Neha Vapiwala, MD and Charles B. Simone, II, MSIV Abramson Cancer Center of the University of Pennsylvania < Last Modified: March 29, 2006
CNS malignancies are one of the most feared cancers among the public and are a leading cause of cancer-related morbidity and mortality in the United States. The majority of newly diagnosed brain tumors actually represent metastases from malignancies originating elsewhere in the body, and the incidence of these metastatic lesions is increasing. Primary brain tumors, which arise directly from CNS tissue, represent less than 2% of all cancers but are the most common solid tumors in children. In addition, there is an increasing number of these primary tumors in the elderly. Notably, most intracranial tumors occur in patients who are over age 45, with the average age of onset of about 62 years. This is possibly attributable to the combined effects of aging immune systems and prolonged environmental carcinogen exposures.
Whether these lesions are benign or malignant, CNS tumors can be devastating to a patient's overall functioning through sheer positional and mass effects. Thus, they often warrant palliative management even when curative measures are not likely to be successful.
Epidemiology and Etiology
Incidence of about 188,500 total new cases of brain tumors yearly in the United States. The majority of these cases represent metastatic brain lesions, which outnumber primary CNS tumors by about ten-fold. The incidence of primary brain and other nervous system malignancies in the United States is 18,500 cases each year. The majority of these tumors occur in the Caucasian population. Primary brain tumors are a third more common in men than women and are the most common solid tumors in children .
Mortality of 12,760 deaths in the United States annually for primary brain tumors. Primary brain tumors account for about 2% of all cancer-related deaths and are the tenth most common cause of cancer death in women. Among children, primary brain tumors are the second most frequent cause of cancer death .
Etiology is incompletely understood, although genetic and environmental factors have been suspected. Chemical, viral, and radiation factors have been implicated as possible inducers of cellular damage in brain tumors.
Hereditary factors and syndromes, including neurofibromatosis, tuberous sclerosis, Li-Fraumeni syndrome, Turcot syndrome, retinoblastoma, von Hippel-Landau disease, and nevoid basal cell carcinoma syndrome, account for less than 10% of all brain tumors. Tumors associated with these syndromes tend to be gliomas in children and young adults .
Risk factors [3, 4, 5]
A diagnosis of a hereditary syndrome associated with an increased risk of primary brain tumors (see above)
Prior cranial radiation exposure, especially during childhood
The usage of cellular phones has not been shown to increase the risk of developing brain tumors
Race: African-Americans have a slightly higher incidence of meningiomas and pituitary adenomas
Sex: incidence and mortality of all primary brain tumors are 33% higher in men than women, although women have a higher incidence of meningiomas and pituitary adenomas
Age: bimodal distribution, with the first spike occurring in children, followed by a steady increase in incidence beginning at age 20; the peak incidence occurs between ages 75 and 85 years
Viral infection: polyomaviruses (JCV is associated with a variety of CNS malignancies, including astrocytoma, glioblastoma multiforme [GBM], and neuroblastoma), HIV (CNS lymphomas), and EBV
Exposure to polyvinyl chloride, phenols, organic solvents, formalin, and hydrocarbons
The presence of non-CNS primary malignancies
Brain metastases are increasing in incidence and are present in 12-15% of all cancer patients
The most common primary malignancies to disseminate to the brain: lung cancer (about 50% of all cases), breast (15%), melanoma (9%), colon, renal cell, and testicular cancers.
There is no current role for universal screening for primary brain tumors. Patients with a known history of a hereditary syndrome or genetic abnormality that increases their risk for developing brain tumors may benefit from periodic radiologic imaging studies of the brain.
Screening for brain metastases in patients with non-CNS primary malignancies is also not routinely performed, but is often conducted in patients with lung and breast primaries or other advanced-stage malignancies.
History: presenting symptoms are often similar for patients with primary and metastatic intracranial neoplasms. General neurological symptoms may include headaches (the predominant presenting symptom in up to 50% of all patients with brain tumors), nausea and vomiting (related to increased intracranial pressure), seizures, hemorrhage, and personality and cognitive changes (occur in up to 75% of patients with brain metastases). More specific symptoms vary based on the neuroanatomic sites that the disease involves.
Frontal lobe = intellectual defects, memory loss, decreased alertness, impaired judgment, personality changes, motor paralysis or weakness, apraxia, expressive aphasia
Parietal lobe = decreased or lost sensations, paralysis, disgraphia, alexia, construction apraxia, anomia, visual perception abnormalities
Physical exam: associated ophthalmologic and neurological findings.
Lab studies: CSF sampling (after the exclusion of elevated intracranial pressure or the relief of any CSF obstructive processes) is often useful in cases of medulloblastomas and primitive neuroendocrine tumors (PNETs), germinomas, suprasellar tumors, choroid plexus tumors, and primary CNS lymphomas; biochemical markers such as beta-HCG and alpha-fetoprotein expression are indicative of malignant germ-cell tumors; findings consistent with syndrome of inappropriate antidiuretic hormone (SIADH) secretion may also be seen.
Molecular markers: increasingly popular in aiding the diagnosis of brain tumors, predicting patient survival, and serving as targets for directed therapies. TP53 mutations are evident in gemistocytic astrocytomas (88%), fibrillary astrocytomas (53%), oligoastrocytomas (44%), and GBMs (31%, higher in secondary GBMs), while LOH 1p/19q mutations are common in oligodendrogliomas (65-75%) and oligoastrocytomas (44%). Among GBMs, other common abnormalities include LOH 10q (60-80%), EGFR amplification (34-62%, higher in primary GBMs), p53 mutations (60-70% of secondary GBMs), p16 INK4a homozygous deletion (30-60%), PTEN mutations (25-40%), and RB gene alterations (25-35%). Additionally, NF2 gene inactivation is evident in 30–70% of patients with sporadic meningiomas, while gene abnormalities in p14 ARF and p16 INK4a occur in 40–60% of patients with primary CNS malignant lymphoma [6, 7, 8].
Radiologic studies: CT and MRI scans of the brain and spine and functional neuroimaging with positron electron emission tomography (PET) and magnetic resonance spectroscopy.
MRI scans are preferred over CT scans in patients with signs or symptoms of an intracranial mass or in patients being evaluated for metastatic brain lesions. MRIs are also more sensitive than PET scans.
MRIs should be contrast-enhanced when evaluating for brain metastases and obtained with and without contrast when assessing for primary brain malignancies.
High-grade and malignant primary tumors typically appear as contrast-enhancing mass lesions with surrounding edema, while low-grade gliomas are often non-enhancing lesions with diffuse infiltration.
Metastatic lesions are much less likely than primary malignancies to cross the midline on radiographic imaging .
Diagnostic studies: definitive diagnosis is achieved by the procurement of a tissue simple that is obtained through histologic tissue biopsy or at the time of surgery in patients with resectable tumors.
Natural Course and Pathology
Staging of primary brain tumors is often not applicable since they very rarely spread to regional lymph nodes or distant sites. Instead, a pathologic determination is made based on the tumor cell type and histologic grade. For some tumors, such as medulloblastomas and ependymomas, location and metastatic spread within the CSF are also used in staging and classification. Brain metastases are staged according to the staging system of the primary malignancy from which they originated. All solid tumors that present with brain metastases are considered stage IV disease .
Histologic type and grade are extremely important in determining tumor behavior and degree of malignancy, and thus dictating prognosis and choice of therapy.
Gliomas are the most common primary brain tumors in adults and represent 55-70% of all primary brain malignancies. These tumors are derived from glial cells, which include astrocytes, oligodendrocytes, and ependymal cells. Among astrocytic tumors, which comprise the majority of gliomas, low-grade astroglial tumors (WHO grade II) generally grow more slowly and have a better prognosis than high-grade astrocytic tumors, which include anaplastic astrocytomas (grade III) and GBMs (grade IV). GBMs are the most common and most invasive glial tumors. They are associated with a poor prognosis. Primary GBMs (~60% of cases) arise de novo, while secondary GBMs (~40%) transform from a lower-grade astrocytoma or oligodendroglioma. Oligodendrogliomas represent about 10% of gliomas and may be low-grade or anaplastic (grade III). Ependymomas are less common and are usually considered low-grade tumors. Gliomas may also have mixed tumor pathology .
Meningiomas are the most common extra-axial tumors and account for 15-25% of all primary brain tumors. They arise from meningothelial cells in the meninges and are usually benign, although they often cause significant neurological symptoms .
Medulloblastomas represent 7-8% of all intracranial tumors and 20-30% of all pediatric brain tumors. These tumors usually arise in the posterior fossa and have a tendency to spread along CSF pathways. Along with histologically similar pineoblastomas, ependymoblastomas, and neuroblastomas, these tumors are often considered primitive neuroectodermal tumors (PNETs).
Acoustic neuromas, or vestibular schwannomas, represent 8-10% of all adult intracranial tumors. They originate from Schwann cells, often from the vestibular portion of the eighth cranial nerve. Although they are benign and generally slow-growing tumors, patients commonly present with hearing loss (>90%), tinnitus, ataxia, and facial paresthesia.
Other CNS neoplasms include tumors of the sellar region, other tumors of cranial and spinal nerves, germ cell tumors, cysts and tumor-like lesions, hematopoietic tumors, non-menigothelial tumors of the meninges, local extensions from regional tumors, and metastatic tumors.
Prognostic factors most strongly associated with a more favorable outcome include young age, lower histological tumor grade, and high patient performance status. Additional favorable prognostic factors include: complete or near-total (>90% removal of the original tumor) surgical resection, long duration of symptoms prior to diagnosis, presence of seizures, normal neurological exam and mini-mental status exam, adjuvant radiation therapy, limited evidence of necrosis, and preoperative tumor size <5 cm. For patients with metastatic disease, a lone metastatic brain lesion and control of the primary malignancy are favorable prognostic factors. Genetic abnormalities and molecular markers are becoming increasingly recognized as having prognostic value [6, 7, 8, 11, 12, 13, 14, 15, 16].
Negative molecular prognosticators: LOH 10q alterations, P TEN abnormalities, and increased cyclin A, cyclin E, VEGF and COX-2 immunoexpression in patients with GBMs and other high-grade gliomas; LOH near the FGFR2 and DMBT1 genes in patients with anaplastic astrocytoma; homozygous deletion of the CDKN2A/p16 gene and elevated p53 expression in patients with oligodendrogliomas; aberrant p53 expression in patients with ependymal tumors; elevated myc mRNA expression and p53 mutations in patients with medulloblastoma and PNETs; and INK4a ARF gene deletions in patients with primary CNS malignant lymphoma.
Positive molecular prognosticators: increased p27 immunohistochemical expression in patients with astrocytic and oligodendroglial tumors; LOH of both 1p and 19q in patients with oligodendrogliomas; and increased TrkC mRNA expression in patients with medulloblastomas.
Supportive Therapy: many patients initially receive corticosteroids (often dexamethasone) to reduce intracranial pressure and peritumoral edema. Antiepileptic medications (often phenytoin [Dilantin, Phenytek]) may also be administered perioperatively to reduce the incidence of postoperative seizures and prophylactically in patients who have had prior seizures.
Surgery remains the initial definitive treatment modality for the majority of patients with primary and metastatic brain tumors, as surgical resection can reduce tumor burden, prolong survival, relieve symptoms from edema and mass effect, and establish an accurate histological diagnosis. Gross total resection should be achieved for all brain tumors whenever technically possible in order to improve patient quality of life and overall survival. Immediate re-resection should be considered in surgical candidates who have radiographic evidence of residual disease postoperatively .
Surgical approaches: biopsies and resections may be achieved through the use of image-based guidance systems (usually CT- or MRI-guided), stereotactic frames (which allow for a three-dimensional coordination system), and intraoperative brain mapping (cortical mapping using electrical stimulation).
Stereotactic resection is particularly useful for small and deep tumors, lesions surrounding critical structures, and in patients with multiple metastatic lesions, with an accuracy of 92-98%, an overall morbidity rate of 2-5%, and a mortality rate of <1% [4, 18, 19].
High-grade tumors: among patients with GBMs, survival is greatest following gross total resection (39.5-52.0 weeks). Survival is similar among patients who undergo a subtotal resection, more limited resection, or biopsy alone (21.0-40.4 weeks) [13, 14, 15].
Low-grade tumors: when compared with subtotal resection, patients who undergo gross total resection for low-grade gliomas have an increased five-year survival (>80% vs. ~50%) and may not require postoperative irradiation or chemotherapy unless there is evidence of recurrence or disease progression .
Metastases: although surgery is rarely curative for metastatic brain lesions, excision in patients with three or fewer brain metastases and limited extracranial disease can improve quality of life, relieve neurological symptoms, and reduce tumor burden to improve the efficacy of adjuvant therapy.
Radiation therapy as adjuvant treatment has a well-established role in significantly prolonging survival in patients with high-grade gliomas and GBMs. Radiation therapy is also used to prevent brain metastases and to treat low-grade gliomas, inoperable or recurrent benign and malignant CNS tumors, and metastatic brain lesions [20, 21].
Radiation therapy approaches: conventionally fractionated external beam (commonly used for whole-brain radiation therapy); stereotactic radiotherapy (conventionally fractionated also, but with highly focused beam); hyperfractionation (multiple treatments each day); stereotactic radiosurgery (noninvasive highly focused radiation that is particularly useful for unresectable lesions, focal gliomas, and small metastatic lesions); and standard brachytherapy or intraoperative GliaSite (radioactive iodine) balloon catheter placement .
High-grade tumors: high-dose postoperative radiation therapy has been shown to significantly prolong overall survival, and can achieve response rates of about 50% in patients with anaplastic astrocytomas and 25% for those with GBMs .
Low-grade tumors: radiation therapy can often be withheld in patients with low-grade glial cell tumors who have undergone complete surgical resection. However, patients should receive irradiation upon disease recurrence that cannot be surgically removed surgically or if an initial complete resection was not achieved, particularly if patients are experiencing neurological symptoms.
Postoperative radiation can improve progression-free survival and achieve five-year survival rates of 50% and 10-year survival rates of 20% in patients with low-grade astrocytomas. Even higher survival rates are achieved in patients with low-grade oligodendrogliomas [4, 23].
Metastases: whole-brain irradiation can achieve symptomatic response rates of >70% in patients with metastatic brain tumors and lengthen survival for symptomatic patients from 1-2 months to 3-6 months. Additionally, patients with three or fewer metastatic lesions may undergo radiosurgery alone to achieve similar survival and local control rates as surgical resection, or radiosurgery as a boost following whole-brain irradiation to improve local tumor control and patient quality of life when compared with whole-brain therapy alone [4, 24, 25].
The Radiation Therapy Oncology Group (RTOG) randomized 333 patients with one to three brain metastases to whole-brain irradiation alone or whole-brain irradiation followed by a stereotactic radiosurgery boost. They found that patients in the radiosurgery group had an improved performance status at 6 months (43% vs. 27%, p=0.03), greater local control at one year (82% vs. 71%; p=0.01), and increased median survival in the subgroup of patients with a single brain metastasis (6.5 months vs. 4.9 months, p=0.0393) .
Prophylactic cranial irradiation (PCI): patients with certain primary malignancies, particularly small cell lung cancer (SCLC), may be offered prophylactic cranial irradiation to decrease the risk of brain metastases and to prolong overall survival. PCI is recommended for patients without significant pre-existing neurological risk factors (cerebrovascular disease, dementia) who have limited-stage SCLC and are in complete remission following localized induction thoracic irradiation and chemotherapy.
An analysis of 987 patients with SCLC in complete remission compared PCI with no prophylactic irradiation and found that the intervention group had an increased three-year survival (20.7% vs. 15.3%, p=0.01), increased disease-free survival, and decreased cumulative incidence of brain metastasis at three years (33.3% vs. 58.6%, p<0.001) .
Chemotherapy alone does not produce a cure but has a role as adjuvant treatment for select patients. Due to the inability of many commonly used chemotherapeutic agents to effectively cross the blood-brain barrier, alternative agents and administration techniques must be employed for patients with brain tumors.
Primary tumors: in patients with malignant gliomas, temozolomide (Temodar), carmustine ( BCNU, Gliadel), or the PVC combination of p rocarbazine (Matulane), v incristine (Vincasar), and lomustine ( C CNU) are the most commonly used chemotherapeutic agents.
Oligodendrogliomas are among the most chemoresponsive brain tumors, with response rates of >75% with temozolomide or PVC. Astrocytic tumors, including GBMs are generally more chemoresistant. However, a recent study randomized 573 patients with GBMs to radiotherapy alone or temozolomide given concomitantly with as well as after radiotherapy. At a median follow-up of 28 months, patients in the temozolomide arm had a higher median survival (14.6 months vs. 12.1 months), two-year survival rate (26.5% vs. 10.4%), and median progression-free survival (6.9 months vs. 5.0 months) [27, 28].
Modes of drug delivery: include continuous infusion, intrathecal/intraventricular, intraarterial, and interstitial.
The intraoperative implantation of biodegradable BCNU (Gliadel) wafers into the tumor bed at the time of primary surgical resection has been investigated in patients with GBM. In a study of 240 patients randomized to receive either BCNU or placebo wafers, patients in the BCNU arm had a higher median survival (13.9 months vs. 11.6 months, p=0.03) and prolonged time to decline in performance status, despite higher rates of complications (CSF leaks, intracranial hypertension) .
Metastases: adjuvant chemotherapy is largely ineffective for many metastatic brain tumors and is often reserved for patients who are unable to undergo repeat brain irradiation. However, brain metastases from primary malignancies that are particularly chemosensitive (lymphomas, testicular, choriocarcinoma, small cell lung, and breast) are generally also sensitive to the same chemotherapeutic agents. Please refer to the MD2B Core Courses (make the link follow this web address: http://www.oncolink.org/resources/section.cfm?c=9&s=19 ) menu to find more information about primary tumor types and their treatments.
Temozolomide is also being investigated in patients with metastatic brain disease. In a study in which 52 patients were randomized to radiation therapy alone or temozolomide given concomitantly with and after radiotherapy, patients in the temozolomide group had a higher response rate (96% vs. 67%), greater objective neurological improvement, and decreased need for corticosteroids two months after treatment (67% vs. 91%) .
Experimental therapies: biologic, targeted, and other experimental therapies to date have had limited success in treating malignant brain tumors. However, with an increasing identification and knowledge of the genetic and molecular basis of brain malignancy progression, novel therapies are being designed against some of these genetic and molecular targets. The following therapies are usually part of multimodality treatment approaches and are being investigated in clinical trials for patients with brain malignancies [31, 32, 33]:
Angiogenesis inhibitors: recombinant humanized monoclonal antibodies to vascular endothelial growth factor (bevacizumab [Avastin]), matrix metalloproteinases inhibitors (marimastat), and thalidomide in patients with recurrent gliomas and GBMs.
Epidermal growth factor receptor (EGFR) inhibitors : monoclonal antibodies that inhibit EGFR and its receptor in patients with high-grade gliomas.
B iologic agents : interferon, adoptive immunotherapy, anticancer vaccines, and oncolytic viruses in patients with high-grade gliomas.
Blood-brain barrier (BBB) disruption : attempts to increase the permeability of the BBB with hyperosmolar solutions ( mannitol ) or vasoactive compounds (TNF-alpha, histamine, leukotrienes, bradykinin) in patients with recurrent gliomas.
Radioimmunotherapy : the administration of intracerebral antitenascin monoclonal antibodies< (I-131 labeled) in patients with gliomas.
Radiosensitizers : motexafin gadolinium [Xcytrin] and efaproxiral [Efaproxyn], which a ttempt to increase the levels of oxygen in a tumor to make it more sensitive to radiation therapy, in patients with metastatic brain disease.
Gene therapy : delivery of the herpes simplex virus thymidine kinase gene into the tumor using viral vectors (adenovirus, retrovirus) in patients with GBMs.
Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin. 2005;55(1):10-30.
Bondy M, Wiencke J, Wrensch M, et al. Genetics of brain tumors, a review. J Neurooncol. 1994;18(1):69-81.
Berleur MP, Cordier S. The role of chemical, physical or viral exposures and health factors in neurocarcinogenesis: implications for epidemiologic studies of brain tumors. Cancer Causes Control 1995;6(3):240-56.
DeAngelis LM, Loeffler JS, Mamelak AN. Primary and metastatic brain tumors. In Pazdur R, et al (Eds), Cancer Management: A Multidisciplinary Approach, Ninth Edition, 2005-6. CMP, Manhasset, NY 2004. p. 615-37.
Pagano JS, Blaser M, Buendia MA, et al. Infectious agents and cancer: criteria for a causal relation. Semin Cancer Biol. 2004;14(6):453-71.
Ohgaki H, Kleihues P. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol. 2005;64(6):479-89.
Hill C, Hunter SB, Brat DJ. Genetic markers in glioblastoma: prognostic significance and future therapeutic implications. Adv Anat Pathol. 2003;10(4):212-7.
Shiraishi T, Tabuchi K. Genetic alterations of human brain tumors as molecular prognostic factors. Neuropathology. 2003;23(1):95-108.
Bruner JM. Neuropathology of malignant gliomas. Semin Oncol. 1994;21(2):126-38.
Black PM. Benign brain tumors. Meningiomas, pituitary tumors, and acoustic neuromas. Neurologic Clinics. 1995;13(4):927-52.
Watkins D, Rouleau GA. Genetics, prognosis and therapy of central nervous system tumors. Cancer Detect Prev. 1994;18(2):139-44.
Devaux BC, O'Fallon JR, Kelly PJ. Resection, biopsy, and survival in malignant glial neoplasms. A retrospective study of clinical parameters, therapy, and outcome. J Neurosurg. 1993;78(5):767-75.
Laws ER, Parney IF, Huang W, et al. Survival following surgery and prognostic factors for recently diagnosed malignant glioma: data from the Glioma Outcomes Project. J Neurosurg. 2003;99(3):467-73.
Lacroix M, Abi-Said D, Fourney DR, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg. 2001;95(2):190-8.
Kim TS, Halliday AL, Hedley-Whyte ET, et al. Correlates of survival and the Daumas-Duport grading system for astrocytomas. J Neurosurg. 1991;74(1):27-37.
Shapiro WR, Shapiro JR. Biology and treatment of malignant glioma. Oncology. 1998;12(2):233-246.
Krieger MD, Chandrasoma PT, Zee CS, et al. Role of stereotactic biopsy in the diagnosis and management of brain tumors. Semin Surg Oncol. 1998;14(1):13-25.
Paleologos TS, Dorward NL, Wadley JP, et al. Clinical validation of true frameless stereotactic biopsy: analysis of the first 125 consecutive cases. Neurosurgery. 2001;49(4):830-5.
Fine HA, Dear KB, Loeffler JS, et al. Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer. 1993;71(8):2585-97.
Shaw EG, Daumas-Duport C, Scheithauer BW, et al. Radiation therapy in the management of low-grade supratentorial astrocytomas. J Neurosurg. 1989;70(6):853-61.
Shrieve DC, Alexander E 3rd, Wen PY, et al. Comparison of stereotactic radiosurgery and brachytherapy in the treatment of recurrent glioblastoma multiforme. Neurosurgery. 1995;36(2):275-84.
Karim AB, Afra D, Cornu P, et al. Randomized trial on the efficacy of radiotherapy for cerebral low-grade glioma in the adult: European Organization for Research and Treatment of Cancer Study 22845 with the Medical Research Council study BRO4: an interim analysis. Int J Radiat Oncol Biol Phys. 2002;52(2):316-24.
Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet. 2004;363(9422):1665-72.
O'Neill BP, Iturria NJ, Link MJ, et al. A comparison of surgical resection and stereotactic radiosurgery in the treatment of solitary brain metastases. Int J Radiat Oncol Biol Phys. 2003;55(5):1169-76.
Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med. 1999;341(7):476-84.
Prados MD, Russo C. Chemotherapy of brain tumors. Semin Surg Oncol. 1998;14(1):88-95.
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-96.
Westphal M, Hilt DC, Bortey E, et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro-oncol. 2003;5(2):79-88.
Antonadou D, Paraskevaidis M, Sarris G, et al. Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. J Clin Oncol. 2002;20(17):3644-50.
Prados MD, Berger MS, Wilson CB. Primary central nervous system tumors: advances in knowledge and treatment. CA Cancer J Clin. 1998;48(6):331-60.
Roth W, Weller M. Chemotherapy and immunotherapy of malignant glioma: molecular mechanisms and clinical perspectives. Cell Mol Life Sci. 1999;56(5-6):481-506.
Butowski N, Chang SM. Small molecule and monoclonal antibody therapies in neurooncology. Cancer Control. 2005;12(2):116-24.