Tipos de Cancer   /   Tumores del Cerebro

NCI/PDQ^® Health professionals: Adult Brain Tumors Treatment (PDQ®)

National Cancer Institute
Ultima Vez Modificado: 9 de julio del 2012

TABLE OF CONTENTS

• General Information About Adult Brain Tumors
  • Incidence and Mortality
  • Disease Overview
  • Clinical Presentation
  • Diagnosis
  • Metastatic Brain Tumors
  • Related Summaries

• Classification of Adult Brain Tumors

• Treatment Option Overview
  • Primary Brain Tumors
  • Surgery
  • Radiation Therapy
    • High-grade tumors
    • Low-grade tumors
    • Repeat radiation therapy (re-irradiation)
  • Chemotherapy
    • Systemic chemotherapy
    • Localized chemotherapy
  • Treatment Options Under Clinical Evaluation
  • Primary Tumors of the Spinal Axis
  • Metastatic Brain Tumors
    • Treatment for patients with a single metastasis
    • Treatment for patients with oligometastases (13 or 4 brain metastases)
    • Treatment for patients with multiple metastases

• Management of Specific Tumor Types and Locations
  • Brain Stem Gliomas
    • Current Clinical Trials
  • Pineal Astrocytic Tumors
  • Pilocytic Astrocytomas
  • Diffuse Astrocytomas
  • Anaplastic Astrocytomas
  • Glioblastomas
  • Oligodendroglial Tumors
    • Oligodendrogliomas
    • Anaplastic oligodendrogliomas
  • Mixed Gliomas
  • Ependymal Tumors
    • Grade I and II ependymal tumors
    • Anaplastic ependymomas
  • Embryonal Cell Tumors: Medulloblastomas
  • Pineal Parenchymal Tumors
  • Meningeal Tumors
    • Grade I meningiomas
    • Grade II and III meningiomas and hemangiopericytomas
  • Germ Cell Tumors
  • Tumors of the Sellar Region: Craniopharyngiomas
  • Current Clinical Trials

• Recurrent Adult Brain Tumors
  • Surgery
  • Localized Chemotherapy
  • Systemic Chemotherapy
  • Radiation Therapy
  • Current Clinical Trials

• Changes to This Summary (07/09/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
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General Information About Adult Brain Tumors

Incidence and Mortality

Note: Estimated new cases and deaths from brain and other nervous system tumors in the United States in 2012: 1

• New cases: 22,910.
• Deaths: 13,700.

Brain tumors account for 85% to 90% of all primary central nervous system (CNS) tumors. 2 Available registry data from the Surveillance, Epidemiology, and End Results (SEER) database for 2007 indicate that the combined incidence of primary invasive CNS tumors in the United States is 6.36 per 100,000 persons per year with an estimated mortality of 4.22 per 100,000 persons per year. 3 Worldwide, approximately 238,000 new cases of brain and other CNS tumors were diagnosed in the year 2008, with an estimated 175,000 deaths. 4 In general, the incidence of primary brain tumors is higher in whites than in blacks, and mortality is higher in males than in females. 2

Few definitive observations on environmental or occupational causes of primary CNS tumors have been made. 2 Exposure to vinyl chloride may predispose to the development of glioma. Epstein-Barr virus infection has been implicated in the etiology of primary CNS lymphoma. Transplant recipients and patients with the acquired immunodeficiency syndrome have substantially increased risks for primary CNS lymphoma. 2 5 (Refer to the PDQ® summary on Primary CNS Lymphoma Treatment for more information.)

Disease Overview

The glial cell tumors, anaplastic astrocytoma and glioblastoma, account for approximately 38% of primary brain tumors. Since anaplastic astrocytomas only represent less than 10% of all CNS gliomas, phase III randomized trials restricted to the anaplastic astrocytomas are not practical. However, since they are aggressive and often included in studies along with glioblastomas, they are generally managed the same way as glioblastomas. Meningiomas and other mesenchymal tumors account for approximately 27% of primary brain tumors. 2

Other less-common primary brain tumors include the following in decreasing order of frequency:

• Pituitary tumors.
• Schwannomas.
• CNS lymphomas.
• Oligodendrogliomas.
• Ependymomas.
• Low-grade astrocytomas.
• Medulloblastomas.

Schwannomas, meningiomas, and ependymomas account for up to 79% of primary spinal tumors. Other less common primary spinal tumors include sarcomas, astrocytomas, vascular tumors, and chordomas, in decreasing order of frequency. The familial tumor syndromes (and respective chromosomal abnormalities that are associated with CNS neoplasms) include neurofibromatosis type I (17q11), neurofibromatosis type II (22q12), von Hippel-Lindau disease (3p25-26), tuberous sclerosis (9q34, 16p13), Li-Fraumeni syndrome (17p13), Turcot syndrome type 1 (3p21, 7p22), Turcot syndrome type 2 (5q21), and nevoid basal cell carcinoma syndrome (9q22.3). 6 7

Clinical Presentation

The clinical presentation of various brain tumors is best appreciated by considering the relationship of signs and symptoms to anatomy. 2 General signs and symptoms include the following:

• Headaches.
• Seizures.
• Visual changes.
• Gastrointestinal symptoms such as nausea, loss of appetite, and vomiting.
• Changes in personality, mood, mental capacity, and concentration.

Whether primary, metastatic, malignant, or benign, brain tumors must be differentiated from other space-occupying lesions such as abscesses, arteriovenous malformations, and infarction, which can have a similar clinical presentation. 8 Other clinical presentations of brain tumors include focal cerebral syndromes such as seizures. 2 Seizures are a presenting symptom in approximately 20% of patients with supratentorial brain tumors and may antedate the clinical diagnosis by months to years in patients with slow-growing tumors. Among all patients with brain tumors, 70% with primary parenchymal tumors and 40% with metastatic brain tumors develop seizures at some time during the clinical course. 9

Diagnosis

Computed tomography (CT) and magnetic resonance imaging (MRI) have complementary roles in the diagnosis of CNS neoplasms. 8 10 The speed of CT is desirable for evaluating clinically unstable patients. CT is superior for detecting calcification, skull lesions, and hyperacute hemorrhage (bleeding less than 24-hours old) and helps direct differential diagnosis as well as immediate management. MRI has superior soft-tissue resolution. MRI can better detect isodense lesions, tumor enhancement, and associated findings such as edema, all phases of hemorrhagic states (except hyperacute), and infarction. High-quality MRI is the diagnostic study of choice in the evaluation of intramedullary and extramedullary spinal cord lesions. 2 In post-therapy imaging, single-photon emission computed tomography (SPECT) and positron emission tomography (PET) may be useful in differentiating tumor recurrence from radiation necrosis. 8

Biopsy confirmation to corroborate the suspected diagnosis of a primary brain tumor is critical, whether before surgery by needle biopsy or at the time of surgical resection, except in cases where the clinical and radiologic picture clearly point to a benign tumor. Radiologic patterns may be misleading, and a definitive biopsy is needed to rule out other causes of space-occupying lesions, such as metastatic cancer or infection. CT- or MRI-guided stereotactic techniques can be used to place a needle safely and accurately into all but a very few inaccessible locations within the brain.

Specific genetic or chromosomal abnormalities involving deletions of 1p and 19q have been identified for a subset of oligodendroglial tumors, which have a high response rate to chemotherapy. 2 7 11 12 13 14 15 Other CNS tumors are associated with characteristic patterns of altered oncogenes, altered tumor-suppressor genes, and chromosomal abnormalities. Familial tumor syndromes with defined chromosomal abnormalities are associated with gliomas. (Refer to the Classification section of this summary for more information.)

Metastatic Brain Tumors

Brain metastases outnumber primary neoplasms by at least 10 to 1, and they occur in 20% to 40% of cancer patients. 16 Because no national cancer registry documents brain metastases, the exact incidence is unknown, but it has been estimated that 98,000 to 170,000 new cases are diagnosed in the United States each year. 2 8 This number may be increasing because of the capacity of MRI to detect small metastases and because of prolonged survival resulting from improved systemic therapy. 2 16

The most common primary cancers metastasizing to the brain are lung cancer (50%), breast cancer (15%20%), unknown primary cancer (10%15%), melanoma (10%), and colon cancer (5%). 2 16 Eighty percent of brain metastases occur in the cerebral hemispheres, 15% occur in the cerebellum, and 5% occur in the brain stem. 2 Metastases to the brain are multiple in more than 70% of cases, but solitary metastases also occur. 16 Brain involvement can occur with cancers of the nasopharyngeal region by direct extension along the cranial nerves or through the foramina at the base of the skull. Dural metastases may constitute as much as 9% of total CNS metastases.

A lesion in the brain should not be assumed to be a metastasis just because a patient has had a previous cancer; such an assumption could result in overlooking appropriate treatment of a curable tumor. Primary brain tumors rarely spread to other areas of the body, but they can spread to other parts of the brain and to the spinal axis.

The diagnosis of brain metastases in cancer patients is based on the following:

• Patient history.
• Neurological examination.
• Diagnostic procedures.

Patients may describe any of the following:

• Headaches.
• Weakness.
• Seizures.
• Sensory defects.
• Gait problems.

Often, family members or friends may notice the following:

• Lethargy.
• Emotional lability.
• Personality change.

A physical examination may show objective neurological findings or only minor cognitive changes. The presence of multiple lesions and a high predilection of primary tumor metastasis may be sufficient to make the diagnosis of brain metastasis. In the case of a solitary lesion or a questionable relationship to the primary tumor, a brain biopsy (usually a stereotactic biopsy) may be necessary. CT scans with contrast or MRIs with gadolinium are quite sensitive in diagnosing the presence of metastases. PET scanning and spectroscopic evaluation are new strategies to diagnose cerebral metastases and to differentiate the metastases from other intracranial lesions. 17

Related Summaries

Other PDQ® summaries containing information related to adult and childhood brain cancer include the following:

• Breast Cancer Treatment
• Childhood Brain and Spinal Cord Tumors Treatment Overview
• Colon Cancer Treatment
• Non-Small Cell Lung Cancer Treatment
• Small Cell Lung Cancer Treatment
• Testicular Cancer Treatment

References:

1. American Cancer Society.: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online [PUBMED Abstract]
2. Mehta M, Vogelbaum MA, Chang S, et al.: Neoplasms of the central nervous system. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1700-49. [PUBMED Abstract]
3. Altekruse SF, Kosary CL, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2007. Bethesda, Md: National Cancer Institute, 2010. Also available online [PUBMED Abstract]
4. Ferlay J, Shin HR, Bray F, et al.: GLOBOCAN 2008: Cancer Incidence and Mortality Worldwide in 2008. Lyon, France: IARC CancerBase No. 10. Available online [PUBMED Abstract]
5. Schabet M: Epidemiology of primary CNS lymphoma. J Neurooncol 43 (3): 199-201, 1999. [PUBMED Abstract]
6. Behin A, Hoang-Xuan K, Carpentier AF, et al.: Primary brain tumours in adults. Lancet 361 (9354): 323-31, 2003. [PUBMED Abstract]
7. Kleihues P, Cavenee WK, eds.: Pathology and Genetics of Tumours of the Nervous System. Lyon, France: International Agency for Research on Cancer, 2000. [PUBMED Abstract]
8. Hutter A, Schwetye KE, Bierhals AJ, et al.: Brain neoplasms: epidemiology, diagnosis, and prospects for cost-effective imaging. Neuroimaging Clin N Am 13 (2): 237-50, x-xi, 2003. [PUBMED Abstract]
9. Cloughesy T, Selch MT, Liau L: Brain. In: Haskell CM: Cancer Treatment. 5th ed. Philadelphia, Pa: WB Saunders Co, 2001, pp 1106-42. [PUBMED Abstract]
10. Ricci PE: Imaging of adult brain tumors. Neuroimaging Clin N Am 9 (4): 651-69, 1999. [PUBMED Abstract]
11. Buckner JC: Factors influencing survival in high-grade gliomas. Semin Oncol 30 (6 Suppl 19): 10-4, 2003. [PUBMED Abstract]
12. DeAngelis LM: Brain tumors. N Engl J Med 344 (2): 114-23, 2001. [PUBMED Abstract]
13. Ueki K, Nishikawa R, Nakazato Y, et al.: Correlation of histology and molecular genetic analysis of 1p, 19q, 10q, TP53, EGFR, CDK4, and CDKN2A in 91 astrocytic and oligodendroglial tumors. Clin Cancer Res 8 (1): 196-201, 2002. [PUBMED Abstract]
14. Giordana MT, Ghimenti C, Leonardo E, et al.: Molecular genetic study of a metastatic oligodendroglioma. J Neurooncol 66 (3): 265-71, 2004. [PUBMED Abstract]
15. Hoang-Xuan K, Capelle L, Kujas M, et al.: Temozolomide as initial treatment for adults with low-grade oligodendrogliomas or oligoastrocytomas and correlation with chromosome 1p deletions. J Clin Oncol 22 (15): 3133-8, 2004. [PUBMED Abstract]
16. Patchell RA: The management of brain metastases. Cancer Treat Rev 29 (6): 533-40, 2003. [PUBMED Abstract]
17. Schaefer PW, Budzik RF Jr, Gonzalez RG: Imaging of cerebral metastases. Neurosurg Clin N Am 7 (3): 393-423, 1996. [PUBMED Abstract]

Classification of Adult Brain Tumors

This classification is based on the World Health Organization (WHO) classification of central nervous system (CNS) tumors. 1 The WHO approach incorporates and interrelates morphology, cytogenetics, molecular genetics, and immunologic markers in an attempt to construct a cellular classification that is universally applicable and prognostically valid. Earlier attempts to develop a TNM-based classification were dropped: tumor size (T) is less relevant than tumor histology and location, nodal status (N) does not apply because the brain and spinal cord have no lymphatics, and metastatic spread (M) rarely applies because most patients with CNS neoplasms do not live long enough to develop metastatic disease. 2

The WHO grading of CNS tumors establishes a malignancy scale based on histologic features of the tumor. 3 The histologic grades are as follows:

WHO grade I includes lesions with low proliferative potential, a frequently discrete nature, and the possibility of cure following surgical resection alone.

WHO grade II includes lesions that are generally infiltrating and low in mitotic activity but recur more frequently than grade I malignant tumors after local therapy. Some tumor types tend to progress to higher grades of malignancy.

WHO grade III includes lesions with histologic evidence of malignancy, including nuclear atypia and increased mitotic activity. These lesions have anaplastic histology and infiltrative capacity. They are usually treated with aggressive adjuvant therapy.

WHO grade IV includes lesions that are mitotically active, necrosis-prone, and generally associated with a rapid preoperative and postoperative progression and fatal outcomes. The lesions are usually treated with aggressive adjuvant therapy.

The following table is from the WHO Classification of Tumours of the Central Nervous System and lists the tumor types and grades. 4 Tumors limited to the peripheral nervous system are not included. Detailed descriptions of histopathology, grading methods, incidence, and what is known about etiology specific to each tumor type can be found in the WHO classification book. 4

References:

1. Kleihues P, Cavenee WK, eds.: Pathology and Genetics of Tumours of the Nervous System. Lyon, France: International Agency for Research on Cancer, 2000. [PUBMED Abstract]
2. Brain and spinal cord. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 593-7. [PUBMED Abstract]
3. Kleihues P, Burger PC, Scheithauer BW: The new WHO classification of brain tumours. Brain Pathol 3 (3): 255-68, 1993. [PUBMED Abstract]
4. Louis DN, Ohgaki H, Wiestler OD, et al.: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114 (2): 97-109, 2007. [PUBMED Abstract]

Treatment Option Overview

Primary Brain Tumors

Radiation therapy and chemotherapy options vary according to histology and anatomic site of the brain tumor. For high-grade malignant gliomasglioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytomacombined modality therapy with resection, radiation, and chemotherapy is standard. Since anaplastic astrocytomas, anaplastic oligodendrogliomas, and anaplastic oligoastrocytomas represent only a small proportion of central nervous system (CNS) gliomas, phase III randomized trials restricted to them are not generally practical. However, since they are aggressive and are often included in studies along with glioblastomas, they are generally managed in a fashion similar to glioblastoma. Therapy involving surgically implanted carmustine-impregnated polymer wafers combined with postoperative external-beam radiation therapy (EBRT) has a role in the treatment of high-grade gliomas regardless of the extent of surgical resection. 1 Specific treatment options for tumor types are listed below under the tumor types and locations. This section covers general treatment principles.

Dexamethasone, mannitol, and furosemide are used to treat the peritumoral edema associated with brain tumors. Use of anticonvulsants is mandatory for patients with seizures. 2

Finally, active surveillance is appropriate in some circumstances. With the increasing use of sensitive neuroimaging tools, there has been increased detection of asymptomatic low-grade meningiomas. The majority appear to show minimal growth and can often be safely observed, with therapy deferred until the detection of tumor growth or the development of symptoms. 3 4

Surgery

For most types of brain tumors in most locations, an attempt at complete or near-complete surgical removal is generally recommended, if possible, within the constraints of preservation of neurologic function and underlying patient health. This recommendation is based on observational evidence that survival is better in patients who undergo tumor resection than in those who have closed biopsy alone. 5 6 However, the benefit of resection has not been tested in randomized trials. Selection bias can enter into observational studies despite attempts to adjust for patient differences that guide the decision to operate. Therefore, the actual difference in outcome between radical surgery and biopsy alone may not be as large as noted in the retrospective studies. 6 An exception to the general recommendation for attempted resection is the case of deep-seated tumors such as pontine gliomas, which are diagnosed on clinical evidence and treated without initial surgery approximately 50% of the time. In most cases, however, diagnosis by biopsy is preferred. Stereotactic biopsy can be used for lesions that are difficult to reach and resect.

Two primary goals of surgery include: 2

1. Establishing a histologic diagnosis.
2. Reducing intracranial pressure by removing as much tumor as is safely possible to preserve neurological function.

However, total elimination of primary malignant intraparenchymal tumors by surgery alone is rarely achievable. Therefore, intraoperative techniques have been developed to reach a balance between removing as much tumor as is practical and the preservation of functional status. For example, craniotomies with stereotactic resections of primary gliomas can be done in cooperative patients while they are awake, with real-time assessment of neurologic function. 7 Resection proceeds until either the magnetic resonance imaging (MRI) signal abnormality being used to monitor the extent of surgery is completely removed or subtle neurologic dysfunction appears (e.g., slight decrease in rapid alternating motor movement or anomia). Likewise, when the tumor is located in or near language centers in the cortex, intraoperative language mapping can be performed by electrode discharge-induced speech arrest while the patient is asked to count or read. 8

As is the case with several other specialized operations 9 10 in which postoperative mortality has been associated with the number of procedures performed, postoperative mortality after surgery for primary brain tumors may be associated with hospital and/or surgeon volume. 11 Using the Nationwide Inpatient Sample hospital discharge database for the years 1988 to 2000, which represented 20% of inpatient admissions to nonfederal U.S. hospitals, investigators found that large-volume hospitals had lower in-hospital mortality rates after craniotomies for primary brain tumors (odds ratio [OR] = 0.75 for a ten-fold higher caseload; 95% confidence interval [CI], 0.620.90) and after needle biopsies (OR = 0.54; 95% CI, 0.350.83). For example, although there was no specific sharp threshold in mortality outcomes between low-volume hospitals and high-volume hospitals, craniotomy-associated in-hospital mortality was 4.5% for hospitals with five or fewer procedures per year and 1.5% for hospitals with at least 42 procedures per year. In-hospital mortality rates decreased over the study years (perhaps because the proportion of elective nonemergent operations increased from 45% to 57%), but the decrease was more rapid in high-volume hospitals than in low-volume hospitals. High-volume surgeons also had lower patient in-hospital mortality rates after craniotomy (OR= 0.60; 95% CI, 0.450.79). 11 As with any study of volume-outcome associations, these results may not be causal because they may be affected by residual confounding factors, such as referral patterns, private insurance, and patient selection, despite multivariable adjustment.

Radiation Therapy

High-grade tumors

Radiation therapy has a major role in the treatment of patients with high-grade gliomas. A systematic review and meta-analysis of five randomized trials (plus one trial with allocation by birth date) comparing postoperative radiation therapy (PORT) with no radiation therapy showed a statistically significant survival advantage with radiation (risk ratio = 0.81; 95% CI, 0.740.88). 12[Level of evidence: 1iiA] Based on a randomized trial comparing 60 Gy (in 30 fractions over 6 weeks) to 45 Gy (in 25 fractions over 4 weeks) that showed superior survival in the first group (12 months vs. 9 months median survival; hazard ratio [HR] = 0.81; 95% CI, 0.660.99), 60 Gy is the accepted standard dose of EBRT for malignant gliomas. 13[Level of evidence: 1iiA]

As with surgical resection, attempts have been made to preserve normal brain function using techniques intended to deliver a full therapeutic dose of radiation to the tumor and a small surrounding margin, while minimizing dose to most of the brain (e.g., 3dimensional conformal radiation or intensity-modulated radiation therapy [IMRT] and radiosurgery). However, it is not clear that these techniques affect overall survival (OS) compared to standard EBRT. 14 There are no randomized trials directly comparing the effects of these techniques as primary PORT on survival.

A randomized trial tested radiosurgery as a boost added to standard EBRT, but the trial found no improvement in survival, quality of life, or patterns of relapse compared to EBRT without the boost. 14 Based upon a similar rationale, the use of single-fraction stereotactic radiosurgery has disseminated into common practice. High doses of radiation are delivered to the tumor bed with a small margin of nonclinically involved brain. Again, there are no randomized trials that test this concept in comparison to standard radiation. 14

For the same theoretical reasons, brachytherapy has been used to deliver high doses of radiation locally to the tumor while sparing normal brain tissue. However, this approach is technically demanding and has fallen out of favor with the advent of the above-mentioned techniques.

Low-grade tumors

The role of immediate PORT for low-grade gliomas (i.e., low-grade astrocytoma, oligodendroglioma, mixed oligoastrocytomas) is not as clear as in the case of high-grade tumors. The European Organisation for Research and Treatment of Cancer (EORTC) randomly assigned 311 patients with low-grade gliomas to radiation versus observation in the EORTC-22845 and MRC BR04 trial. 15 16 (On central pathology review, about 25% of the patients on the trial were felt to actually have high-grade tumors.) Most of the control patients received radiation at the time of progression. After a median follow-up of 93 months, median progression-free survival was 5.3 years in the radiation arm versus 3.4 years in the control arm (HR = 0.59; 95% CI, 0.450.77). 15 16[Level of evidence: 1iiDiii] However, there was no difference in the OS rate (median survival = 7.4 years vs. 7.2 years; HR = 0.97; 95% CI, 0.711.34; P = .87). 15 16[Level of evidence: 1iiA] This was caused by a longer survival after progression in the control arm (3.4 years) than in the radiation arm (1.0 years) (P < .0001). The investigators did not collect reliable quality-of-life measurements, so it is not clear whether the delay in initial relapse in the radiation therapy arm translated into improved function or quality of life.

Repeat radiation therapy (re-irradiation)

Because there are no randomized trials, the role of repeat radiation after disease progression or the development of radiation-induced cancers is also ill defined. The literature is limited to small retrospective case series, which makes interpretation difficult. 17 The decision to use repeat radiation must be made carefully because of the risk of neurocognitive deficits and radiation-induced necrosis. One advantage of radiosurgery is the ability to deliver therapeutic doses to recurrences that may require the reirradiation of previously irradiated brain tissue beyond tolerable dose limits.

Chemotherapy

Systemic chemotherapy

For many years, the nitrosourea carmustine (BCNU) was the standard chemotherapy added to surgery and radiation for malignant gliomas. This was based upon a randomized trial (RTOG-8302) of 467 patients conducted by the Brain Tumor Study Group that compared four regimens after initial resection: 18

1. Semustine (methyl-CCNU).
2. Radiation therapy.
3. Radiation therapy plus carmustine.
4. Radiation therapy plus semustine.

The radiation therapy plus carmustine arm had the best survival rate. 18[Level of evidence: 1iiA] A modest impact on survival using nitrosourea-containing chemotherapy regimens for malignant gliomas was confirmed in a patient-level meta-analysis of 12 randomized trials (combined HR death = 0.85; 95% CI, 0.780.91). 19

However, the oral agent, temozolomide, has since replaced the nitrosoureas as the standard systemic chemotherapy for malignant gliomas based upon a large multicenter trial (NCT00006353) of glioblastoma patients conducted by the EORTC-National Cancer Institute of Canada (NCIC) that showed a survival advantage. 20 21[Level of evidence: 1iiA] In that study, 573 patients with glioblastoma were randomly assigned to receive standard radiation to the tumor volume with a 23 cm margin (60 Gy, 2 Gy per fraction, over 6 weeks) alone or with temozolomide (75 mg/m² orally per day during radiation therapy for up to 49 days, followed by a 4-week break, and then up to six cycles of five daily doses every 28 days at a dose of 150 mg/m² increasing to 200 mg/m² after the first cycle). Patients in the combined therapy group were given prophylactic therapy for Pneumocystis carinii during the period of concomitant radiation therapy and temozolomide. OS was statistically significantly better in the combined radiation therapy/temozolomide group (HR for death = 0.6; 95% CI, 0.50.7; survival at 3 years was 16.0% vs. 4.4%).

Localized chemotherapy

Because malignant glioma-related deaths are nearly always the result of an inability to control intracranial disease (rather than the result of distant metastases), the concept of delivering high doses of chemotherapy while avoiding systemic toxicity is attractive. A biodegradable carmustine wafer has been developed for that purpose. The wafers contain 3.85% carmustine, and up to eight wafers are implanted into the tumor bed lining at the time of open resection, with an intended total dose of about 7.7 mg per wafer (61.6 mg maximum per patient) over a period of 2 to 3 weeks. There have been two randomized placebo-controlled trials of this focal drug delivery method, both showing an OS advantage associated with the carmustine wafers. Both trials had an upper age limit of 65 years. The first was a small trial closed after 32 patients with high-grade gliomas had been entered because of a lack of continued availability of the carmustine wafers. 22 Although OS was better in the carmustine-wafer group (median 58.1 vs. 39.9 weeks; P = .012), there was an imbalance in the study arms (only 11 of the16 patients in the carmustine-wafer group vs. 16 of the 16 patients in the placebo-wafer group had Grade IV glioblastoma tumors).

The second study was, therefore, more informative. 23 24 It was a multicenter study of 240 patients with primary malignant gliomas, 207 of whom had glioblastoma. At initial surgery, they received the carmustine versus placebo wafers, followed by radiation therapy (55 Gy60 Gy). Systemic therapy was not allowed until recurrence, except in the case of anaplastic oligodendrogliomas, of which there were nine patients. Unlike the initial trial, patient characteristics were well balanced between the study arms. Median survival in the two groups was 13.8 months versus 11.6 months; P = .017 (HR = 0.73; 95% CI, 0.560.96). A systematic review combining both studies estimated a HR for overall mortality of 0.65; 95% CI, 0.480.86; P = .003. 25[Level of evidence: 1iA]

Treatment Options Under Clinical Evaluation

Patients who have brain tumors that are either infrequently curable or unresectable should be considered candidates for clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Heavy-particle radiation, such as proton-beam therapy, carries the theoretical advantage of delivering high doses of ionizing radiation to the tumor bed while sparing surrounding brain tissue. The data are preliminary for this investigational technique, and it is not widely available.

Novel biologic therapies under clinical evaluation for patients with brain tumors include the following: 26

• Dendritic cell vaccination. 27
• Tyrosine kinase receptor inhibitors. 28
• Farnesyl transferase inhibitors.
• Viral-based gene therapy. 29 30
• Oncolytic viruses.
• Epidermal growth factor-receptor inhibitors.
• Vascular endothelial growth factor inhibitors. 26
• Other antiangiogenesis agents.

Primary Tumors of the Spinal Axis

Surgery and radiation therapy are the primary modalities used to treat tumors of the spinal axis; therapeutic options vary according to the histology of the tumor. 2 The experience with chemotherapy for primary spinal cord tumors is limited; no reports of controlled clinical trials are available for these types of tumors. 2 31 Chemotherapy is indicated for most patients with leptomeningeal involvement (from a primary or metastatic tumor) and positive cerebrospinal fluid cytology. 2 Most patients require treatment with corticosteroids, particularly if they are receiving radiation therapy.

Patients who have spinal axis tumors that are either infrequently curable or unresectable should be considered candidates for clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Metastatic Brain Tumors

Approximately 20% to 40% of cancer patients develop brain metastases, with a subsequent median survival generally less than 6 months. Common primary tumors with brain metastases include the following cancers:

• Lung.
• Breast.
• Cancer of unknown primary.
• Melanoma.
• Colon.
• Kidney.

The optimal therapy for patients with brain metastases continues to evolve. 31 32 33 Corticosteroids, anticonvulsants, radiation therapy, radiosurgery, and, possibly, surgical resection have roles in management. Because most cases of brain metastases involve multiple metastases, a mainstay of therapy has historically been whole-brain radiation therapy (WBRT), but stereotactic radiosurgery has come into increasingly common use. The role of radiosurgery continues to be defined. Chemotherapy is usually not the primary therapy for most patients; however, it may have a role in the treatment of patients with brain metastases from chemosensitive tumors and can even be curative when combined with radiation for metastatic testicular germ cell tumors. 32 34 Intrathecal chemotherapy is also used for meningeal spread of metastatic tumors.

Treatment for patients with a single metastasis

About 10% to 15% of patients with cancer will have a single brain metastasis. Radiation therapy is the mainstay of palliation for these patients. The extent of extracranial disease can influence treatment of the brain lesions. In the presence of extensive active systemic disease, surgery provides little benefit for OS. In patients with stable minimal extracranial disease, combined modality treatment may be considered, using surgical resection followed by radiation therapy. However, the published literature does not provide clear guidance. There have been three randomized trials of resection of solitary brain metastases followed by WBRT versus WBRT alone, totaling 195 randomly assigned patients. 35 36 37 The process that necessarily goes into selecting appropriate patients for surgical resection may account for the small numbers in each trial. In the first trial, performed at a single center, all patients were selected and operated upon by one surgeon. The first two trials showed an improvement in survival in the surgery group, but the third showed a trend in favor of the WBRT-only group. The three trials were combined in a trial-level meta-analysis. 25 The combined analysis did not show a statistically significant difference in OS (HR = 0.72; 95% CI, 0.341.53; P = .4); nor was there a statistically significant difference in death from neurologic causes (relative risk of death = 0.68; 95% CI, 0.431.09; P = .11). None of the trials assessed or reported quality of life. One of the trials reported that combined therapy increased the duration of functionally independent survival. 35[Level of evidence: 1iiD]

The need for WBRT after resection of solitary brain metastases has been tested. 38 Patients in the WBRT group were less likely to have tumor progression in the brain and were significantly less likely to die of neurological causes, but OS was the same, and there was no difference in duration of functional independence. 38 One additional randomized study of observation versus WBRT after either surgery or stereotactic radiosurgery for solitary brain metastases was closed because of slow accrual after 19 patients had been entered, so little can be deduced from the trial. 39 (Refer to the following Treatment for patients with oligometastases (13 or 4 brain metastases) section of this summary for evidence of the role of WBRT after focal treatment, whether surgery or stereotactic radiosurgery, in the setting of one to three or four metastases.)

Treatment for patients with oligometastases (13 or 4 brain metastases)

A Radiation Therapy Oncology Group (RTOG) study (RTOG-9508) randomly assigned 333 patients with one to three metastases with a maximum diameter of 4 cm to WBRT (37.5 Gy over 3 weeks) with or without a stereotactic boost. 40 Patients with active systemic disease requiring therapy were excluded. The primary endpoint was OS with predefined hypotheses in both the full study population and the 186 patients with a solitary metastasis (and no statistical adjustment of P values for the two separate hypotheses). Mean OS in the combined-therapy and WBRT-alone groups was 5.7 months and 6.5 months, respectively (P = .14). In the subgroup with solitary metastases, OS was better in the combined-therapy group (6.5 months vs. 4.9 months; P =.039 in univariate analysis; P = .053 in a multivariable analysis adjusting for baseline prognostic factors); in patients with multiple metastases, survival was 5.8 months in the combined-therapy group versus 6.7 months in the WBRT-only group (P = .98). (The combined-treatment group had a survival advantage of 2½ months in patients with a single metastasis but not in patients with multiple lesions.) Local control was better in the full population with combined therapy. At the 6-month follow-up, Karnofsky performance status (considered a soft endpoint because of its imprecision and subjectivity) was better in the combined-therapy group, but there was no difference in mental status between the treatment groups. Acute and late toxicities were similar in both treatment arms. Quality of life was not assessed. 40[Levels of evidence: 1