Primary and Metastatic Brain Tumors
April Fitzsimmons Eichler
Tracy T. Batchelor
I. PRIMARY BRAIN TUMORS
A. Incidence
According to the Central Brain Tumor Registry of the United States (CBTRUS), there were an estimated 51,510 cases of new malignant and nonmalignant primary brain tumors (PBTs) diagnosed in the United States in 2007. This includes an estimated 20,500 new cases of malignant brain and central nervous system (CNS) tumors, representing 1.42% of all malignant cancers and accounting for 12,740 deaths in the same year. The age-adjusted 5-year relative survival from 1999 to 2005 for all malignant PBTs—including lymphomas, leukemias, tumors of the pituitary and pineal glands, and olfactory tumors of the nasal cavity—was 35%. The only established risk factor for PBT is ionizing radiation at high doses, which has been associated with an increased incidence of nerve sheath tumors, meningiomas, and gliomas. However, radiation-associated tumors account for only a small percentage of PBTs.
B. Gliomas
Gliomas account for 36% of all PBTs and include astrocytic, oligodendroglial, and ependymal tumors. Astrocytomas are the most frequent type and these tumors manifest a wide spectrum of clinical behavior. Malignant gliomas—including anaplastic oligodendroglioma, anaplastic astrocytoma, and glioblastoma (GBM; the most common malignant PBT)—are not curable, although each may respond to radiation and chemotherapy. Astrocytomas are graded based on the presence or absence of the following histologic features: nuclear atypia, mitoses, endothelial proliferation, and necrosis.
1. Grades I and II astrocytoma. Pilocytic astrocytomas are World Health Organization (WHO) grade I tumors that most commonly arise in the posterior fossa. These tumors are most common in the pediatric population and can be cured if a total resection is achieved. WHO grade II astrocytomas (low-grade astrocytomas) are most commonly observed in the third and fourth decades of life. This tumor typically appears as a nonenhancing, diffuse, hypointense mass on T1-weighted magnetic resonance imaging (MRI). Even with a characteristic appearance, biopsy is necessary to determine the histologic subtype and because up to 30% of nonenhancing tumors are shown to be anaplastic (WHO grade III) at the time of surgery. Median survival for lowgrade gliomas (LGGs)—which includes low-grade astrocytoma, oligoastrocytoma, and low-grade oligodendroglioma—ranges from 7 to 9 years with a 5-year survival of 60% to 70%. Important prognostic factors for survival include age, performance status, preoperative tumor size, extent of resection, and histology, with astrocytic tumors fairing worse than oligodendroglial tumors.
If feasible, a maximal safe resection should be performed and then the patient should be followed regularly with serial MRI studies and clinical examinations. Data from four prospective randomized clinical trials in adults with LGG indicate that (1) postoperative radiation therapy compared with observation is associated with improved progression-free survival but not overall survival and (2) radiation doses of 45 to 54 Gy result in similar outcomes to higher doses (59 to 65 Gy) and are associated with improved tolerability. Based on these data, postoperative radiation therapy is often recommended for patients after a subtotal resection or biopsy, particularly if there are additional “high risk” features such as advanced age (>40 years), elevated MIB-1 labeling index (>3% to 5%), or pure astrocytoma histology. Even in low-risk LGG patients, defined in one recent prospective observation study as adults < 40 years of age with neurosurgeon-determined gross-total resection, the risk of tumor progression at 5 years may be as high as 50%.
In the event of tumor progression on computed tomography (CT) or MRI, further surgery, if possible, may be performed and involved field radiation (IFR) or chemotherapy is recommended, depending on the histologic subtype. If, at the time of the recurrence, the histopathology demonstrates a higher grade astrocytoma, chemotherapy can be initiated, which will be discussed in the following section.
2. Grades III and IV astrocytoma. Anaplastic astrocytoma (WHO grade III) occurs most commonly in the fourth and fifth decades, whereas glioblastoma (WHO grade IV) occurs most commonly in the fifth and sixth decades. Median survival times are
24 to 36 months and 12 to 15 months, respectively. These two types of tumors may be indistinguishable by MRI because both often appear as diffuse hypointense lesions on T1-weighted images and both readily enhance after administration of intravenous contrast. These tumors are most commonly observed in the cerebral hemispheres and can have cystic or hemorrhagic components.
Histologic diagnosis is made by stereotactic biopsy or resection. Surgical debulking is the preferred initial treatment to minimize neurologic morbidity. Retrospective studies and the adjusted analysis of a prospective randomized trial of fluorescence-guided resection have suggested that gross total resection is associated with longer survival. Resection also relieves mass effect, which allows a patient to better tolerate subsequent IFR and often allows discontinuation of corticosteroids. Following surgery, standard therapy includes IFR up to 60 Gy, given in combination with temozolomide for grade IV tumors (see later). Management of anaplastic astrocytoma remains controversial because of a lack of randomized prospective data, but postoperative IFR or IFR with concurrent temozolomide are the most common treatment approaches. Positive prognostic factors include high Karnofsky performance score, gross total resection, and younger age. In addition, multiple studies have now shown that methylation of the O6-methylguanineDNA methyltransferase (MGMT) promoter is prognostic of improved survival and may be predictive of increased responsiveness to temozolomide chemotherapy in GBM.
a. Chemotherapy. Chemotherapy is now considered the standard of care for newly diagnosed glioblastoma based on the results of a European Organization for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada (NCIC) randomized, multicenter trial of 573 patients comparing IFR (radiation arm) with IFR plus concurrent temozolomide (TMZ) followed by 6 months of postradiation, monthly TMZ (chemoradiation arm). Patients treated with chemoradiation had a median survival of 14.6 months, compared with 12.1 months in the radiation arm. In addition, the 2- and 5-year survival rates were 27% and 10% in the chemoradiation group compared with 11% and 2% in the radiation group, respectively.
In 2009, the U.S. Food and Drug Administration (FDA) approved bevacizumab (Avastin), a monoclonal antibody against vascular endothelial growth factor (VEGF), as a single agent for use in treatment of recurrent glioblastoma. Approval was based on two prospective studies showing a 20% to 30% objective response rate and a median response duration of
approximately 4 months. In addition, bevacizumab was associated with decreased steroid use over time. The most frequent adverse events were infection, fatigue, headache, hypertension, epistaxis, and diarrhea. Grade 3 or higher adverse events were similar to those seen in other primary cancer types and included bleeding/hemorrhage, CNS hemorrhage, hypertension, venous and arterial thrombosis, wound-healing complications, proteinuria, gastrointestinal perforation, and reversible posterior leukoencephalopathy. There is also a large experience with bevacizumab in combination with irinotecan (CPT-11) for recurrent malignant glioma. However, in a randomized noncomparative trial, median progression-free survival and overall survival were not significantly different in the combination arm (5.6 months and 8.7 months, respectively) compared with the bevacizumab monotherapy arm (4.2 months and 9.2 months) and toxicity was higher with combination therapy. Several large randomized placebo controlled trials are investigating the efficacy of bevacizumab in combination with chemoradiation for newly diagnosed glioblastoma.
Recurrent glioblastoma may also be treated by surgical debulking with or without carmustine (BCNU) wafers, radiosurgery, nitrosoureas such as BCNU or lomustine (CCNU), or other single agent therapies such as carboplatin. A wide range of targeted agents are also in clinical trials. The following are regimens that have been used both in the adjuvant setting and for patients who have recurrence after surgery, IFR, or both.
b. Regimens for newly diagnosed malignant glioma
(1) Temozolomide (TMZ) is administered differently depending upon whether it is being used in combination with IFR or not.
TMZ is dosed at 75 mg/m2 daily, 7 days per week, when given concurrently with IFR, for the entire duration of radiation. Trimethoprim-sulfamethoxazole should be administered thrice weekly with the daily temozolomide as prophylaxis against Pneumocystis jiroveci pneumonia.
TMZ is dosed at 150 to 200 mg/m2 by mouth daily for 5 consecutive days in a 28-day treatment cycle when given alone.
Administration of TMZ using a 21-day on followed by 7-day off schedule, a strategy aimed at overcoming resistance by depleting MGMT, has been compared with standard 5 days on, 23 days off TMZ in the postradiation setting for newly diagnosed GBM in a randomized study of 1153 patients but results are not yet available. Until then, 5-day per month TMZ remains the standard of care, regardless of a patient’s MGMT methylation status.
(2) PCV is a combination of three antineoplastic agents given in a 6-week cycle:
Lomustine 110 mg/m2 by mouth on day 1
Vincristine 1.4 mg/m2 (maximum 2 mg) intravenously (IV) on days 8 and 29
Procarbazine 60 mg/m2 by mouth days 8 through 21 of the 42-day cycle
PCV is typically administered for 6 to 12 months or until tumor progression. PCV is associated with more myelotoxicity and neurotoxicity than other commonly prescribed chemotherapeutic drugs for malignant glioma.
c. Regimens for recurrent GBM
(1) Bevacizumab is administered at a dose of 10 mg/kg IV every 2 weeks. Dose reductions may be required, most commonly for hypertension or proteinuria. When given in combination with irinotecan, the dose of bevacizumab remains the same and irinotecan is dosed at 340 mg/m2 for patients on enzyme-inducing anticonvulsants and 125 mg/m2 for patients not on enzyme-inducing anticonvulsants.
(2) BCNU may be administered as monotherapy and is given in either one dose or in two to three divided consecutive daily doses for a total of 150 to 200 mg/m2 IV every 6 weeks.
(3) BCNU wafers are a depot source of BCNU that can be surgically implanted at the time of resection. The FDA approved the 3.85% BCNU wafer for recurrent GBM after a phase III, double-blind, placebo-controlled clinical study involving 222 patients undergoing surgery for recurrent malignant glioma showed that BCNU wafers increased median survival from 20 to 28 weeks. A second randomized trial was conducted using BCNU wafers at the time of initial diagnosis of malignant glioma and led to FDA approval for newly diagnosed malignant glioma. This study showed a median survival of 13.9 months in the BCNU wafer group versus 11.6 months in the placebo arm. However, when anaplastic and nonglial histologies were excluded from the analysis, a survival advantage for patients with GBM was not observed.
3. Oligodendroglioma (WHO grades II and III)
a. Characteristics. Low-grade (WHO grade II) oligodendroglioma (LGO) and anaplastic (WHO grade III) oligodendrogliomas (AO) are glial tumors that are found almost exclusively in the cerebral hemispheres and represent 4% to 15% of all gliomas. The peak incidence occurs in the fourth through sixth decades of life. Oligodendrogliomas have increased cellularity with homogeneous, hyperchromatic nuclei surrounded by clear cytoplasm: the classic “fried-egg” appearance. Allelic loss of
the short arm of chromosome 1p and the long arm of chromosome 19q occurs in 50% to 70% of both AO and LGO and predicts better response to chemotherapy and longer survival. These tumors are hypointense on T1-weighted MRI scans and hyperintense on T2-weighted images and are located in the deep white matter. The median survival for WHO grade II oligodendrogliomas and WHO grade III oligodendrogliomas has been reported as 9.8 to 16.7 years and 3.5 to 5 years, respectively. However, these estimates do not stratify patients based on the underlying status of chromosomes 1p and 19q and patients with codeleted anaplastic oligodendroglioma have a median survival of 10 to 13 years in some series.
b. Treatment.Related posts:
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