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Adult Brain Tumors Treatment (PDQ®): Treatment - Health Professional Information [NCI]

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.

Adult Brain Tumors Treatment

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 2013:[1]

  • New cases: 23,130.
  • Deaths: 14,080.

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 2013. Atlanta, Ga: American Cancer Society, 2013. Available online. Last accessed March 13, 2013.
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.
3. Altekruse SF, Kosary CL, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2007. Bethesda, Md: National Cancer Institute, 2010. Also available online. Last accessed January 10, 2013.
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. Last accessed February 15, 2013.
5. Schabet M: Epidemiology of primary CNS lymphoma. J Neurooncol 43 (3): 199-201, 1999.
6. Behin A, Hoang-Xuan K, Carpentier AF, et al.: Primary brain tumours in adults. Lancet 361 (9354): 323-31, 2003.
7. Kleihues P, Cavenee WK, eds.: Pathology and Genetics of Tumours of the Nervous System. Lyon, France: International Agency for Research on Cancer, 2000.
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.
9. Cloughesy T, Selch MT, Liau L: Brain. In: Haskell CM: Cancer Treatment. 5th ed. Philadelphia, Pa: WB Saunders Co, 2001, pp 1106-42.
10. Ricci PE: Imaging of adult brain tumors. Neuroimaging Clin N Am 9 (4): 651-69, 1999.
11. Buckner JC: Factors influencing survival in high-grade gliomas. Semin Oncol 30 (6 Suppl 19): 10-4, 2003.
12. DeAngelis LM: Brain tumors. N Engl J Med 344 (2): 114-23, 2001.
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.
14. Giordana MT, Ghimenti C, Leonardo E, et al.: Molecular genetic study of a metastatic oligodendroglioma. J Neurooncol 66 (3): 265-71, 2004.
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.
16. Patchell RA: The management of brain metastases. Cancer Treat Rev 29 (6): 533-40, 2003.
17. Schaefer PW, Budzik RF Jr, Gonzalez RG: Imaging of cerebral metastases. Neurosurg Clin N Am 7 (3): 393-423, 1996.

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]

WHO Grades of CNS Tumorsa

I II III IV
a Reprinted with permission from Louis, DN, Ohgaki H, Wiestler, OD, Cavenee, WK.World Health Organization Classification of Tumours of the Nervous System. IARC, Lyon, 2007.
Astrocytic tumors
Subependymal giant cell astrocytoma X      
Pilocytic astrocytoma X      
Pilomyxoid astrocytoma   X    
Diffuse astrocytoma   X    
Pleomorphic xanthoastrocytoma   X    
Anaplastic astrocytoma     X  
Glioblastoma       X
Giant cell glioblastoma       X
Gliosarcoma       X
Oligondendroglial tumors
Oligodendroglioma   X    
Anaplastic oligodendroglioma     X  
Oligoastrocytic tumors
Oligoastrocytoma   X    
Anaplastic oligoastrocytoma     X  
Ependymal tumors
Subependymoma X      
Myxopapillary ependymoma X      
Ependymoma   X    
Anaplastic ependymoma     X  
Choroid plexus tumors
Choroid plexus papilloma X      
Atypical choroid plexus papilloma   X    
Choroid plexus carcinoma     X  
Other neuroepithelial tumors
Angiocentric glioma X      
Chordoid glioma of the third ventricle   X    
Neuronal and mixed neuronal-glial tumors
Gangliocytoma X      
Ganglioglioma X      
Anaplastic ganglioma     X  
Desmoplastic infantile astrocytoma and ganglioglioma X      
Dysembryoplastic neuroepithelial tumor X      
Central neurocytoma   X    
Extraventricular neurocytoma   X    
Cerebellar liponeurocytoma   X    
Paraganglioma of the spinal cord X      
Papillary glioneuronal tumor X      
Rosette-forming glioneural tumor of the fourth ventricle X      
Pineal tumors        
Pineocytoma X      
Pineal parenchymal tumor of intermediate differentiation   X X  
Pineoblastoma       X
Papillary tumor of the pineal region   X X  
Embryonal tumors
Medulloblastoma       X
CNS primitive neuroectodermal tumor (PNET)       X
Atypical teratoid/rhabdoid tumor       X
Tumors of the cranial and paraspinal nerves
Schwannoma X      
Neurofibroma X      
Perineurioma X X X  
Malignant peripheral nerve sheath tumor (MPNST)   X X X
Meningeal tumors
Meningioma X      
Atypical meningioma   X    
Anaplastic/malignant meningioma     X  
Hemangiopericytoma   X    
Anaplastic hemangiopericytoma     X  
Hemangioblastoma X      
Tumors of the sellar region
Craniopharyngioma X      
Granular cell tumor of the neurohypophysis X      
Pituicytoma X      
Spindle cell oncocytoma of the adenohypophysis X      

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.
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.
3. Kleihues P, Burger PC, Scheithauer BW: The new WHO classification of brain tumours. Brain Pathol 3 (3): 255-68, 1993.
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.

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 gliomas—glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma—combined 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], 0.62–0.90) and after needle biopsies (OR = 0.54; 95% CI, 0.35–0.83). 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, 0.45–0.79).[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, 0.74–0.88).[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, 0.66–0.99), 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., 3–dimensional 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, 0.45–0.77).[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, 0.71–1.34; 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, 0.78–0.91).[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 2–3 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, 0.5–0.7; 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 Gy–60 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, 0.56–0.96). A systematic review combining both studies estimated a HR for overall mortality of 0.65; 95% CI, 0.48–0.86; 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, 0.34–1.53; P = .4); nor was there a statistically significant difference in death from neurologic causes (relative risk of death = 0.68; 95% CI, 0.43–1.09; 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 (1–3 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 (1–3 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: 1iiDii for the full study population and 1iiA for patients with solitary metastases]

The converse question has also been addressed—whether WBRT is necessary after focal treatment (i.e., resection or stereotactic radiosurgery) of oligometastases. Several randomized trials have been performed that were designed with varying primary endpoints.[41,42,43] However, the results can be summarized as follows:

1. Studies consistently show that the addition of WBRT to focal therapy decreases the risk of progression and new metastases in the brain.
2. The addition of WBRT does not improve OS.
3. The decrease in risk of intracranial disease progression does not translate into improved functional or neurologic status, nor does it appear to decrease the risk of death from neurologic deterioration.
4. About half or more of patients that receive focal therapy alone ultimately require salvage therapy, such as WBRT or radiosurgery, compared to about a quarter of patients given up-front WBRT.
5. The impact of better local control associated with WBRT on quality of life has not been reported and remains an open question.

The study that had a primary endpoint of learning and neurocognition, using a standardized test for total recall, was stopped by the data-safety monitoring committee because of worse outcomes in the WBRT group.[42]

Given this body of information, focal therapy plus WBRT or focal therapy alone, with follow-up and initiation of salvage therapy when clinically indicated, appear to be reasonable treatment options. The pros and cons of each approach should be discussed with the patient.[42][Level of evidence: 1iiD]

Treatment for patients with multiple metastases

Patients with multiple brain metastases are treated with WBRT. Surgery is generally restricted to obtaining tissue from metastases with an unknown primary tumor. Stereotactic radiosurgery in combination with WBRT has been assessed and is associated with good local control, but median survival was not affected. Survival was determined by the extent of extracranial disease.[44][Level of evidence: 1iiDii]

References:

1. Lallana EC, Abrey LE: Update on the therapeutic approaches to brain tumors. Expert Rev Anticancer Ther 3 (5): 655-70, 2003.
2. Cloughesy T, Selch MT, Liau L: Brain. In: Haskell CM: Cancer Treatment. 5th ed. Philadelphia, Pa: WB Saunders Co, 2001, pp 1106-42.
3. Nakamura M, Roser F, Michel J, et al.: The natural history of incidental meningiomas. Neurosurgery 53 (1): 62-70; discussion 70-1, 2003.
4. Yano S, Kuratsu J; Kumamoto Brain Tumor Research Group.: Indications for surgery in patients with asymptomatic meningiomas based on an extensive experience. J Neurosurg 105 (4): 538-43, 2006.
5. Laws ER, Parney IF, Huang W, et al.: Survival following surgery and prognostic factors for recently diagnosed malignant glioma: data from the Glioma Outcomes Project. J Neurosurg 99 (3): 467-73, 2003.
6. Chang SM, Parney IF, Huang W, et al.: Patterns of care for adults with newly diagnosed malignant glioma. JAMA 293 (5): 557-64, 2005.
7. Meyer FB, Bates LM, Goerss SJ, et al.: Awake craniotomy for aggressive resection of primary gliomas located in eloquent brain. Mayo Clin Proc 76 (7): 677-87, 2001.
8. Sanai N, Mirzadeh Z, Berger MS: Functional outcome after language mapping for glioma resection. N Engl J Med 358 (1): 18-27, 2008.
9. Begg CB, Cramer LD, Hoskins WJ, et al.: Impact of hospital volume on operative mortality for major cancer surgery. JAMA 280 (20): 1747-51, 1998.
10. Birkmeyer JD, Finlayson EV, Birkmeyer CM: Volume standards for high-risk surgical procedures: potential benefits of the Leapfrog initiative. Surgery 130 (3): 415-22, 2001.
11. Barker FG 2nd, Curry WT Jr, Carter BS: Surgery for primary supratentorial brain tumors in the United States, 1988 to 2000: the effect of provider caseload and centralization of care. Neuro Oncol 7 (1): 49-63, 2005.
12. Laperriere N, Zuraw L, Cairncross G, et al.: Radiotherapy for newly diagnosed malignant glioma in adults: a systematic review. Radiother Oncol 64 (3): 259-73, 2002.
13. Bleehen NM, Stenning SP: A Medical Research Council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma. The Medical Research Council Brain Tumour Working Party. Br J Cancer 64 (4): 769-74, 1991.
14. Tsao MN, Mehta MP, Whelan TJ, et al.: The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for malignant glioma. Int J Radiat Oncol Biol Phys 63 (1): 47-55, 2005.
15. Karim AB, Afra D, Cornu P, et al.: Randomized trial on the efficacy of radiotherapy for cerebral low-grade glioma in the adult: European Organization for Research and Treatment of Cancer Study 22845 with the Medical Research Council study BRO4: an interim analysis. Int J Radiat Oncol Biol Phys 52 (2): 316-24, 2002.
16. van den Bent MJ, Afra D, de Witte O, et al.: Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet 366 (9490): 985-90, 2005.
17. Paulino AC, Mai WY, Chintagumpala M, et al.: Radiation-induced malignant gliomas: is there a role for reirradiation? Int J Radiat Oncol Biol Phys 71 (5): 1381-7, 2008.
18. Walker MD, Green SB, Byar DP, et al.: Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 303 (23): 1323-9, 1980.
19. Stewart LA: Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359 (9311): 1011-8, 2002.
20. Stupp R, Mason WP, van den Bent MJ, et al.: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352 (10): 987-96, 2005.
21. Stupp R, Hegi ME, Mason WP, et al.: Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10 (5): 459-66, 2009.
22. Valtonen S, Timonen U, Toivanen P, et al.: Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study. Neurosurgery 41 (1): 44-8; discussion 48-9, 1997.
23. Westphal M, Hilt DC, Bortey E, et al.: A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro-oncol 5 (2): 79-88, 2003.
24. Westphal M, Ram Z, Riddle V, et al.: Gliadel wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial. Acta Neurochir (Wien) 148 (3): 269-75; discussion 275, 2006.
25. Hart MG, Grant R, Garside R, et al.: Chemotherapeutic wafers for high grade glioma. Cochrane Database Syst Rev (3): CD007294, 2008.
26. Fine HA: Promising new therapies for malignant gliomas. Cancer J 13 (6): 349-54, 2007 Nov-Dec.
27. Fecci PE, Mitchell DA, Archer GE, et al.: The history, evolution, and clinical use of dendritic cell-based immunization strategies in the therapy of brain tumors. J Neurooncol 64 (1-2): 161-76, 2003 Aug-Sep.
28. Newton HB: Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 1: Growth factor and Ras signaling pathways. Expert Rev Anticancer Ther 3 (5): 595-614, 2003.
29. Kew Y, Levin VA: Advances in gene therapy and immunotherapy for brain tumors. Curr Opin Neurol 16 (6): 665-70, 2003.
30. Chiocca EA, Aghi M, Fulci G: Viral therapy for glioblastoma. Cancer J 9 (3): 167-79, 2003 May-Jun.
31. 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.
32. Patchell RA: The management of brain metastases. Cancer Treat Rev 29 (6): 533-40, 2003.
33. Soffietti R, Cornu P, Delattre JY, et al.: EFNS Guidelines on diagnosis and treatment of brain metastases: report of an EFNS Task Force. Eur J Neurol 13 (7): 674-81, 2006.
34. Ogawa K, Yoshii Y, Nishimaki T, et al.: Treatment and prognosis of brain metastases from breast cancer. J Neurooncol 86 (2): 231-8, 2008.
35. 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 (8): 494-500, 1990.
36. Vecht CJ, Haaxma-Reiche H, Noordijk EM, et al.: Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol 33 (6): 583-90, 1993.
37. Mintz AH, Kestle J, Rathbone MP, et al.: A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis. Cancer 78 (7): 1470-6, 1996.
38. Patchell RA, Tibbs PA, Regine WF, et al.: Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA 280 (17): 1485-9, 1998.
39. Roos DE, Wirth A, Burmeister BH, et al.: Whole brain irradiation following surgery or radiosurgery for solitary brain metastases: mature results of a prematurely closed randomized Trans-Tasman Radiation Oncology Group trial (TROG 98.05). Radiother Oncol 80 (3): 318-22, 2006.
40. Andrews DW, Scott CB, Sperduto PW, et al.: Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 363 (9422): 1665-72, 2004.
41. Aoyama H, Shirato H, Tago M, et al.: Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 295 (21): 2483-91, 2006.
42. Chang EL, Wefel JS, Hess KR, et al.: Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 10 (11): 1037-44, 2009.
43. Kocher M, Soffietti R, Abacioglu U, et al.: Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol 29 (2): 134-41, 2011.
44. Kondziolka D, Patel A, Lunsford LD, et al.: Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 45 (2): 427-34, 1999.

Management of Specific Tumor Types and Locations

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Brain Stem Gliomas

Standard treatment options:

  • Radiation therapy.

Brain stem gliomas have relatively poor prognoses that correlate with histology (when biopsies are performed), location, and extent of tumor. The overall median survival time of patients in studies has been 44 to 74 weeks.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with adult brain stem glioma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Pineal Astrocytic Tumors

Standard treatment options:

1. Surgery plus radiation therapy for patients with pilocytic or diffuse astrocytoma.
2. Surgery plus radiation therapy and chemotherapy for patients with higher grade tumors.

Depending on the degree of anaplasia, pineal astrocytomas vary in prognoses. Higher grades have worse prognoses.

Pilocytic Astrocytomas

Standard treatment options:

1. Surgery alone if the tumor is totally resectable.
2. Surgery followed by radiation therapy to known or suspected residual tumor.

This astrocytic tumor is classified as a World Health Organization (WHO) grade I tumor and is often curable.

Diffuse Astrocytomas

Standard treatment options:

  • Surgery plus radiation therapy; however, some controversy exists. Some physicians treat these patients with surgery alone if the patient is younger than 35 years and if the tumor does not contrast-enhance on a computed tomographic (CT) scan.[1]

This WHO grade II astrocytic tumor is less often curable than pilocytic astrocytoma.

Anaplastic Astrocytomas

Standard treatment options:

1. Surgery plus radiation therapy.
2. Surgery plus radiation therapy and chemotherapy.

Anaplastic astrocytomas (WHO grade III) have a low cure rate with standard local treatment. Because anaplastic astrocytomas represent less than 10% of all central nervous system gliomas, phase III randomized trials restricted to them are not practical. However, because they are aggressive and often included in studies along with glioblastomas, they are generally managed the same way as glioblastomas, with surgery and radiation, and often with chemotherapy even though it is not known whether the improved survival with chemotherapy in glioblastoma can be extrapolated to anaplastic astrocytomas.

Postoperative radiation alone has been compared to postoperative chemotherapy alone in patients with anaplastic gliomas (i.e., 144 astrocytomas, 91 oligoastrocytomas, and 39 oligodendrogliomas) with crossover to the other modality at the time of tumor progression. One hundred thirty-nine patients were randomly assigned to radiation therapy, and 135 were randomly assigned to chemotherapy with a 32-week course of either procarbazine + lomustine + vincristine (PCV) or single-agent temozolomide (2:1:1 randomization). The order of the modalities did not affect time to treatment failure (TTF) or OS.[2][Levels of evidence: 1iiA and 1iiD] Neither TTF nor OS differed across the treatment arms.

Patients with anaplastic astrocytomas are appropriate candidates for clinical trials designed to improve local control by adding newer forms of treatment to standard treatment. Information about ongoing clinical trials is available from the NCI Web site.

Glioblastomas

Standard treatment options:

1. Surgery plus radiation therapy.
2. Surgery plus radiation therapy and chemotherapy.
3. Carmustine-impregnated polymer implanted during initial surgery.
4. Radiation therapy and concurrent chemotherapy.

For patients with glioblastoma (WHO grade IV), the cure rate is very low with standard local treatment. These patients are appropriate candidates for clinical trials designed to improve local control by adding newer forms of treatment to standard treatment. Information about ongoing clinical trials is available from the NCI Web site.

Oligodendroglial Tumors

Oligodendrogliomas

Standard treatment options:

  • Surgery plus radiation therapy; however, some controversy exists concerning the timing of radiation therapy. A study (EORTC-22845) of 300 patients who had surgery and were randomly assigned to either radiation therapy or watch and wait did not show a difference in OS in the two groups.[3][Level of evidence: 1iiA]

Oligodendrogliomas (WHO grade II) behave like diffuse astrocytomas.

Anaplastic oligodendrogliomas

Standard treatment options:

1. Surgery plus radiation therapy.
2. Surgery plus radiation therapy plus chemotherapy.[4]
3. Patients with an allelic loss at 1p and 19q have a higher than average response rate to PCV chemotherapy.[5][Level of evidence: 3iiiDiv]
4. A recent phase III study compared radiation therapy alone with chemotherapy plus radiation therapy. Progression-free survival was increased but OS was not.[6][Level of evidence: 1iiDiii] This was true in the 1p and 19q allelic deletion group as well. These studies are ongoing.

Anaplastic oligodendrogliomas (WHO grade III) have a low cure rate with standard local treatment, but their prognosis is generally better than that of anaplastic astrocytomas. Since anaplastic oligodendrogliomas are uncommon, phase III randomized trials restricted to them are not practical. They are generally managed with the following:

  • Postoperative radiation therapy (PORT) alone, with chemotherapy at progression.
  • Postoperative chemotherapy with radiation at progression.
  • PORT plus chemotherapy, even though the combination of radiation plus chemotherapy is not known to be superior in outcome to sequential modality therapy.

PORT alone has been compared to postoperative chemotherapy alone in patients with anaplastic gliomas (i.e., 144 astrocytomas, 91 oligoastrocytomas, and 39 oligodendrogliomas) with crossover to the other modality at the time of tumor progression. One hundred thirty-nine patients were randomly assigned to radiation therapy and 135 were randomly assigned to chemotherapy with a 32-week course of either PCV or single-agent temozolomide (2:1:1 randomization). The order of the modalities did not affect TTF or OS.[2][Levels of evidence: 1iiA and 1iiD]. Neither TTF nor OS differed across the treatment arms.

These patients are appropriate candidates for clinical trials designed to improve local control by adding newer forms of treatment. Information about ongoing clinical trials is available from the NCI Web site.

Mixed Gliomas

Standard treatment options:

1. Surgery plus radiation therapy.
2. Surgery plus radiation therapy plus chemotherapy.

Mixed glial tumors, which include oligoastrocytoma (WHO grade II) and anaplastic oligoastrocytoma (WHO grade III), have a prognosis similar to that for astrocytic tumors of corresponding grades and can be treated as such.

Ependymal Tumors

Grade I and II ependymal tumors

Standard treatment options:

1. Surgery alone if the tumor is totally resectable.
2. Surgery followed by radiation therapy to known or suspected residual tumor.

Ependymomas (WHO grade II) and ependymal tumors (WHO grade I), i.e., subependymoma and myxopapillary ependymomas, are often curable.

Anaplastic ependymomas

Standard treatment options:

  • Surgery plus radiation therapy.[7]

Anaplastic ependymomas (WHO grade III) have variable prognoses that depend on the location and extent of disease. Frequently, but not invariably, anaplastic ependymomas have worse prognoses than lower grade ependymal tumors.

Embryonal Cell Tumors: Medulloblastomas

Standard treatment options:

  • Surgery plus craniospinal radiation therapy for good-risk patients.[8]

Treatment options under clinical evaluation:

  • Surgery plus craniospinal radiation therapy and various chemotherapy regimens are being evaluated for poor-risk patients.[8]

Medulloblastoma occurs primarily in children, but it also occurs with some frequency in adults.[9] Other embryonal tumors are pediatric conditions. (Refer to the PDQ summary on Childhood Central Nervous System Embryonal Tumors Treatment for more information.)

Pineal Parenchymal Tumors

Standard treatment options:

1. Surgery plus radiation therapy for pineocytoma.
2. Surgery plus radiation therapy and chemotherapy for pineoblastoma.

Pineocytoma (WHO grade II), pineoblastoma (WHO grade IV), and pineal parenchymal tumors of intermediate differentiation are diverse tumors that require special consideration. Pineocytomas are slow growing and carry variable prognoses for cure. Pineoblastomas are more rapidly growing and have worse prognoses. Pineal parenchymal tumors of intermediate differentiation have unpredictable growth and clinical behavior.

Meningeal Tumors

Grade I meningiomas

Standard treatment options:

1. Active surveillance with deferred treatment, especially for incidentally discovered asymptomatic tumors.[10,11].
2. Surgery.
3. Surgery plus radiation therapy is used in selected cases, such as for patients with known or suspected residual disease or with recurrence after previous surgery.
4. Radiation therapy for patients with unresectable tumors.[12]

WHO grade I meningiomas are usually curable when resectable. With the increasing use of sensitive neuroimaging tools, there has been greater detection of asymptomatic low-grade meningiomas. The majority appear to show minimal growth and can often be safely observed while therapy is deferred until growth or the development of symptoms.[10,11]

Grade II and III meningiomas and hemangiopericytomas

Standard treatment options:

  • Surgery plus radiation therapy.

The prognoses for patients with meningiomas (WHO grade II) (i.e., atypical, clear cell, and chordoid), meningiomas (WHO grade III) (i.e., anaplastic/malignant, rhabdoid, and papillary), and hemangiopericytomas are worse than for patients with low-grade meningiomas because complete resections are less commonly feasible, and the proliferative capacity is greater.

Germ Cell Tumors

The prognosis and treatment of patients with germ cell tumors—which include germinoma, embryonal carcinoma, choriocarcinoma, and teratoma—depend on tumor histology, tumor location, presence and amount of biological markers, and surgical resectability.

Tumors of the Sellar Region: Craniopharyngiomas

Standard treatment options:

1. Surgery alone if the tumor is totally resectable.
2. Debulking surgery plus radiation therapy if the tumor is unresectable.

Craniopharyngioma (WHO grade I) is often curable.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with adult brain tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Kaye AH, Walker DG: Low grade astrocytomas: controversies in management. J Clin Neurosci 7 (6): 475-83, 2000.
2. Wick W, Hartmann C, Engel C, et al.: NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol 27 (35): 5874-80, 2009.
3. van den Bent MJ, Afra D, de Witte O, et al.: Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet 366 (9490): 985-90, 2005.
4. van den Bent MJ, Chinot O, Boogerd W, et al.: Second-line chemotherapy with temozolomide in recurrent oligodendroglioma after PCV (procarbazine, lomustine and vincristine) chemotherapy: EORTC Brain Tumor Group phase II study 26972. Ann Oncol 14 (4): 599-602, 2003.
5. Brandes AA, Tosoni A, Vastola F, et al.: Efficacy and feasibility of standard procarbazine, lomustine, and vincristine chemotherapy in anaplastic oligodendroglioma and oligoastrocytoma recurrent after radiotherapy. A Phase II study. Cancer 101 (9): 2079-85, 2004.
6. van den Bent MJ, Carpentier AF, Brandes AA, et al.: Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol 24 (18): 2715-22, 2006.
7. Oya N, Shibamoto Y, Nagata Y, et al.: Postoperative radiotherapy for intracranial ependymoma: analysis of prognostic factors and patterns of failure. J Neurooncol 56 (1): 87-94, 2002.
8. Brandes AA, Franceschi E, Tosoni A, et al.: Long-term results of a prospective study on the treatment of medulloblastoma in adults. Cancer 110 (9): 2035-41, 2007.
9. Brandes AA, Ermani M, Amista P, et al.: The treatment of adults with medulloblastoma: a prospective study. Int J Radiat Oncol Biol Phys 57 (3): 755-61, 2003.
10. Nakamura M, Roser F, Michel J, et al.: The natural history of incidental meningiomas. Neurosurgery 53 (1): 62-70; discussion 70-1, 2003.
11. Yano S, Kuratsu J; Kumamoto Brain Tumor Research Group.: Indications for surgery in patients with asymptomatic meningiomas based on an extensive experience. J Neurosurg 105 (4): 538-43, 2006.
12. Debus J, Wuendrich M, Pirzkall A, et al.: High efficacy of fractionated stereotactic radiotherapy of large base-of-skull meningiomas: long-term results. J Clin Oncol 19 (15): 3547-53, 2001.

Recurrent Adult Brain Tumors

Surgery

Re-resection of recurrent brain tumors is used in some patients. However, the majority of patients do not qualify because of a deteriorating condition or technically inoperable tumors. The evidence is limited to noncontrolled studies and case series on patients who are healthy enough and have small enough tumors to technically debulk. The impact of reoperation versus patient selection on survival is not known.

Localized Chemotherapy

Carmustine wafers have been investigated in the setting of recurrent malignant gliomas, but the impact on survival is less clear than at the time of initial diagnosis and resection. In a multicenter randomized, placebo-controlled trial, 222 patients with recurrent malignant primary brain tumors requiring reoperation were randomly assigned to receive implanted carmustine wafers or placebo biodegradable wafers.[1] Approximately half of the patients had received prior systemic chemotherapy. The two treatment groups were well balanced at baseline. Median survival was 31 versus 23 weeks in the two groups. The statistical significance between the two OS curves depended upon the method of analysis. The hazard ratio (HR) for risk of dying in the direct intention-to-treat comparison between the two groups was 0.83 (95% CI, 0.63–1.10; P = .19). The baseline characteristics were similar in the two groups, but the investigators did an additional analysis, adjusting for prognostic factors, because they felt that even small differences in baseline characteristics could have a powerful influence on outcomes. In the adjusted proportional hazards model, the HR for risk of death was 0.67 (95% CI, 0.51–0.90, P = .006). The investigators put their emphasis on this latter analysis and reported this as a positive trial.[1][Level of evidence: 1iA] However, a Cochrane Collaboration systematic review of chemotherapeutic wafers for high-grade glioma focused on the unadjusted analysis and reported the same trial as negative.[2]

Systemic Chemotherapy

Systemic therapy (e.g., temozolomide or the combination of procarbazine, a nitrosourea, and vincristine in patients who have not previously received the drugs) has been used at the time of recurrence of primary malignant brain tumors. However, it has not been tested in controlled studies. Patient-selection factors likely play a strong role in determining outcomes, so the impact of therapy on survival is not clear.

Radiation Therapy

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. Interpretation is difficult because the literature is limited to small retrospective case series.[3] The decision must be made carefully because of the risk of neurocognitive deficits and radiation necrosis.

Patients who have recurrent brain tumors are rarely curable and should be considered candidates for clinical trials when they have exhausted standard therapy. Information about ongoing clinical trials is available from the NCI Web site.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent adult brain tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Brem H, Piantadosi S, Burger PC, et al.: Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet 345 (8956): 1008-12, 1995.
2. Hart MG, Grant R, Garside R, et al.: Chemotherapeutic wafers for high grade glioma. Cochrane Database Syst Rev (3): CD007294, 2008.
3. Paulino AC, Mai WY, Chintagumpala M, et al.: Radiation-induced malignant gliomas: is there a role for reirradiation? Int J Radiat Oncol Biol Phys 71 (5): 1381-7, 2008.

Changes to This Summary (02 / 15 / 2013)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information About Adult Brain Tumors

Updated statistics with estimated new cases and deaths for 2013 (cited American Cancer Society as reference 1).

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult brain tumors. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewer for Adult Brain Tumors Treatment is:

  • Minh Tam Truong, MD (Boston University Medical Center)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."

The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Adult Brain Tumors Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/adultbrain/HealthProfessional. Accessed <MM/DD/YYYY>.

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Coping with Cancer: Financial, Insurance, and Legal Information page.

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Last Revised: 2013-02-15

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