Treatment Option Overview
Primary Brain Tumors
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:
- Establishing a histologic diagnosis.
- Reducing intracranial pressure by removing as much tumor as is safely possible to preserve neurological function.
However, total elimination of primary malignant intraparenchymal tumors by surgery alone is rarely achievable. Therefore, intraoperative techniques have been developed to reach a balance between removing as much tumor as is practical and the preservation of functional status. For example, craniotomies with stereotactic resections of primary gliomas can be done in cooperative patients while they are awake, with real-time assessment of neurologic function. 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:
- Intrathecal chemotherapy.
- Intrathecal chemotherapy and systemic chemotherapy.
- Intrathecal chemotherapy and radiation therapy.
- Supportive care.
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.
Metastatic Brain Tumors
Approximately 20% to 40% of cancer patients develop brain metastases, with a subsequent median survival generally less than 6 months. Common primary tumors with brain metastases include the following cancers:
- Cancer of unknown primary.
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.[39-41] 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.[45-47] However, the results can be summarized as follows:
- Studies consistently show that the addition of WBRT to focal therapy decreases the risk of progression and new metastases in the brain.
- The addition of WBRT does not improve OS.
- The decrease in risk of intracranial disease progression does not translate into improved functional or neurologic status, nor does it appear to decrease the risk of death from neurologic deterioration.
- About half or more of the patients who receive focal therapy alone ultimately require salvage therapy, such as WBRT or radiosurgery, compared with about a quarter of the patients who are given up-front WBRT.
- The impact of better local control associated with WBRT on quality of life has not been reported and remains an open question.
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]
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