Incidence and Mortality
Brain tumors account for 85% to 90% of all primary central nervous system (CNS) tumors. Estimated new cases and deaths from brain tumors and other nervous system tumors in the United States in 2021:
Data from the Surveillance, Epidemiology, and End Results (SEER) database for 2013 to 2017 indicated that the combined incidence of brain and other CNS tumors in the United States was 6.4 per 100,000 persons per year. Data for 2014 to 2018 indicated an estimated mortality rate of 4.4 deaths per 100,000 persons per year. Worldwide, approximately 308,102 new cases of brain and other CNS tumors were diagnosed in the year 2020, with an estimated 251,329 deaths.
In general, the incidence of primary CNS tumors is higher in White individuals than in Black individuals, and mortality is higher in males than in females.
Primary brain tumors include the following in decreasing order of frequency:
Primary spinal tumors include the following in decreasing order of frequency:
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.
Anatomy of the inside of the brain. The supratentorium contains the cerebrum, ventricles (with cerebrospinal fluid shown in blue), choroid plexus, hypothalamus, pineal gland, pituitary gland, and optic nerve. The infratentorium contains the cerebellum and brain stem.
Few definitive observations have been made about environmental or occupational causes of primary CNS tumors.
The following potential risk factors have been considered:
The clinical presentation of various brain tumors is best appreciated by considering the relationship of signs and symptoms to anatomy.
General signs and symptoms include the following:
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.
All brain tumors, whether primary, metastatic, malignant, or benign, must be differentiated from other space-occupying lesions that can have similar clinical presentations, such as abscesses, arteriovenous malformations, and infarctions.
In posttherapy imaging, single-photon emission computed tomography (SPECT) and positron emission tomography (PET) may be useful in differentiating tumor recurrence from radiation necrosis.
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. Cases in which the clinical and radiologic picture clearly point to a benign tumor, which could potentially be managed with active surveillance without biopsy or treatment, are the exception. For other cases, 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 almost all locations in the brain.
Several genetic alterations have emerged in recent years as powerful prognostic factors in diffuse glioma (astrocytoma, oligodendroglioma, mixed glioma, and glioblastoma), and these alterations may guide patient management. Specific alterations include the following:
In an exploratory analysis of 318 patients with low-grade glioma treated with either radiation therapy alone or temozolomide chemotherapy alone, a combination of these prognostic factors demonstrated the following:
(Refer to the Treatment of Primary Central Nervous System Tumors by Tumor Type section of this summary for more information.)
Refer to the following PDQ summaries for more information:
This classification is based on the World Health Organization (WHO) classification of central nervous system (CNS) tumors. 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 for the following reasons:
The WHO grading of CNS tumors establishes a malignancy scale based on histologic features of the tumor. The histologic grades are as follows:
Table 1 lists the tumor types and grades. Tumors limited to the peripheral nervous system are not included. Histopathology, grading methods, incidence, and what is known about etiology specific to each tumor type have been described in detail elsewhere.[4,5]
|a Reprinted with permission from Louis, DN, Ohgaki H, Wiestler, OD, Cavenee, WK.World Health Organization Classification of Tumours of the Central Nervous System. IARC, Lyon, 2007.|
|Subependymal giant cell astrocytoma||X|
|Giant cell glioblastoma||X|
|Choroid plexus tumors|
|Choroid plexus papilloma||X|
|Atypical choroid plexus papilloma||X|
|Choroid plexus carcinoma||X|
|Other neuroepithelial tumors|
|Chordoid glioma of the third ventricle||X|
|Neuronal and mixed neuronal-glial tumors|
|Desmoplastic infantile astrocytoma and ganglioglioma||X|
|Dysembryoplastic neuroepithelial tumor||X|
|Paraganglioma of the spinal cord||X|
|Papillary glioneuronal tumor||X|
|Rosette-forming glioneural tumor of the fourth ventricle||X|
|Pineal parenchymal tumor of intermediate differentiation||X||X|
|Papillary tumor of the pineal region||X||X|
|CNS primitive neuroectodermal tumor||X|
|Atypical teratoid/rhabdoid tumor||X|
|Tumors of the cranial and paraspinal nerves|
|Malignant peripheral nerve sheath tumor||X||X||X|
|Tumors of the sellar region|
|Granular cell tumor of the neurohypophysis||X|
|Spindle cell oncocytoma of the adenohypophysis||X|
Alterations in the BRAF, IDH1, and IDH2 genes, and genomic 1p/19q codeletion, appear to be hallmark aberrations in particular glioma subtypes. Assessment for the presence of these mutations aids diagnosis and prognosis and, with regard to 1p/19q codeletion, predicts for response to chemotherapy.
In pilocytic astrocytomas (WHO grade I), tandem duplication at 7q34 leading to a fusion between KIAA1549 and BRAF is found in approximately 70% of pilocytic astrocytomas.[6,7,8] An activating point mutation in BRAF (V600E) is found in an additional 5% to 9% of these tumors and in general, RAF alterations occur in approximately 80% of pilocytic astrocytomas.
BRAF V600E mutations are observed (in about 60%) of other benign glioma variants, including pleomorphic xanthoastrocytoma and ganglioglioma, while BRAF tandem duplications are not found in these variant glioma tumors.[9,10,11]
The majority of WHO grade II and III diffuse gliomas (astrocytomas, oligodendrogliomas, and oligoastrocytomas) and 5% to 10% of glioblastomas (WHO grade IV) harbor point mutations in the R132 position of IDH1 or, rarely, the analogous codon in IDH2 (R172).[12,13,14,15,16] The presence of an IDH1 or IDH2 mutation is a strong prognostic factor. Patients with these mutant tumors have significantly longer survival independent of WHO grade or histologic subtype.
Deletion of chromosomes 1p and 19q occurs through a translocation event  and is common in oligodendrogliomas. 1p/19q codeletion is a powerful prognostic factor and may predict for response to chemotherapy. (Refer to the Anaplastic oligodendrogliomas treatment section of this summary for more information.)
These genetic alterations have potential diagnostic utility. Presence of the IDH1 and IDH2 mutations may distinguish diffuse gliomas from other glioma variants, which often have BRAF genetic alterations, and non-neoplastic reactive astrocytosis. Most (90%) IDH mutations in gliomas result in an R132H substitution, which can be detected with a highly sensitive and specific monoclonal antibody. A rapid immunohistochemical analysis using the mutant-specific IDH1 antibody can aid diagnostic analysis.
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.
Primary CNS Tumors
This section discusses general treatment modalities for primary central nervous system (CNS) tumors. (Refer to the Treatment of Primary Central Nervous System Tumors by Tumor Type section of this summary for a description of specific treatment options for each tumor type.)
Radiation therapy and chemotherapy options vary according to histology and anatomic site of the CNS tumor. For glioblastoma, combined modality therapy with resection, radiation, and chemotherapy is standard. Anaplastic astrocytomas, anaplastic oligodendrogliomas, and anaplastic oligoastrocytomas represent only a small proportion of CNS gliomas; therefore, phase III randomized trials restricted to these tumor types are not generally practical. The natural histories of these tumors are variable, depending on histological and molecular factors; therefore, treatment guidelines are evolving. Therapy involving surgically implanted carmustine-impregnated polymer wafers combined with postoperative external-beam radiation therapy (EBRT) may play a role in the treatment of high-grade (grades III and IV) gliomas in some patients.
Standard treatment options for primary CNS tumors include the following:
For most types of CNS tumors in most locations, complete or near-complete surgical removal is generally attempted, within the constraints of preserving neurologic function and the patient's underlying health. This practice is based on observational evidence that survival is better in patients who undergo tumor resection than in those who have closed biopsy alone.[2,3] 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 resect the tumor; therefore, the actual difference in outcome between radical surgery and biopsy alone may not be as large as noted in the retrospective studies.
An exception to the use of 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.
The primary goals of surgical resection include the following:
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 preserving functional status. For example, craniotomies with stereotactic resections of primary gliomas can be performed in cooperative patients while they are awake, with real-time assessment of neurologic function. Examples of intraoperative neurologic assessment include the following:
As is the case with several other specialized operations [7,8] 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. 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 observed the following:
As with any study of volume-outcome associations, these results may not be causal because of residual confounding factors such as referral patterns, private insurance, and patient selection, despite multivariable adjustment.
Radiation therapy has a major role in the treatment of patients with high-grade gliomas.
Evidence (postoperative radiation therapy [PORT]):
EBRT using either 3-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) is considered an acceptable technique in radiation therapy delivery. Typically used are 2- to 3-cm margins on the MRI-based volumes (T1-weighted and fluid-attenuated inversion recovery [FLAIR]) to create the planning target volume.
Dose escalation using radiosurgery has not improved outcomes. 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 with EBRT without the boost.[12,13]
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 3D-CRT and IMRT.
Treatment options for patients with low-grade gliomas (i.e., low-grade astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas) are not as clear as in the case of high-grade tumors and include observation, PORT, and chemotherapy with temozolomide.
Evidence (PORT vs. observation):
Evidence (PORT versus temozolomide for patients with low-grade World Health Organization (WHO) grade II tumors with at least one high-risk feature):
Disease progression, subsequent neoplasms, or recurrences
There are no randomized trials to delineate the role of repeat radiation after disease progression or the development of radiation-induced cancers. The literature is limited to small retrospective case series, which makes interpretation difficult. The decision to 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 recurrent tumors that may require the re-irradiation of previously irradiated brain tissue beyond tolerable dose limits.
For many years, the nitrosourea carmustine ([bis-chloroethylnitrosourea] BCNU) was the standard chemotherapy agent added to surgery and radiation therapy for malignant gliomas, based on the Radiation Therapy Oncology Group's (RTOG's) randomized trial (RTOG-8302).[Level of evidence: 1iiA] A modest impact on survival with the use of nitrosourea-containing chemotherapy regimens for malignant gliomas was confirmed in a patient-level meta-analysis of 12 randomized trials (combined HRdeath, 0.85; 95% CI, 0.78–0.91).
A large multicenter trial (NCT00006353) of glioblastoma patients conducted by the EORTC-National Cancer Institute of Canada reported a survival advantage with the use of temozolomide in addition to radiation therapy.[21,22][Level of evidence: 1iiA] On the basis of these results, the oral agent temozolomide has replaced BCNU as the standard systemic chemotherapy for malignant gliomas. (Refer to the Glioblastomas treatment section of this summary for more information.)
Long-term results of randomized trials in high-risk, low-grade (WHO grade II) gliomas [Level of evidence: 1iiA] and anaplastic (WHO grade III) oligodendroglial tumors [24,25][Level of evidence: 1iiA] have demonstrated that the addition of procarbazine, lomustine, and vincristine (PCV) chemotherapy to radiation therapy after surgery extends survival. Radiation and PCV chemotherapy should be considered for patients deemed appropriate for therapy. (Refer to the Treatment of Primary Central Nervous System Tumors by Tumor Type section of this summary for more information.)
Localized chemotherapy (carmustine wafer)
The concept of delivering high doses of chemotherapy while avoiding systemic toxicity is attractive because malignant glioma–related deaths are nearly always the result of an inability to control intracranial disease rather than the result of distant metastases. 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.
Two randomized, placebo-controlled trials of this focal drug-delivery method have shown an OS advantage associated with the carmustine wafers versus radiation therapy alone. In both trials, the upper age limit for patients was 65 years.
Evidence (carmustine wafer):
Active surveillance is appropriate in some circumstances. With the increasing use of sensitive neuroimaging tools, detection of asymptomatic low-grade meningiomas has increased; most 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.[30,31]
Dexamethasone, mannitol, and furosemide are used to treat the peritumoral edema associated with brain tumors. The use of anticonvulsants is mandatory for patients with seizures.
|Tumor Type||Standard Treatment Options|
|—Brain stem gliomas||Radiation therapy|
|—Pineal astrocytic tumors||Surgery plus radiation therapy|
|Surgery plus radiation therapy and chemotherapy for higher-grade tumors|
|—Pilocytic astrocytomas||Surgery alone|
|Surgery followed by radiation therapy|
|—Diffuse astrocytomas (WHO grade II)||Surgery with or without radiation therapy|
|Surgery followed by radiation therapy and chemotherapy|
|—Anaplastic astrocytomas (WHO grade III)||Surgery plus radiation therapy with or without chemotherapy|
|Surgery plus chemotherapy|
|—Glioblastomas||Surgery plus radiation therapy and chemotherapy|
|Surgery plus radiation therapy|
|Carmustine-impregnated polymer implant|
|Radiation therapy and concurrent chemotherapy|
|—Oligodendrogliomas||Surgery with or without radiation therapy|
|Surgery with radiation therapy and chemotherapy|
|—Anaplastic oligodendrogliomas||Surgery plus radiation therapy with or without chemotherapy|
|Mixed gliomas||Surgery plus radiation therapy with or without chemotherapy|
|—Grades I and II ependymal tumors||Surgery alone|
|Surgery followed by radiation therapy|
|—Anaplastic ependymoma||Surgery plus radiation therapy|
|Embryonal cell tumors|
|—Medulloblastomas||Surgery plus craniospinal radiation therapy|
|Pineal parenchymal tumors||Surgery plus radiation therapy(for pineocytoma)|
|Surgery plus radiation therapy and chemotherapy(for pineoblastoma)|
|—Grade I meningiomas||Active surveillance with deferred treatment|
|Surgery plus radiation therapy|
|Fractionated radiation therapy|
|—Grades II and III meningiomas and hemangiopericytomas||Surgery plus radiation therapy|
|Germ cell tumors||Depends on multiple factors|
|Tumors of the sellar region|
|Debulking surgery plus radiation therapy|
Astrocytic Tumors Treatment
Brain stem gliomas treatment
Patients with 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.
Standard treatment options for brain stem gliomas include the following:
Pineal astrocytic tumors treatment
Depending on the degree of anaplasia, patients with pineal astrocytomas have variable prognoses. Patients with higher-grade tumors have worse prognoses.
Standard treatment options for pineal astrocytic tumors include the following:
Pilocytic astrocytomas treatment
This astrocytic tumor is classified as a World Health Organization (WHO) grade I tumor and is often curable.
Standard treatment options for pilocytic astrocytomas include the following:
Diffuse astrocytomas treatment
This WHO grade II astrocytic tumor is less often curable than is a pilocytic astrocytoma.
Standard treatment options for diffuse astrocytomas (WHO grade II) include the following:
Controversy exists about the timing of radiation therapy after surgery. (Refer to Low-grade tumors in the Radiation therapy section of the Treatment Option Overview for Adult Central Nervous System Tumors Treatment section in this summary for more information.)
Some physicians use surgery alone if a patient has clinical factors that are considered low risk, such as age younger than 40 years and the lack of contrast enhancement on a computed tomographic scan.
Evidence (surgery followed by radiation therapy and chemotherapy):
The discovery of the IDH1 and IDH2 mutations in diffuse gliomas has greatly helped to identify patients who are considered high risk. A number of large, retrospective studies has demonstrated that the IDH1 and IDH2 mutations are a powerful independent prognostic factor for improved survival.[5,6,7,8,9] The majority of WHO grade II and III gliomas harbor the IDH1 and IDH2 mutations,[6,10,11] and, therefore, the presence of the IDH1 and IDH2 mutations should be included in the assessment of high risk. Molecular correlative data from the RTOG 98-02 trial, which would be informative about which patients benefited the most from the addition of PCV, have not yet been reported.
Anaplastic astrocytomas treatment
Patients with anaplastic astrocytomas (WHO grade III) have a low cure rate with standard local treatment.
Standard treatment options for anaplastic astrocytomas include the following:
A subset of anaplastic astrocytomas is aggressive; these tumors are frequently managed in the same way as glioblastomas, with surgery and radiation, and often with chemotherapy. However, the optimal treatment for these tumors is not established. Two phase III randomized trials restricted to patients with anaplastic gliomas (NCT00626990 and NCT00887146) are currently enrolling patients, but efficacy data are not available. It is not known whether the improved survival of patients with chemotherapy-treated glioblastoma can be extrapolated to patients with anaplastic astrocytomas.
The IDH1 and IDH2 mutations are present in 50% to 70% of anaplastic astrocytomas and are independently associated with significantly improved survival.[6,9] Assessment of the IDH1 and IDH2 mutation status may guide decisions about treatment options.
Evidence (surgery plus radiation therapy or chemotherapy):
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 website.
For patients with glioblastoma (WHO grade IV), the cure rate is very low with standard local treatment.
Methylation of the promoter of the MGMT DNA repair enzyme gene is an independent prognostic factor for improved survival in newly diagnosed glioblastoma.[13,14]MGMT promoter methylation and concomitant inactivation of the DNA repair enzyme activities may also predict for response to temozolomide chemotherapy. However, the clinical data that MGMT promoter methylation is a predictive marker is less certain. (Refer to Glioblastomas treatment in the Astrocytic Tumors Treatment section of the Treatment of Primary Central Nervous System Tumors by Tumor Type section of this summary for more information about the RTOG-0525 [NCT00304031] trial.)
Standard treatment options for patients with newly diagnosed glioblastoma include the following:
The standard treatment for patients with newly diagnosed glioblastoma is surgery followed by concurrent radiation therapy and daily temozolomide, and then followed by six cycles of temozolomide. The addition of bevacizumab to radiation therapy and temozolomide did not improve OS.
Evidence (surgery plus radiation therapy and chemotherapy):
Evidence (surgery and chemoradiation with or without bevacizumab):
In 2013, final data from two multicenter, phase III, randomized, double-blind, placebo-controlled trials of bevacizumab in patients who had newly diagnosed glioblastoma were reported: RTOG 0825 (NCT00884741) and the Roche-sponsored AVAglio (NCT00943826).[17,18][Level of evidence: 1iA] Bevacizumab did not improve OS in either trial.
There was significant crossover in both trials. Approximately 40% of RTOG 0825 patients and approximately 30% of AVAglio patients received bevacizumab at the first sign of disease progression.
The two trials had contradictory results in health-related quality of life (HRQoL) and neurocognitive outcomes studies. In the mandatory HRQoL studies in the AVAglio trial, bevacizumab-treated patients experienced improved HRQoL, but bevacizumab-treated patients in the elective RTOG 0825 studies showed more decline in patient-reported HRQoL and neurocognitive function. The reasons for these discrepancies are unclear.
On the basis of these results, there is no definite evidence that the addition of bevacizumab to standard therapy is beneficial for all newly diagnosed glioblastoma patients. Certain subgroups may benefit from the addition of bevacizumab, but this is not yet known.
Glioblastoma 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 website.
Oligodendroglial Tumors Treatment
Patients who have oligodendrogliomas (WHO grade II) generally have better prognoses than do patients who have diffuse astrocytomas. In particular, patients who have oligodendrogliomas with 1p/19q codeletion have a much longer survival. Most of the oligodendrogliomas eventually progress.
Standard treatment options for oligodendrogliomas include the following:
Controversy exists concerning the timing of radiation therapy after surgery. A study (EORTC-22845) of 300 patients with low-grade gliomas who had surgery and were randomly assigned to either radiation therapy or watchful waiting, did not show a difference in OS between the two groups.[Level of evidence: 1iiA] (Refer to Low-grade tumors in the Radiation Therapy section of the Treatment Option Overview for Adult Primary CNS Tumors section of this summary for more information.)
For low-grade (WHO grade II) tumors that are considered high risk, radiation therapy followed by six cycles of PCV chemotherapy is a recommended option based on the long-term follow-up results of RTOG-9802, a randomized trial for high-risk, low-grade gliomas.[Level of evidence: 1iiA] (Refer to Diffuse astrocytomas treatment in the Astrocytic Tumors Treatment section of the Treatment of Primary Central Nervous System Tumors by Tumor Type section of this summary for more information.)
Notably, the RTOG-9802 study enrolled patients with a mixed variety of tumors, including astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas; in a retrospective subset analysis, only the oligodendroglial tumors appeared to benefit from the addition of PCV. (Refer to Diffuse astrocytomas treatment in the Astrocytic Tumors Treatment section of the Treatment of Primary Central Nervous System Tumors by Tumor Type section of this summary for more information.)
The discovery of the IDH1 and IDH2 mutations, which are independent prognostic factors for significantly improved survival in diffuse gliomas, has greatly helped to identify patients who are considered high risk. (Refer to Diffuse astrocytomas treatment in the Astrocytic Tumors Treatment section of the Treatment of Primary Central Nervous System Tumors by Tumor Type section of this summary for more information.) In addition, a high proportion of WHO grade II oligodendrogliomas have 1p/19q codeletion, which is a powerful prognostic factor for improved survival.[19,20,21] Therefore, the presence of the IDH1 and IDH2 mutations and 1p/19q codeletion should be included in the assessment of high-risk patients. Molecular correlative data from the RTOG-9802 trial, which would be informative about which patients benefited most from the addition of PCV, have not yet been reported.
Anaplastic oligodendrogliomas treatment
Patients with anaplastic oligodendrogliomas (WHO grade III) have a low cure rate with standard local treatment, but their prognoses are generally better than are the prognoses of patients with anaplastic astrocytomas. Prognoses are particularly better for patients with 1p/19q codeletion, which occurs in a majority of these tumors. Two phase III randomized trials restricted to patients with anaplastic gliomas (NCT00626990 and NCT00887146) are currently enrolling patients; however, efficacy data are not yet available. (Refer to Anaplastic astrocytomas treatment in the Astrocytic Tumors Treatment section of the Treatment of Primary Central Nervous System Tumors by Tumor Type section of this summary for more information.) 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 website.
Standard treatment options for anaplastic oligodendrogliomas include the following:
Evidence (surgery followed by radiation therapy with or without chemotherapy):
On the basis of these data, CODEL (NCT00887146), a study that randomly assigned patients to receive radiation therapy alone (control arm), radiation therapy with temozolomide, and temozolomide alone (exploratory arm), was halted because radiation therapy alone was no longer considered adequate treatment in patients with anaplastic oligodendroglioma with 1p/19q-codeletions. Temozolomide and PCV chemotherapy in anaplastic oligodendroglioma have not been compared, although in the setting of grade 3 anaplastic gliomas, no survival difference was seen between PCV chemotherapy and temozolomide.[12,26]
The combination of radiation and chemotherapy is not known to be superior in outcome to sequential modality therapy.
A high proportion of anaplastic oligodendrogliomas have the IDH1 andIDH2 mutations and 1p/19q codeletion, both powerful prognostic factors for improved survival. (Refer to Diffuse astrocytomas treatment in the Astrocytic Tumors Treatment section of the Treatment of Primary Central Nervous System Tumors by Tumor Type of this summary for more information.)[23,24] In addition, PCV chemotherapy has been shown to be predictive in a retrospective analysis of the phase III trials described earlier. Therefore, assessment of these molecular markers may aid management decisions for anaplastic oligodendrogliomas.
Mixed Gliomas Treatment
Patients with mixed glial tumors, which include oligoastrocytoma (WHO grade II) and anaplastic oligoastrocytoma (WHO grade III), have highly variable prognoses based upon their status of the IDH1 and IDH2 genes and 1p/19q chromosomes.[27,28,29] Therefore, the optimal treatment for these tumors as a group is uncertain. Often, they are treated similarly to astrocytic tumors because a subset of tumors may have outcomes similar to WHO grade III astrocytic or WHO grade IV glioblastoma tumors. Testing for these known, strong, prognostic molecular markers should be performed, which may help to guide the assessment of risk and subsequent management.
Standard treatment options for mixed gliomas include the following:
(Refer to the Astrocytic Tumors Treatment section in the Treatment of Primary Central Nervous System Tumors by Tumor Type section of this summary for more information about astrocytic tumors.)
Ependymal Tumors Treatment
Ependymal tumors (WHO grade I) and ependymomas (WHO grade II)—i.e., subependymomas and myxopapillary ependymomas—are often curable.
Standard treatment options for grades I and II ependymal tumors include the following:
Patients with anaplastic ependymomas (WHO grade III) have variable prognoses that depend on the location and extent of disease. Frequently, but not invariably, patients with anaplastic ependymomas have worse prognoses than do those patients with lower-grade ependymal tumors.
Standard treatment options for anaplastic ependymomas include the following:
Embryonal Cell Tumors (Medulloblastomas) Treatment
Medulloblastoma occurs primarily in children, but may also occur in adults. (Refer to the PDQ summary on Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment for more information.)
Standard treatment options for medulloblastomas include the following:
Treatment options under clinical evaluation for medulloblastomas
Treatment options under clinical evaluation include the following:
Pineal Parenchymal Tumors Treatment
Pineocytomas (WHO grade II), pineoblastomas (WHO grade IV), and pineal parenchymal tumors of intermediate differentiation are diverse tumors that require special consideration. Pineocytomas are slow-growing tumors and prognosis varies.
Pineoblastomas grow more rapidly and patients with these tumors have worse prognoses. Pineal parenchymal tumors of intermediate differentiation have unpredictable growth and clinical behavior.
Standard treatment options for pineal parenchymal tumors include the following:
Meningeal Tumors Treatment
WHO grade I meningiomas are usually curable when they are resectable. With the increasing use of sensitive neuroimaging tools, there has been more detection of asymptomatic low-grade meningiomas. Most appear to show minimal growth and can often be safely observed while therapy is deferred until growth or the development of symptoms.[33,34]
Standard treatment options for meningeal tumors include the following:
The prognoses for patients with WHO grade II meningiomas (atypical, clear cell, and chordoid), WHO grade III meningiomas (anaplastic/malignant, rhabdoid, and papillary), and hemangiopericytomas are worse than the prognoses for patients with low-grade meningiomas because complete resections are less commonly feasible, and the proliferative capacity is greater.
Standard treatment options for grades II and III meningiomas and hemangiopericytomas include the following:
Germ Cell Tumors Treatment
The prognoses and treatment of patients with germ cell tumors—which include germinomas, embryonal carcinomas, choriocarcinomas, and teratomas—depend on tumor histology, tumor location, presence and amount of biological markers, and surgical resectability.
Treatment of Tumors of the Sellar Region
Craniopharyngiomas (WHO grade I) are often curable.
Standard treatment options for craniopharyngiomas include the following:
Treatment Options Under Clinical Evaluation for Primary CNS Tumors
Patients who have CNS 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 website.
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 are not widely available.
Novel biologic therapies under clinical evaluation for patients with CNS tumors include the following:
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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. The experience with chemotherapy for primary spinal cord tumors is limited; no reports of controlled clinical trials are available for these types of tumors.[1,2] Chemotherapy is indicated for most patients with leptomeningeal involvement from a primary or metastatic tumor and positive cerebrospinal fluid cytology. 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 website.
General Information About Metastatic Brain Tumors
Brain metastases outnumber primary neoplasms by at least 10 to 1, and they occur in 20% to 40% of cancer patients, with subsequent median survival generally less than 6 months. The exact incidence is unknown because no national cancer registry documents brain metastases, but it has been estimated that 98,000 to 170,000 new cases are diagnosed in the United States each year.[2,3] This number may be increasing because of the capacity of magnetic resonance imaging (MRI) to detect small metastases and because of prolonged survival resulting from improved systemic therapy.[1,2]
Eighty percent of brain metastases occur in the cerebral hemispheres, 15% occur in the cerebellum, and 5% occur in the brain stem. Metastases to the brain are multiple in more than 70% of cases, but solitary metastases also occur.
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 brain metastases.
The diagnosis of brain metastases in cancer patients is based on the following:
Patients may describe any of the following:
Often, family members or friends may notice the following:
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.
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.
Computed tomography scans with contrast or MRIs with gadolinium are quite sensitive in diagnosing the presence of metastases. Positron emission tomography scanning and spectroscopic evaluation are new strategies to diagnose cerebral metastases and to differentiate the metastases from other intracranial lesions.
In the case of a solitary lesion or a questionable relationship to the primary tumor, a brain biopsy (via resection or stereotactic biopsy) may be necessary.
Treatment of Metastatic Brain Tumors
Because most cases of brain metastases involve multiple metastases, a mainstay of therapy has historically been whole-brain radiation therapy (WBRT); however, stereotactic radiosurgery has come into increasingly common use. The role of radiosurgery continues to be defined. Stereotactic radiosurgery in combination with WBRT has been assessed.
Surgery is indicated to obtain tissue from a metastasis with an unknown primary tumor or to decompress a symptomatic dominant lesion that is causing significant mass effect.
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.[1,6] Intrathecal chemotherapy is also used for meningeal spread of metastatic tumors.
Treatment for patients with one to four metastases
Standard treatment options for patients with one to four metastases
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 overall survival (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.
Standard treatment options for patients with one to four metastases include the following:
Evidence (treatment for one to four metastases):
A study that had a primary endpoint of learning and neurocognition, using a standardized test for total recall, was stopped by the Data and Safety Monitoring Board because of worse outcomes in the WBRT group.[Level of evidence: 1iiD]
Given this body of information, focal therapy plus WBRT or focal therapy alone, with close follow-up with serial MRIs 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.
Several randomized trials have been performed that were designed with varying primary endpoints to address whether WBRT is necessary after focal treatment. The results can be summarized as follows:[16,17,18]
Leptomeningeal Carcinomatosis (LC)
LC occurs in about 5% of all cancer patients. The most common types of cancer to spread to the leptomeninges are:
Diagnosis includes a combination of neurospinal axis imaging and cerebrospinal fluid (CSF) cytology. Median OS is in the range of 10 to 12 weeks.
The management of LC includes the following:
In a series of 149 patients with metastatic non-small cell lung carcinoma, cytologically proven LC, poor performance status, high protein level in the CSF, and a high initial CSF white blood cell count were significant poor prognostic factors for survival. Patients received active treatment, including intrathecal chemotherapy, WBRT, or epidermal growth factor receptor-thymidine kinase-1, or underwent a ventriculoperitoneal shunt procedure.
In a retrospective series of 38 patients with metastatic breast cancer and LC, the proportion of LC cases varied by breast cancer subtype:
Patients with triple-negative breast cancer had a shorter interval between metastatic breast cancer diagnosis and the development of LC. Median survival did not differ across breast cancer subtypes. Consideration of intrathecal administration of trastuzumab in patients with HER2-positive LC has also been described in case reports.
Patients who have recurrent CNS tumors are rarely curable and should be considered candidates for clinical trials. Information about ongoing clinical trials is available from the NCI website.
Standard treatment options for recurrent CNS tumors include the following:
Localized chemotherapy (carmustine wafer)
Carmustine wafers have been investigated for the treatment of recurrent malignant gliomas, but the impact on survival is less clear than at the time of initial diagnosis and resection.
Evidence (localized chemotherapy):
Systemic therapy (e.g., temozolomide, lomustine, or the combination of procarbazine, a nitrosourea, and vincristine (PCV) in patients who have not previously received the drugs) has been used at the time of recurrence of primary malignant brain tumors. However, this approach 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.
In 2009, the U.S. Food and Drug Administration (FDA) granted accelerated approval of bevacizumab monotherapy for patients with progressive glioblastoma. The indication was granted under the FDA's accelerated approval program that permits the use of certain surrogate endpoints or an effect on a clinical endpoint other than survival or irreversible morbidity as bases for approvals of products intended for serious or life-threatening illnesses or conditions.
The approval was based on the demonstration of improved objective response rates observed in two historically controlled, single-arm, or noncomparative phase II trials.[3,4][Level of evidence: 3iiiDiv] On the basis of these data and FDA approval, bevacizumab monotherapy has become standard therapy for recurrent glioblastoma.
Evidence (antiangiogenesis therapy):
Currently, however, no data are available from prospective, randomized controlled trials demonstrating improvement in health outcomes, such as disease-related symptoms or increased survival with the use of bevacizumab to treat glioblastoma.
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. The decision must be made carefully because of the risk of neurocognitive deficits and radiation necrosis.
Re-resection of recurrent CNS tumors is used for some patients. However, most patients do not qualify because of a deteriorating condition or technically inoperable tumors. The evidence is limited to noncontrolled studies and case series of patients who are healthy enough and have tumors that are small enough to technically debulk. The impact on survival of reoperation versus patient selection is not known.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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.
Editorial changes were made to this summary.
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.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult central nervous system 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:
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 Central Nervous System Tumors Treatment is:
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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.
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The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Adult Central Nervous System Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/brain/hp/adult-brain-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389419]
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Last Revised: 2021-06-16
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