results of therapy. J Thorac Cardiovasc Surg 103:399-411, 1992.
57. DeAngelis LM, Delattre JY, Posner JB: Radiation-induced dementia in
patients cured of brain metastases. Neurology 39:789-796, 1989.
58. Patchell RA: Metastatic brain tumors. Neurol Clin 13:915-925, 1995.
59. Borgelt B, Gelber R, Kramer S, et al: The palliation of brain metastases:
Final results of the first two studies by the Radiation Therapy Oncology group.
Int J Radiat Oncol Biol Phys 6:1-9, 1980.
60. Borgelt B, Gelber R, Larson M, et al: Ultra-rapid high-dose irradiation
schedules for the palliation of brain metastases: Final results of the first two
studies by the Radiation Therapy Oncology group. Int J Radiat Oncol Biol Phys
61. Sause W, Scott C, Krisch R, et al: Phase I/II trial of accelerated
fractionation in brain metastases RTOG 85-28. Int J Radiat Oncol Biol Phys
62. Murray KJ, Scott C, Greenberg HM, et al: A randomized phase III study of
accelerated hyperfractionation vs standard in patients with unresected brain
metastases: A report of the Radiation Therapy Oncology Group (RTOG) 9104. Int J
Radiat Oncol Biol Phys 39:571-574, 1997.
63. Rosenstein M, Armstrong J, Kris M, et al: A reappraisal of the role of
prophylactic cranial irradiation in limited small-cell lung cancer. Int J Radiat
Oncol Biol Phys 24:43-48, 1992.
64. Fleck JF, Einhorn LH, Lauer RC, et al: Is prophylactic cranial
irradiation indicated in small-cell lung cancer? J Clin Oncol 8:209-214, 1990.
65. Johnson BE, Patronas N, Hayes W, et al: Neurologic, computed cranial
tomographic, and magnetic resonance imaging abnormalities in patients with
small-cell lung cancer: Further follow-up of 6- to 13-year survivors. J Clin
Oncol 8:48-56, 1990.
66. Laukkanen E, Klonoff H, Allan B, et al: The role of prophylactic brain
irradiation in limited stage small-cell lung cancer: Clinical, neuropsychologic,
and CT sequelae. Int J Radiat Oncol Biol Phys 14:1109-1117, 1988.
67. Hardy J, Smith I, Cherryman G, et al: The value of computed tomographic
(CT) scan surveillance in the detection and management of brain metastases in
patients with small-cell lung cancer. Br J Cancer 62:684-686, 1990.
68. Delattre JY, Posner JB: Neurological complications of chemotherapy and
radiation therapy, in Aminoff MJ (ed): Neurology and General Medicine, pp
421-446. New York, Churchill Livingstone, 1994.
69. Hazuka MB, Burleson W, Stroud DN, et al: Multiple brain metastases are
associated with poor survival in patients treated with surgery and radiotherapy.
J Clin Oncol 11:369-373, 1993.
70. Sundaresan N, Sachdev VP, DiGiacinto GV, et al: Reoperation for brain
metastases. J Clin Oncol 6:1625-1629, 1988.
71. Arbit E, Wronski M, Burt M, et al: The treatment of patients with
recurrent brain metastases: A retrospective analysis of 109 patients with non-small-cell
lung cancer. Cancer 76:765-773, 1995.
72. Patchell RA, Tibbs PA, Regine WF, et al: Postoperative radiotherapy in
the treatment of single metastases to the brain: A randomized trial. JAMA
73. Skibber JM, Soong SJ, Austin L, et al: Cranial irradiation after surgical
excision of brain metastases in melanoma patients. Ann Surg Oncol 3(2):118-123,
74. Alexander E 3rd, Moriarty TM, Davis RB, et al: Stereotactic radiosurgery
for the definitive, noninvasive treatment of brain metastases. J Natl Cancer
Inst 87(1):34-40, 1995.