Brain Tumors

Introduction

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. Many newly diagnosed brain tumors represent metastases from malignancies originating elsewhere in the body, and the incidence of metastatic lesions is increasing. Primary brain tumors, many of which resemble normal glial cells and are known as gliomas, arise directly from CNS tissue. Though they represent less than 2% of all cancers, they are the most common solid tumors in children. In addition, there is an increasing number of 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 60 years [1]. This may be attributable to the combined effects of aging immune systems and prolonged exposure to environmental carcinogens.

Whether these lesions are benign or malignant, CNS tumors can be devastating to a patient's overall functioning and quality of life. Thus, they often warrant symptom directed management.

Epidemiology and Etiology

Incidence of about 188,500 total new cases of brain tumors yearly in the United States [2,3]. Most 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 25,000 cases each year [4]. Many of these tumors occur in the Caucasian population. Primary malignant brain tumors are a third more common in men than women and are the most common solid tumors in children [5-7].

Mortality of 18,760 deaths in the United States annually for primary brain tumors [8]. 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 most frequent cause of cancer death [2].

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 about 5% of all brain tumors. Tumors associated with these syndromes tend to be gliomas in children and young adults [8, 9].

Risk factors [10-12]

• 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 may increase risk for brain tumors
• Lower socioeconomic status [13]
• The presence of non-CNS primary malignancies
• Brain metastases are increasing in incidence and are present in 20-40% 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

Screening Recommendations

• There is no current role for 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

Clinical Presentation, Work Up and Diagnosis

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, dysgraphia, alexia, construction apraxia, anomia, visual perception abnormalities
• Temporal lobe: hearing changes, hallucinations, behavioral disturbances, emotional changes, receptive aphasia, dysnomia, spatial disorientation
• Occipital lobe: visual field defects, blindness, hallucinations
• Thalamus/Hypothalamus:  sensory/endocrine/emotional abnormalities, visual field defects
• Pituitary: amenorrhea and galactorrhea in women and impotence in men (from the secretion of prolactin by secretory pituitary adenomas), visual field defects
• Brain stem: cranial nerve defects, sensory defects, ataxia, paralysis, change in consciousness, vertigo, sleep dysfunction
• Cerebellum: ataxia, vertigo, dysarthria, visual dysfunction, nystagmus

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.

Histopathology

• Neurofilaments: Medulloblastoma
• Synaptophysin: Medulloblastoma
• GFAP: Astrocytoma, glioblastoma, oligodendroglioma
• S100: Schwannoma

Radiologic studies

• MRI scans are preferred over CT scans in patients with signs or symptoms of an intracranial tumor. MRIs are also more sensitive than PET scans
• MRIs should be obtained with and without contrast
• High-grade and malignant primary tumors typically appear as contrast-enhancing mass lesions with surrounding edema
• 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 [11]. Brain metastases typically present as one or multiple enhancing, well circumscribed lesions along the gray-white matter junction, likely owing to narrowing of vasculature in this region [14].

Histologic Type, Grade and Molecular Markers

Definitive diagnosis is achieved by obtaining a tissue sample either through tissue biopsy or at the time of surgical resection. The diagnosis of a primary brain tumor is highly reliant on molecular markers. The presence or absence of certain markers determines the primary tumor subtype. Molecular markers can also serve as targets for directed therapies. These are obtained from tissue samples obtained from biopsy or surgical resection. Tumor grading is assigned based on pathologic features seen under the microscope.

There are several markers in adult gliomas of particular importance:

• Isocitrate dehydrogenase (IDH) mutations are common in oligodendrogliomas and astrocytomas and confer improved prognosis. IDH-wildtype, however, is commonly associated with GBMs which confers poor overall survival [15]. One study found a nearly 40% difference in overall survival in IDH-mutated tumors as compared to IDH-wild type tumors at any time point [16].
  • Astrocytomas may be grade 2, 3 or 4
  • GBMs are always grade 4 tumors
• 1p/19q codeletions are associated with oligodendrogliomas. This marker predicts response to PCV chemotherapy and is a favorable prognostic indicator
  • Oligodendrogliomas may be grade 2 or 3
• O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status is an important marker in GBM. Tumors that are MGMT methylated have improved survival and response to treatment with temozolomide as compared to non-methylated tumors

WHO Grade 1 pilocytic astrocytomas are associated with BRAF mutations in pediatric patients

Staging of primary brain tumors is often not applicable since they very rarely spread to regional lymph nodes or distant sites. For some tumors commonly found in children, such as medulloblastoma and ependymoma, 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 [11].

Natural Course and Pathology

Low grade:

Grade 1: Non-malignant, well-circumscribed, carcinoma in situ (An example is a pilocytic astrocytoma)

Grade 2: malignant or non-malignant, can recurHigh grade:

Grade 3: malignant, often recur

Grade 4: fast growing, aggressive tumors (Often associated with glioblastoma)

Gliomas 

Gliomas are the most common primary brain tumors in adults and represent 80% of all malignantprimary brain tumors [5,8]. These tumors are derived from glial cells, which include astrocytes, oligodendrocytes, and ependymal cells. Generally, WHO grade 2 gliomas tend to grow slowly and have a better prognosis than higher grade 3 and 4 tumors. Grade 2 astrocytomas and oligodendrogliomas, however, may transform into a higher-grade tumor years later. Oligodendrogliomas represent about 5% of gliomas and are defined by presence of an IDH mutation and 1p/19q codeletion [8]. When compared to other gliomas, these tumors have a favorable response to chemotherapy and radiotherapy and thus have an improved prognosis.

GBMs are the most common and most invasive glial tumors (58%) [8]. They are always considered grade 4, commonly lack a mutation in IDH and are associated with a poor prognosis. Primary GBMs (~90% of cases) arise de novo, while secondary GBMs (~10%) transform from a lower-grade astrocytoma or oligodendroglioma [17]. 

Other CNS tumors include:

• Ependymomas, which are less common and are usually considered low-grade tumors [10]
• Medulloblastomas are more common in children, representing 10-20% of all pediatric primary brain tumors [18, 19]. These tumors usually arise in the posterior fossa and tend to spread along CSF pathways to the spine, referred to as “drop metastases.” Along with histologically similar pineoblastomas, ependymoblastomas, and neuroblastomas, these tumors are often considered primitive neuroectodermal tumors (PNETs)
• 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 beyond molecular markers that are 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 (can lead to earlier diagnosis), normal neurological exam and mini-mental status exam, adjuvant radiation therapy, limited evidence of necrosis, and preoperative tumor size <5 cm.

For patients with brain metastases, a lone metastatic brain lesion and control of the primary malignancy are favorable prognostic factors. As above, genetic abnormalities and molecular markers are becoming increasingly recognized as having prognostic value [17, 20, 21, 22-27].

Treatment

Supportive Therapy: many patients initially receive corticosteroids (often dexamethasone) to reduce intracranial pressure and peritumoral edema. Clinically, this can improve symptoms related to increased intracranial pressure, such as headaches, blurry vision, weakness, or numbness. Antiepileptic medications (often levetiracetam [Keppra]) 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 most 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 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 [28].

• Surgical approaches: biopsies and resections may be achieved using 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 and using the fluorescent dye, 5-aminolevulinic acid (5-ALA).
• 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% [11, 29, 30].
• 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) [24-26].
• 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 [11].
• 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 treat low-grade gliomas, inoperable or recurrent benign and malignant CNS tumors, and metastatic brain lesions [31,32].

• Radiation therapy approaches: stereotactic radiotherapy (conventionally fractionated also, but with highly focused beam); 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 [33].
• Proton therapy may be considered if the patient is felt to be an appropriate candidate.
• 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 high grade astrocytomas and 25% for those with GBMs [11].
• Low-grade tumors: radiation therapy may not be needed 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 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 [11, 34].
• Adding chemotherapy to RT in patients with a low-grade glioma at high risk of recurrence is standard of care. One trial showed the addition of chemotherapy to RT extended PFS to 10.4 years vs. 4.0 years with RT alone [35].
•  Brain Metastases
  • The optimal management of brain metastases requires a multidisciplinary approach and shared decision making with the patient. Additionally, one should consider how well the extra-cranial disease is controlled, available targeted therapies and the patient’s performance status/eligibility for surgery.
  • While prior studies have shown that upfront whole brain radiation may result in better tumor control when compared to stereotactic radiosurgery (a more focal treatment), some patients may experience cognitive dysfunction after whole brain radiation, leading to a decrease in quality of life. Thus, some patients and providers may opt for radiosurgery, with the understanding that there may be a higher risk of recurrence in the brain.
    • Patients with three or fewer metastatic lesions may undergo stereotactic radiosurgery alone or in combination with surgery if the lesions are resectable. The combination of surgery and SRS achieved lower rates of local recurrence relative to surgery alone (42% vs 72%, P=0.015) [36].
    • For patients with at least 4 lesions, 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.
      • 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) [37].
    • 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) [39]

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 PCV combination of procarbazine (Matulane), vincristine (Vincasar), and lomustine (CCNU) are the most used chemotherapeutic agents.

• Oligodendrogliomas are among the most chemoresponsive brain tumors, with response rates of >75% with temozolomide or PCV.
• Astrocytic tumors, including GBMs are generally more chemoresistant. However, surgery followed by radiotherapy and concomitant temozolomide chemotherapy remains the standard of care.
• 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) [42].
• In a 787-patient multicenter retrospective comparison of RT/TMZ vs. Gliadel + RT/TMZ showed further prolongation of OS and PFS (18.4 months vs. 20.0 months, 10 months vs 12 months, p=0.0048) [43].

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. With the rise of target therapies, that cross the blood brain barrier, patients are living longer with cancer that has spread to the brain. One example is Osimertinib, a targeted therapy for patients with EGFR+ lung cancer. Please refer to the MD2B Core Courses menu to find more information about primary tumor types and their treatments.

• Temozolomide has been studied extensively for brain metastases, showing only modest efficacy. The strongest evidence for the use of temozolomide for brain metastases is in the setting of metastatic melanoma or small cell lung cancer [44].

Immunotherapies have shown considerable promise for treating brain metastases. One trial followed melanoma patients with brain metastasis treated with a combination of ipilimumab and nivolumab and found a three-year OS rate in asymptomatic and symptomatic patients of 71.9% and 18.9%, respectively [45].

Experimental therapies: The last few decades have seen considerable progress owing to an increasing identification and knowledge of the genetic and molecular basis of brain malignancy progression.  While targeted therapies continue to be developed with great promise, immunotherapies have taken the center stage for the treatment of brain cancer. The following therapies are usually part of multimodality treatment approaches and are being investigated in clinical trials for patients with brain malignancies [47-49]:

• IDH1/2 inhibitors: in a double-blind phase III trial with 331 IDH-mutant GBM patients, vorasidenib showed significantly increased progression free survival relative to placebo (27.7 months vs. 11.1 months, P<0.001) [50].
• 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 [51].
• Biologic agents: interferon, adoptive immunotherapy, anticancer vaccines, and oncolytic viruses in patients with high-grade gliomas.
• Blood-brain barrier (BBB) disruption: numerous attempts have been made to increase the permeability of the BBB but have shown little success. Compounds currently under investigation include Avidin-biotin, nanoparticle drug carrriers, Arginine-glycine-aspartic acid (RGD) drug conjugates and liposomal drug delivery [52].
• 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.