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Incidence and Mortality
Estimated new cases and deaths from brain and other nervous system tumors in the United States in 2014:
Brain tumors account for 85% to 90% of all primary central nervous system (CNS) tumors. 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. Worldwide, approximately 238,000 new cases of brain and other CNS tumors were diagnosed in the year 2008, with an estimated 175,000 deaths. In general, the incidence of primary brain tumors is higher in whites than in blacks, and mortality is higher in males than in females.
Few definitive observations on environmental or occupational causes of primary CNS tumors have been made. 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.)
The glial cell tumors, anaplastic astrocytoma and glioblastoma, account for approximately 38% of primary brain tumors. Since anaplastic astrocytomas represent less than 10% of all CNS gliomas, phase III randomized trials restricted to the anaplastic astrocytomas are not practical. Meningiomas and other mesenchymal tumors account for approximately 27% of primary brain tumors.
Other less-common primary brain tumors include the following in decreasing order of frequency:
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]
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:
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. Other clinical presentations of brain tumors include focal cerebral syndromes such as seizures. 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.
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. 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, except in cases in which 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. 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]
Origins of metastatic brain tumors
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. 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 CNS metastases.
Primary Brain Tumors
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:
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. 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. 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.
Other PDQ summaries containing information related to adult and childhood brain cancer include the following:
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: 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.
The WHO grading of CNS tumors establishes a malignancy scale based on histologic features of the tumor. 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. 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.
Radiation therapy and chemotherapy options vary according to histology and anatomic site of the brain tumor. For glioblastoma, 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 gliomas, phase III randomized trials restricted to them 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 gliomas (grade III and IV gliomas) in some patients. 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.
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]
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. 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:
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. 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.
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. 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 tenfold 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 in-hospital patient mortality rates after craniotomy (OR= 0.60; 95% CI, 0.45–0.79). 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 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 (RR) = 0.81; 95% CI, 0.74–0.88).[Level of evidence: 1iiA] Based on a randomized trial comparing 60 Gy (in 30 fractions over 6 weeks) with 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.[Level of evidence: 1iiA]
EBRT using either 3-dimensional conformal radiation therapy or intensity-modulated radiation therapy is considered an acceptable technique in radiation therapy delivery. Typically 2- to 3-cm margins on the MRI-based volumes (T1-weighted and FLAIR [fluid-attentuated inversion recovery]) to create the planning target volume are used. 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.[14,15]
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.
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 trials.[16,17] (On central pathology review, about 25% of the patients on the trial were reported 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).[16,17][Level of evidence: 1iiDiii] However, there was no difference in the overall survival (OS) rate (median survival = 7.4 years vs. 7.2 years; HR = 0.97; 95% CI, 0.71–1.34; P = .87).[16,17][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. 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 re-irradiation of previously irradiated brain tissue beyond tolerable dose limits.
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, including semustine (methyl-CCNU), radiation therapy, radiation therapy plus carmustine, and radiation therapy plus semustine.
The radiation therapy plus carmustine arm had the best survival rate.[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).
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 that showed a survival advantage.[21,22][Level of evidence: 1iiA] (Refer to the Glioblastoma section of the Management of Specific Tumor Types and Locations section of this summary for more information.)
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. 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. Both trials had an upper age limit of 65 years. The first was a small trial closed because of a lack of continued availability of the carmustine wafers after 32 patients with high-grade gliomas had been entered. 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.[24,25] 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.[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 are not widely available.
Novel biologic therapies under clinical evaluation for patients with brain tumors include the following:
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. The experience with chemotherapy for primary spinal cord tumors is limited; no reports of controlled clinical trials are available for these types of tumors.[2,32] Chemotherapy is indicated for most patients with leptomeningeal involvement (from a primary or metastatic tumor) and positive cerebrospinal fluid (CSF) 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 Web site.
Leptomeningeal carcinomatosis (LC)
The management of LC includes the following:
LC occurs in about 5% of all cancer patients. The most common types include breast tumors (35%), lung tumors (24%), and hematologic malignancies (16%). Diagnosis includes a combination of neurospinal axis imaging and CSF cytology. Median OS is in the range of 10 to 12 weeks.
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, whole-brain radiation therapy (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 luminal A, B, human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer subtype was 18.4%, 31.6%, 26.3% and 23.7%, respectively. 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 reported in case reports.
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:
The optimal therapy for patients with brain metastases continues to evolve.[32,36,37] 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 WBRT, but stereotactic radiosurgery (SRS) 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.[36,38] 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.[39,40,41] 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. 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 (RRdeath = 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.[Level of evidence: 1iiD]
The need for WBRT after resection of solitary brain metastases has been tested. 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. One additional randomized study of observation versus WBRT after either surgery or SRS for solitary brain metastases was closed because of slow accrual after 19 patients had been entered, so little can be deduced from the trial. (Refer to the Treatment for patients with oligometastases (1–3 or 4 brain metastases) section of this summary for more information.)
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. 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.[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 SRS) of oligometastases. Several randomized trials have been performed that were designed with varying primary endpoints.[45,46,47] However, the results can be summarized as follows:
A phase III randomized trial compared adjuvant WBRT with observation after surgery or radiosurgery for a limited number of brain metastases in patients with stable solid tumors. Health-related quality of life was improved in the observation-only arm compared with WBRT. Patients in the observation arm had better mean scores in physical, role, and cognitive functioning at 9 months. In an exploratory analysis, statistically significant worse scores for bladder control, communication deficit, drowsiness, hair loss, motor dysfunction, leg weakness, appetite loss, constipation, nausea/vomiting, pain, and social functioning were observed in patients who underwent WBRT compared with those who underwent observation only.[Level of evidence: 1iiC]
The 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 committee because of worse outcomes in the WBRT group.
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.[Level of evidence: 1iiD]
Treatment for patients with multiple metastases
Patients with multiple brain metastases may be treated with WBRT. 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. SRS in combination with WBRT has been assessed. A meta-analysis of two trials with a total of 358 participants found no statistically significant difference in OS between the WBRT plus SRS and WBRT alone groups (HR, 0.82; 95% CI, 0.65–1.02). Patients in the WBRT plus SRS group had decreased local failure compared with patients who received WBRT alone (HR, 0.27; 95% CI, 0.14–0.52). Unchanged or improved Karnofsky Performance Scale at 6 months was seen in 43% of patients in the combined therapy group versus only 28% in the WBRT group (P = .03).[Level of evidence: 1iiDiii]
Brain Stem Gliomas
Standard treatment options:
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.
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
Depending on the degree of anaplasia, patients with pineal astrocytomas vary in prognoses. Higher grades have worse prognoses.
This astrocytic tumor is classified as a World Health Organization (WHO) grade I tumor and is often curable.
Diffuse Astrocytomas (WHO grade II)
This WHO grade II astrocytic tumor is less often curable than is a pilocytic astrocytoma.
Anaplastic Astrocytomas (WHO grade III)
Patients with 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 patients with them are not practical. However, because these tumors are often aggressive, they are frequently 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 with 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. Of the 139 patients randomly assigned to radiation therapy, 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 overall survival (OS).[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.
Standard treatment options for patients with newly diagnosed disease:
The standard-of-care 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. This standard therapy is based on a large, multicenter, randomized trial (NCT00006353) conducted by the European Organization for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada (NCIC), which reported a survival benefit with concurrent radiation therapy and temozolomide compared with radiation therapy alone.[3,4][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- to 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 (hazard ratio [HR]death, 0.6; 95% confidence interval [CI], 0.5–0.7; OS at 3 years was 16.0% vs. 4.4%).
O6-methylguanine–DNA methyltransferase (MGMT) promoter DNA methylation
A companion molecular, correlation subset study to the EORTC-NCIC trial provided strong evidence that epigenetic silencing of the MGMT DNA-repair gene by promoter DNA methylation was associated with increased OS in patients with newly diagnosed glioblastoma. MGMT promoter methylation was an independent favorable prognostic factor (P < .001 by the log-rank test; HR, 0.45; 95% CI, 0.32–0.61). The median OS for MGMT-methylated patients was 18.2 months (95% CI, 15.5–22.0), compared with 12.2 months (95% CI, 11.4–13.5) for MGMT-unmethylated patients.
MGMT DNA-repair activity has been proposed as a major mechanism of resistance to alkylating agents. Intracellular depletion of MGMT has been hypothesized to enhance treatment response, and protracted temozolomide schedules have been shown to deplete intracellular MGMT in peripheral blood mononuclear cells. To test whether protracted temozolomide enhances treatment response in patients with newly diagnosed glioblastoma, a multicenter, randomized, phase III trial conducted by the Radiation Therapy Oncology Group (RTOG), EORTC, and the North Central Cancer Therapy Group, RTOG 0525 (NCT00304031), compared standard adjuvant temozolomide treatment (days 1–5 of a 28-day cycle) with a dose-dense schedule (days 1–21 of a 28-day cycle). All patients were treated with surgery followed by radiation therapy and concurrent daily temozolomide. Patients were then randomly assigned to receive either standard adjuvant temozolomide or dose-dense temozolomide.[Level of evidence: 1iiA]
Among 833 randomly assigned patients, no statistically significant difference between standard and dose-dense temozolomide was observed for median OS (16.6 months for standard temozolomide vs. 14.9 months for dose-dense temozolomide; HR, 1.03; P = .63) or median progression-free survival (PFS) (5.5 vs. 6.7 months; HR, 0.87; P = .06). MGMT status was determined in 86% of randomly assigned patients, and no difference in efficacy was observed in either the MGMT-methylated or MGMT-unmethylated subsets. However, this study confirmed the strong prognostic effect of MGMT methylation because the median OS was 21.2 months (95% CI, 17.9–24.8) for methylated patients versus 14 months (95% CI, 12.9–14.7) (HR, 1.74; P < .001) for unmethylated patients.
In summary, there was no survival advantage for the use of dose-dense temozolomide versus standard-dose temozolomide in newly diagnosed glioblastoma patients, regardless of MGMT status. The efficacy of dose-dense temozolomide for patients who have recurrent glioblastoma, however, is yet to be determined.
Bevacizumab in newly diagnosed glioblastoma
In 2013, final data from two multicenter, phase III, randomized, double-blind, placebo-controlled trials of bevacizumab in patients who have newly diagnosed glioblastoma were reported: RTOG 0825 (NCT00884741) and the Roche-sponsored AVAglio (NCT00943826).[7,8][Level of evidence: 1iA] Patients in both studies were randomly assigned to receive standard therapy (chemoradiation with temozolomide) or standard therapy plus bevacizumab. OS and PFS were coprimary endpoints in both trials, and these outcomes were similar. Bevacizumab did not improve OS in either study (median OS was 16–17 months for each arm in both studies); however, it increased median PFS to a similar degree (AVAglio study: 10.6 vs. 6.2 months; HR, 0.64; P < .0001; RTOG 0825 study: 10.7 vs. 7.3 months; HR, 0.79; P = .007). The PFS result in the AVAglio study was statistically significant and associated with clinical benefit because bevacizumab-treated patients remained functionally independent for longer (9.0 months vs. 6.0 months) and went longer before their Karnofsky Performance scale deteriorated (HR, 0.65; P < .0001). Furthermore, bevacizumab-treated patients went longer before corticosteroids were initiated (12.3 vs. 3.7 months; HR, 0.71; P = .002), and a larger proportion of patients was able to discontinue corticosteroids if they were already taking them (66% vs. 47%). However, the PFS result in the RTOG 0825 trial did not meet the prespecified significance level (P = .004). Of note, 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. It is yet to be determined whether certain subgroups may benefit from the addition of bevacizumab.
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.
Patients who have oligodendrogliomas (WHO grade II) generally have better prognoses than do patients who have diffuse astrocytomas; however, most of the oligodendrogliomas eventually progress.
Mature results from the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group Study 26951 (NCT00002840), a phase III, randomized study with 11.7 years of follow up demonstrated increased OS and progression-free survival in patients with anaplastic oligodendroglial tumors with six cycles of adjuvant PCV chemotherapy after radiation therapy compared with radiation therapy alone. The OS was significantly longer in the radiation therapy and PCV arm (42.3 months vs. 30.6 months; HR, 0.75; 95% CI, 0.60–0.95). 1p/19q-codeleted tumors derived more benefit from adjuvant PCV chemotherapy compared with non-1p/19q-deleted tumors.[Level of evidence: 1iiA]
In contrast, the Radiation Therapy Oncology Group (RTOG) trial (RTOG-9402 [NCT00002569]) demonstrated no differences in median survival by treatment arm between an 8-week, intensive PCV chemotherapy regimen followed by immediate involved-field-plus-radiation therapy and radiation therapy alone. However, in an unplanned subgroup analysis, patients with 1p/19q codeleted anaplastic oligodendroglioma and mixed anaplastic astrocytoma demonstrated a median survival of 14.7 years versus 7.3 years (HR, 0.59; 95% CI, 0.37–0.95; P = .03). For patients with noncodeleted tumors, there was no difference in median survival by treatment arm (2.6 vs. 2.7 years; HR, 0.85; 95% CI, 0.58–1.23; P = .39).[Level of evidence: 1iiA]
On the basis of these data, CODEL, a study that randomly assigned patients to 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 codeletion. A comparison between temozolomide and PCV chemotherapy in anaplastic oligodendroglioma has not been done, although in the setting of grade 3 anaplastic gliomas, no survival difference was seen between PCV chemotherapy and temozolomide.[2,14]
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. Since anaplastic oligodendrogliomas are uncommon, phase III randomized trials restricted to patients with them are not practical. Patients with these tumors are generally managed with the following:
PORT alone has been compared with 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. Of the 139 patients randomly assigned to radiation therapy, 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.[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.
Patients with mixed glial tumors, which include oligoastrocytoma (WHO grade II) and anaplastic oligoastrocytoma (WHO grade III), have prognoses similar to that for astrocytic tumors of corresponding grades and are often treated as such.
Grade I and II ependymal tumors
Ependymomas (WHO grade II) and ependymal tumors (WHO grade I), i.e., subependymoma and myxopapillary ependymomas, are often curable.
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.
Embryonal Cell Tumors: Medulloblastomas
Treatment options under clinical evaluation:
Medulloblastoma occurs primarily in children, but it also occurs with some frequency in adults. 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
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 tumors, and patients with them carry variable prognoses for cure. Pineoblastomas are more rapidly growing tumors, and patients with them have worse prognoses. Pineal parenchymal tumors of intermediate differentiation have unpredictable growth and clinical behavior.
Grade I meningiomas
WHO grade I meningiomas are usually curable when the mengiomas are 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.[18,19]
Grade II and III meningiomas and hemangiopericytomas
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 are those for patients with low-grade meningiomas because complete resections are less commonly feasible, and the proliferative capacity is greater.
Germ Cell Tumors
The prognoses 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
Craniopharyngiomas (WHO grade I) are often curable.
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.
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.
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. 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 overall survival (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% confidence interval [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.[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.
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]
The FDA independently reviewed an open-label, multicenter, noncomparative phase II study that randomly assigned 167 recurrent glioblastoma multiforme (GBM) patients to receive bevacizumab alone or bevacizumab in combination with irinotecan, although only efficacy data from the bevacizumab monotherapy arm (n = 85) were used to support drug approval. According to the FDA analysis of this study, tumor responses were observed in 26% of patients treated with bevacizumab alone, and the median duration of response in these patients was 4.2 months. On the basis of this externally controlled trial, the incidence of adverse events associated with bevacizumab did not appear to be significantly increased in GBM patients. The FDA independently assessed another single-arm, single-institution trial in which 56 recurrent glioblastoma patients were treated with bevacizumab alone. Responses were observed in 20% of patients, and the median duration of response was 3.9 months.
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. On the basis of these data and FDA approval, bevacizumab monotherapy has become standard therapy for recurrent glioblastoma.
Systemic therapy (e.g., temozolomide, lomustine, 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.
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.
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.
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.
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 2014 (cited American Cancer Society as reference 1).
Treatment Option Overview
Added text to state that the natural histories of these tumors are variable, depending on histological and molecular factors; therefore, treatment guidelines are evolving. Also revised text to state that therapy involving surgically implanted carmustine-impregnated polymer wafers combined with postoperative external-beam radiation therapy may play a role in the treatment of high-grade gliomas (grade III and IV gliomas) in some patients.
Management of Specific Tumor Types and Locations
Revised the Glioblastomas subsection extensively.
Revised text to state that patients who have oligodendrogliomas (WHO grade II) generally have a better prognoses than do patients who have diffuse astrocytomas; however, most of the oligodendrogliomas eventually progress.
Added text to include stereotactic radiosurgery for tumors less than 3 cm as a standard treatment option for grade 1 meningiomas and revised a treatment option to read fractionated radiation therapy for patients with resectable tumors.
Recurrent Adult Brain Tumors
Added Bevacizumab as a new subsection.
Revised text to add lomustine as an additional systemic chemotherapy drug.
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 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:
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 reviewers for Adult Brain Tumors Treatment are:
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.
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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>.
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Last Revised: 2014-02-28
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