Primary brain tumors

Primary tumors originate in the CNS, whereas metastatic or secondary tumors spread to the CNS from systemic cancer sites outside the brain. Characteristics of the most common brain tumors are discussed in the following paragraphs, with information provided regarding age at onset, location, medical treatment, and prognosis.

Gliomas are primary tumors that arise from supportive tissues of the brain and are frequently located in the cerebral hemispheres. These tumors may also occur in the brain stem, optic nerve, and spinal cord. In children, the cerebellum is a primary location for gliomas. Gliomas have four primary categories and are classified by their predominant cellular components: astrocytomas and oligodendrogliomas originate from glial cells, ependymomas from ependymal cells, and medulloblastomas from primitive cells.

Astrocytomas are derived from astrocytes, which are star-shaped glial cells, and are the most common glial tumor in adults and children. Astrocytomas vary in morphology and biological behavior, from those that are diffuse and infiltrate surrounding brain structures, to those that are circumscribed with a decreased likelihood of progression. In adults, the typical age of onset is after age 45, with the tumor frequently found in the frontal lobe. Most childhood astrocytomas occur in the cerebellum. ^,

Astrocytomas are further classified into four grades: pilocytic astrocytoma (grade I), which are well-differentiated, relatively benign low-grade tumors most common in children and young adults; diffuse astrocytoma (grade II), which are well-differentiated, low-grade tumors that grow slowly; anaplastic astrocytoma (grade III), which are high-grade tumors that typically have tentacle-like projections growing into the surrounding brain tissue and grow more rapidly; and glioblastoma (grade IV), which is the most aggressive of the astrocytoma tumors. The glioblastoma can be primary or evolve from a lower grade astrocytoma (secondary). The higher the grade, the worse the prognosis. ^,

Astrocytomas are typically treated with surgery, radiation therapy, and chemotherapy, depending on the grade, location of the tumor, age of the patient, and Karnofsky performance scale score ( Table 25.1 ). ^{, ,} Typically, lower grade tumors are treated with surgery followed by radiation if necessary. Grade III tumors are treated with surgery, followed by radiation and possibly chemotherapy when needed. The lower grade tumors, pilocytic astrocytomas, carry a 5-year survival rate of 94%; however, patients with grade III astrocytomas have a 5-year survival rate of only 29.8%.

Glioblastoma is the distinct name given to the highly malignant grade IV astrocytoma. These tumors grow rapidly, invade nearby tissue, and contain highly malignant cells. Glioblastomas are predominantly located in the deep white matter of the cerebral hemispheres, but may be found in the brain stem, cerebellum, or spinal cord. Fifty percent of these tumors are bilateral or occupy more than one lobe of a hemisphere. Glioblastomas account for 14.9% of all primary brain tumors and 47.1% of all primary malignant brain tumors (see Fig. 25.1 ). They are most common in older adults, with males having a 1.6:1 incidence rate over females. In children and adolescents (aged 0 to 19 years), only 3% of brain and other CNS tumors are glioblastomas. The medical prognosis is poor for patients with glioblastoma: less than 40% survive more than 1 year and less than 5.5% survive 5 years. Researchers have recently discovered that glioblastomas have four distinct genetic subtypes that respond differently to aggressive therapies, making treatment difficult and challenging. These tumors are treated by surgical resection (only part of the tumor is typically resected), radiation therapy, stereotactic radiosurgery, and chemotherapy. ^,

Oligodendrogliomas are slow-growing but progressive tumors that typically develop over a period of several years. These tumors are most commonly located in the frontal and temporal lobes; however, they can be found anywhere in the cerebral hemisphere. Seizures, headaches, and personality changes are the primary clinical manifestations of the tumor. Oligodendrogliomas typically appear in the fourth to sixth decades of life, and the ratio of affected males to females is 2:1. These patients have a 5-year survival rate of 81% and 10-year survival rate of 65%. The 5-year survival rate decreases to 56% with anaplastic oligodendroglioma. Treatment is dependent on symptoms and ranges from observation and seizure control with anticonvulsant drugs to surgical resection, radiation, and chemotherapy. ^,

Ependymomas are tumors arising from ependymal cells—cells that line the ventricles of the brain and central canal of the spinal cord. These cells have glial and epithelial characteristics. Ependymomas grow into the ventricle or adjacent brain tissue. The most common site is the fourth ventricle (70% originate here), and they occur less frequently in the lateral and third ventricles. Ependymomas are primarily treated with surgical resection followed by radiation therapy; however, chemotherapy is also used to treat tumor recurrence or when trying to delay radiation in young children. ^, Because of increased intracranial pressure (ICP), a shunt is commonly placed to improve survival. These tumors frequently recur, and prognosis is dependent on the success of resection, with a 5-year survival rate approaching 84%.

Medulloblastomas are malignant embryonal tumors thought to arise from primitive neuroectodermal cells—specifically pluripotential stem cells that have been prevented from maturing to their normal growth-arrested state. These tumors are typically located in the cerebellum. Medulloblastomas typically grow into the fourth ventricle, blocking cerebrospinal fluid (CSF) flow, and cause hydrocephalus and ICP. These tumors primarily occur in children or adults under the age of 45, accounting for 8% of childhood (0 to 14 years) brain tumors. The most common age of onset is 7 years old, with a prevalence in males over females. ^, An overall 5-year survival rate of 73% has been noted among adults and children, and the most common treatment is surgery followed by radiation and chemotherapy. ^{, ,}

Meningiomas are slow-growing tumors that primarily originate from cells located in the dura mater or arachnoid membrane, and account for 36.8% of reported brain tumors. ^, The incidence increases with age, with a more dramatic increase over age 65, and in females at a 2:1 ratio over males. ^{, ,} Often clinical symptoms are not manifested until the growing tumor compresses adjacent structures. Headache and weakness are the most common symptoms, followed by seizures, personality changes, and visual deficits. ^, If possible, tumors are treated with surgical resection. Recurring tumors are treated with surgery, radiation therapy, or stereotactic radiosurgery. Tumors in highly eloquent areas of the brain, however, may best be treated with serial scans to monitor for growth and compression of neural structures. ^, Patients with nonmalignant meningiomas (most meningiomas are not malignant) have a 10-year survival rate of 81.4% versus a 10-year survival rate of 57.4% with malignant meningiomas.

Pituitary adenomas are benign epithelial tumors originating from the adenohypophysis of the pituitary gland and frequently encroach on the optic chiasm. These tumors are characterized by hypersecretion or hyposecretion of hormones. Age at onset spans all ages, but pituitary adenomas are rare before puberty, more common in older people, and more common in females than males, especially during child bearing years. These tumors are primarily treated by surgical resection, drug therapy, and radiation. ^, Prognosis is dependent on tumor size and cell type, with a 5-year survival rate of 96%.

Schwannomas are encapsulated tumors composed of neoplastic Schwann cells that can arise on any cranial or spinal nerve. A schwannoma on the eighth cranial nerve is called an acoustic neuroma . The tumors’ location on the nerve produces otological, focal, or generalized neurological impairments. These tumors are often located in the internal auditory canal but may extend into the cerebellopontine angle. ^, Treatment typically involves surgical resection; however, stereotactic radiosurgery is increasing in popularity as an alternative method of treatment when the tumor is near vital nerves or blood vessels. The prognosis for patients with these tumors is good, yet complications can result from treatment, including facial paralysis, deafness, and equilibrium impairments. Deficits after surgery vary depending on the size and location of the tumor. A 10-year follow-up study looking at low dose linear accelerator stereotactic radiosurgery confirmed excellent tumor control and acceptable cranial neuropathy rates but a continual decrease in hearing preservation.

Primary CNS lymphomas are rare tumors arising from cells in the lymphatic system, representing only 2% of primary brain tumors. These lymphomas have a slightly higher incidence in men and peak in the sixth through eighth decades of life. The tumor cells are similar in histology to systemic non-Hodgkin lymphoma cells, but it is uncertain how this tumor arises, as the CNS lacks lymphatic tissue. ^, The tumor may be solitary or multifocal, forming a poorly defined mass that may be difficult to distinguish from an astrocytoma. Primary brain lymphomas appear primarily in the cerebral hemispheres, and the most common symptoms are behavioral and personality changes, confusion, dizziness, and focal cerebral signs, rather than headache and other signs of increased ICP. ^, Surgical resection is typically ineffective because of the deep location of these tumors. Radiation, chemotherapy, and steroids are the most common forms of treatment; however, the tumor recurs in 90% of individuals. CNS lymphoma carries a poor prognosis, with only 33% of patients surviving longer than 5 years.

Secondary brain tumors: Metastatic brain tumors

Metastatic brain tumors originate from malignancies outside of the CNS and spread to the brain, typically through the arterial circulation. Approximately 25% of individuals with systemic cancer develop brain metastases, with approximately 80% of tumors in cerebral hemispheres and 20% in the posterior fossa. ^, One-third of brain metastases originate in the lung, followed by the breast, skin, gastrointestinal tract, and kidneys in order of frequency. Common clinical manifestations of metastatic brain tumors are similar to those of gliomas, including seizures, headache, focal weakness, mental and behavioral changes, ataxia, aphasia, and signs of increased ICP.

Treatment for these tumors is tailored to the individual and dependent on the management of the systemic disease, the accessibility of the lesion, and the number of lesions. Current treatment regimens include surgery and radiosurgery if the lesions are limited in number and accessible. Chemotherapy and whole brain radiation therapy (WBRT) may also be used. The average survival with treatment is approximately 6 months but varies widely and is affected by the extent of other systemic metastases. With some radiosensitive tumors, survival increases to 15% to 30% for 1 year and 5% to 10% for 2 years.

General signs and symptoms

General signs and symptoms of the presence of a brain tumor include headache, seizures, altered mental status, and papilledema. Headache is the presenting symptom in 50% of brain tumor cases; however, it is rarely the sole complaint or symptom in these patients. ^, It is important to identify the specific nature of the headaches, as certain features often indicate the presence of a brain tumor. These features include the following:

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  The headache interrupts sleep or is worse on waking and improves throughout the day.

  
  
• 2.
  

  The headache is elicited by postural changes, coughing, or exercise.

  
  
• 3.
  

  The headache of recent onset is more severe or a different type than usual.

  
  
• 4.
  

  The new onset of headache occurs in an older person.

  
  
• 5.
  

  The headache is associated with nausea and vomiting, papilledema, or focal neurological signs. ^{, ,}

Headaches can be caused by local tissue edema, distortion of blood vessels in the dura overlying the tumor, and increased ICP. The location of the headache is typically determined by the tumor’s location. Tumors above the tentorium cause headaches on the same side as the tumor and the immediate surrounding area. Posterior fossa tumors cause headaches in the occipital lobe and ipsilateral retroauricular area. Increased ICP causes bi-frontal or bi-occipital headaches regardless of the tumor location. ^,

Seizures are a frequent symptom in patients with a brain tumor, and a first seizure during adulthood is suggestive of a brain tumor. ^, Seizure incidence and management is dependent on the tumor type, location, and at what point in the disease course the seizure presents. Seizures may be solitary or occur frequently, preceding or following other symptoms. More than 50% of patients with gliomas experience recurrent seizures, while only 11% of patients with brain metastases experience recurrent seizures. Tumors can cause epilepsy, and the prognosis for complete seizure control in patients with tumor related epilepsy is poor.

Altered mental status including cognitive and mental deficits are frequently seen in patients with brain tumors. Cognitive changes range from decrease in concentration, memory, affect, personality, initiative, and abstract reasoning to severe cognitive deficits and confusion. Subtle changes may be incorrectly attributed to worry, anxiety, or depression. Changes in mentation are common with frontal lobe tumors and in the presence of elevated ICP. Increased ICP causes drowsiness and decreased level of consciousness, which can progress to stupor or coma if edema is not immediately reduced.

The incidence of papilledema, swelling of the optic nerve, is less frequent today because brain tumors are being diagnosed earlier with the use of sensitive imaging techniques. Papilledema is associated with symptoms of transient visual loss, especially with positional changes, and reflects evidence of ICP transmitted through the optic nerve sheath. Papilledema is more common in children than adults.

Vomiting and dizziness are other less common symptoms associated with brain tumors located in the posterior fossa. ^, Vomiting can indicate a generally elevated ICP but can also occur due to pressure on the vomiting center (posterior fossa) with brain stem tumors. Projectile vomiting is usually seen in posterior fossa tumors in children but not adults. Dizziness and/or positional vertigo can be a symptom of a tumor in the posterior fossa but also has other more common benign causes.

Specific signs and symptoms

Certain clinical features are related to functional areas of the brain and thus have a specific localizing value in medically diagnosing a brain tumor. Therefore it is essential that clinicians be familiar with the lobes of the brain and their distinct functions to effectively manage the impairments resulting from the tumor ( Fig. 25.2 ). These symptoms may vary among individuals and result in physical and cognitive deficits that range from mild to severe.

Correlation between clinical symptoms and anatomical location of the tumor.

(Used with permission from Barrow Neurological Institute.)

The frontal lobe is responsible for motor functioning, initiation of movement, and interpretation of emotion, including motor speech, motor praxis, attention, cognition, emotion, intelligence, judgment, motivation, and memory. Therefore frontal lobe tumors may result in movement disorders such as hemiparesis, seizures, aphasia, and gait difficulties, and cognitive impairments including personality changes such as disinhibition, irritability, impaired judgment, and lack of initiation. Initially, the tumor may be clinically silent; however, as the tumor grows, progressive symptoms develop based on the tumor’s location in the frontal lobe.

The parietal lobe processes complex sensory and perceptual information related to somesthetic sensation, spatial relations, body schema, and praxis. General symptoms of a parietal lobe tumor include contralateral sensory loss and hemiparesis, homonymous visual deficits or neglect, agnosias, apraxias, and visual-spatial disorders. If the dominant parietal lobe is involved, agraphesthesia, left-right confusion, and finger agnosia are typically present. With nondominant parietal lobe involvement, contralateral neglect and limited awareness of impairments is commonly found. Seizures with focal onset are often associated with tumors in the parietal lobe—particularly those in the region of the motor cortex.

The occipital lobe is the primary processing area of visual information. Therefore lesions of the occipital lobe often result in dysfunction of eye movement and homonymous hemianopsia. If the parieto-occipital junction is involved, visual agnosia and agraphia are often present. Seizures are not common with occipital lobe tumors.

The temporal lobe is responsible for auditory and limbic processing. If the lateral hemispheres are involved, auditory and perceptual changes may occur. When the medial aspects are affected, changes in cognitive integration, long-term memory, learning, and emotions may be seen. Anomia, agraphia, acalculia, and Wernicke aphasia (fluent, nonsensical speech) are specific to left temporal lobe lesions. Similar to the parietal lobe, seizures are common with temporal lobe tumors.

The cerebellum is responsible for coordination and equilibrium. Midline cerebellar lesions can compromise CSF flow and produce hydrocephalus, resulting in truncal ataxia. Lateral tumors are typically larger and are associated with limb ataxia (upper greater than lower extremity) and impaired coordination and nystagmus. Tumors invading the cerebellar pontine angle present with hearing loss, headache, ataxia, dizziness, and tinnitus. Facial palsy may occur due to cranial nerve compression, especially in the facial and acoustic nerves. If the cerebellar tumor infiltrates the meninges at the foramen magnum causing cerebellar tonsil herniation, sudden death may occur due to fourth ventricle obstruction and compression of the medulla.

The brain stem , which communicates information to and from the cerebral cortex via fiber tracts, controls vital life functions. Even small tumors invading or compressing the brain stem can lead to death or devastating signs and symptoms. Within the brain stem, the reticular formation of the pons and medulla controls consciousness, sleep, and attention. If the reticular system is involved, symptoms of apnea, hypoventilation or hyperventilation, orthostatic hypotension, or syncope may occur. Symptoms of a brain stem tumor have an insidious onset and may include gait disturbances, diplopia, focal weakness, headache, vomiting, facial numbness and weakness, and personality changes. If the dorsal midbrain is involved, Parinaud syndrome, characterized by loss of upward gaze, pupillary areflexia to light, and loss of convergence, may be seen. ^,

The pituitary gland is an endocrine gland that secretes the hormones necessary to regulate the functions of the other endocrine glands in the body. The symptoms of pituitary tumors are caused by either a hypersecretion of hormones or the tumor compressing the gland itself, resulting in hormone hyposecretion (pituitary hypofunction). The symptoms that present are based on the specific hormone excess or deficiency, which can include headache, depression, vision loss, nausea and/or vomiting, behavior and cognitive changes, abnormal weight gain, abnormal growth in hands and feet, hair growth in women, amenorrhea, and impotence in men. ^,

Conventional imaging

CT and magnetic resonance imaging (MRI) are the most common imaging modalities used to assess neurological deficits. Acutely, CT is a cost-effective method to quickly detect a hemorrhage; however, MRI is the modality of choice to evaluate a brain tumor. Conventional MRI provides exquisite anatomical details about tumor size and location, as well as surrounding intracranial structures. With MRI, different signal intensities differentiate normal brain from tumor and contrast enhancement sharpens the definition of a lesion. MRI enhanced with gadolinium can distinguish between tumor and edema. Conventional MRI sequences with T1W, T2W, and fluid attenuated inversion recovery (FLAIR) are commonly used with cerebral malignancy. ^, Although conventional MRI can evaluate edema, hydrocephalus, and hemorrhage, it cannot reliably predict subtype or grade of glioma, and advanced imaging may be indicated to identify the pathophysiological characteristics of the tumor.

Advanced imaging

After the diagnosis has been confirmed, advanced imaging techniques are utilized to evaluate the cellular, hemodynamic, metabolic, and functional properties of the tumor have been shown to improve diagnostic, intraoperative, and postoperative management. Understanding pathophysiological properties such as microscopic tumor infiltration, microvascular characteristics, and early response changes is critical to the ongoing management of brain tumors. Advanced imaging improves the delineation of tumor margins and evaluates the extent of tumor invasion, including its relationship to eloquent cortical areas and major white-matter tracts. This advanced knowledge of the tumor has allowed for improvements in identifying optimal biopsy sites and making critical preoperative decisions, resulting in more effective treatment interventions. ^,

Diffusion-weighted imaging

Diffusion-weighted imaging (DWI) is a quantitative technique routinely used in research and clinical settings. DWI utilizes MR to analyze the diffusion of water molecules in the extravascular extracellular space and determines an apparent diffusion calculation (ADC). ADC can measure cellularity, cell density, and properties of the extracellular matrix. Restricted diffusion favors increased cellularity and therefore is a sign of tumor progression. DWI has the capability of detecting tumor progression before it can be seen with contrast enhancement.

Functional magnetic resonance imaging

Functional MRI (fMRI) has become an important clinical tool in surgical planning by identifying eloquent areas of the cortex and their relationship to the tumor. When patients perform different tasks, fMRI can identify the different areas of the brain activated during the task. Research has shown that fMRI can be used for accurate mapping of motor, sensory, and language areas. ^, Identifying these critical areas preoperatively can ultimately improve a patient’s quality of life by preserving these critical areas during surgery.

Magnetic resonance spectroscopy

Magnetic resonance spectroscopy (MRS) is used in conjunction with other imaging techniques to assess the molecular content of brain tumors by using an imaging voxel. Placement of the voxel in the center of the tumor ensures the sample contains only tumor cells. MRS has been shown to discriminate tumor recurrence from radiation necrosis. Studies have identified Cho, a marker that identifies membrane turnover, which can identify the progression of low to high-grade malignant tumors.

Perfusion weighted imaging

Perfusion weighted imaging (PWI) evaluates microvasculature and can indirectly measure the metabolic activity of a tumor. Tumors can initiate angiogenesis, developing blood vessels that are histologically disorganized, tortuous, and more permeable than normal. These pathological vessels lead to hemodynamic changes that can be identified with perfusion imaging. Newer methods of MR perfusion with arterial spin labeling are completely noninvasive and do not require contrast media.

Molecular imaging

Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are molecular imaging techniques that utilize radioactive compounds to study the metabolism and physiology of the brain tumor and the surrounding tissue. PET scans using radioactive markers to measure glucose metabolism can be useful in determining the grade of primary brain tumors and in differentiating tumor regrowth from radiation necrosis. PET with carbon 11 methionine tracer can differentiate between high- and low-grade tumors. PET, along with MRS and magnetic resonance perfusion, are being explored as possible methods to distinguish tumor progression from treatment-related pseudoprogression. SPECT evolved from PET and uses isotopes to assess cerebral blood flow and determine tumor location. SPECT with Thallium-201 chloride can be used to stage gliomas and assess the tumor postoperatively; however, its anatomical resolution is limited. ^, PET and SPECT are not commonly used clinically due to high expense and limited availability, especially if other more cost-effective imaging modalities yield the same reliable diagnosis.

Biopsy

Surgical biopsy is performed to obtain tumor tissue as part of tumor resection or as a separate diagnostic procedure. Stereotactic biopsy is a computer-directed needle biopsy. When guided by advanced imaging tools, stereotactic biopsy yields the lowest surgical morbidity and highest degree of diagnostic information. This technique is frequently used with deep-seated tumors in functionally important or inaccessible areas of the brain in order to preserve function.

In the past, the biopsy site of a deep inoperable lesion was selected based on areas of solid enhancement on T1-weighted gadolinium-enhanced MRI or contrast-enhanced CT. However, sometimes a higher grade glioma would be misdiagnosed as a lower grade if necrotic tissue was centrally located and contained in the biopsy. Newer modalities, MRS and PET imaging, highlight those areas of greatest metabolic activity, thereby improving diagnostic yield and minimizing sampling error. PET with carbon 11 tracer can detect the most malignant areas of the tumor improving the accuracy of diagnosis. Recently, a procedure in which a neuroendoscope simultaneously treats hydrocephalus while obtaining the biopsy (endoscopic tumor biopsy) has been successful with midline paraventricular gliomas.

Molecular diagnosis

As discussed earlier in the chapter, molecular and genetic characteristics of glial tumors are now being incorporated into tumor classification. Studies of the molecular pathology of gliomas have led to the discovery of molecular biomarkers that can be used to improve diagnosis, estimate prognosis, and determine treatment efficacy. Researchers have discovered specific tumor mutations can be used as prognostic indicators and imaging can play a vital role in identifying these characteristics. Conventional MRI can identify enhancement, necrosis, and edema, which are associated with poor outcomes. Mutations specific to oligodendrogliomas and glioblastomas are also visible on MRI. MR imaging with 5-ALA increases the concentration of intracellular iron by synthesizing heme in glioblastoma.

Traditional surgery

The primary goal of traditional surgery is maximal tumor resection with the least amount of damage to neural or supporting structures. Gross total resection is associated with longer survival rates and decreased neurological impairment. Benign tumors, if accessible, are resected completely, whereas malignant tumors are typically partially resected secondary to location or size of the tumor. The purposes of surgery in the management of brain tumors include the following:

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  Biopsy to establish a diagnosis

  
  
• 2.
  

  Partial resection to decrease the tumor mass to be treated by other methods

  
  
• 3.
  

  Complete resection of the tumor

Biopsies are performed through open, needle, and stereotactic needle techniques. Open biopsies involve exposure of the tumor followed by removal of a sample through surgical excision. Needle biopsies involve insertion of a needle into the tumor through a hole in the skull and the excision of the tissue sample drawn through the needle. Stereotactic needle biopsies use computers and MRI or CT scanning equipment to assist in directing the needle into the tumor. This type of biopsy is useful for deep-seated or multiple brain lesions.

Partial and complete resections are accomplished through craniotomy. Craniotomy involves removal of a portion of the skull and separation of the dura mater to expose the tumor. Stereotactic craniotomy uses technology to create computed three-dimensional pictures of the brain to guide the neurosurgeon during the procedure. CT scanning and MRI scanners are used to provide an evaluation of the tumor resection during the procedure. Awake craniotomy allows for intraoperative brain mapping that helps identify and protect functional cortex, and in recent years has been used more frequently for most supratentorial tumors.

Preoperative management. Before surgery, patients are evaluated for general surgical risks and the possibility of tumors in additional locations. Unless medically contraindicated, steroids are administered before surgery if brain edema is present or if extensive manipulation is anticipated during surgery. Anticonvulsant medications are also administered preoperatively to prevent seizures during or after surgery.

Intraoperative management. During surgery, precautions are taken to prevent an increase in edema or ICP. Mannitol, a vasodiuretic to decrease ICP, is used to shrink the surrounding brain tissue, thus providing easier access to the tumor. Steroid use is continued and antibiotics are administered to prevent infection. Hyperventilation, with a carbon dioxide (CO ₂ ) level of 25 mEq/L, is also used to reduce ICP.

Postoperative management. Patients are observed in an intensive care unit for at least 24 hours for possible intracranial bleeding or seizures. Blood pressure is monitored continuously. After surgery, patients are at risk for developing deep vein thrombosis or pulmonary embolism, secondary to decreased muscle activity. Anticoagulants cannot be given, because these patients are at risk for intracranial bleeding. Therefore mechanical prophylaxis is used in an attempt to prevent deep vein thrombosis. Steroids are tapered after surgery over 5 to 10 days. Antiepileptic medications are continued after surgery, with the length of time dependent on the presence of seizure activity before and after surgery. The primary limitations of traditional surgery include the following:

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  Medical complications such as hematoma, hydrocephalus, infection, and infarction from the surgical procedure

  
  
• 2.
  

  Complications resulting from general anesthesia

  
  
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  Increased cost of the hospital stay and surgical procedure

Chemotherapy

Chemotherapy is another treatment frequently used to manage brain tumors. It can be used independently or as an adjuvant to surgery or radiation. Chemotherapeutic drugs are not effective on all types of tumors. Some tumors are known to be resistant to certain drugs, and other treatment options must be pursued. Drugs can be given in combination to target all cell types present within the tumor. Because different drugs have different modes of action and side effects, combined drug therapy often proves to be one of the most effective treatments. Chemotherapy can be administered in a number of different ways. Most agents are delivered intravenously through a peripheral intravenous line or through a catheter such as a peripherally inserted central catheter (PICC) or tunneled access central catheter (TACC). Other drugs are placed directly into the tumor bed or are given intramuscularly, orally, or by means of an implanted device.

Chemotherapy drugs impede cellular replication of the tumor cells, interfering with their ability to copy deoxyribonucleic acid (DNA) and reproduce. Once the replicating capability of the tumor cell has been disrupted, the cell dies. In this way, the tumor is prevented from growing and is destroyed at the cellular level.

Methotrexate is a highly toxic drug and is usually paired with an antidote drug, leucovorin, to reverse the side effects on normal cells. Typically methotrexate is used to treat cancer outside of the CNS; however, it is the major chemotherapy drug used to treat CNS lymphoma. The introduction of methotrexate has been found to increase the median survival for patients with primary CNS lymphoma, even those older than 60 years of age.

Neurotoxic to surrounding tissue, methotrexate and cytarabine are drugs able to be introduced directly into the CSF through an intraventricular Ommaya reservoir. The reservoir, implanted under the scalp, is filled by use of a syringe, and the medication is then circulated through the ventricles to the brain. The drugs are routinely given in a clinic setting by a registered nurse certified in chemotherapy administration. A patient’s chemotherapy schedule varies depending on the drug given. An on-off cycle is used to allow the patient time to recover from the drugs’ harmful side effects.

One of the challenges in delivering cytotoxic drugs to the brain is the blood-brain barrier (BBB). The BBB is the brain’s natural protective barrier against transmission of foreign substances from the blood into the brain. One class of drugs that does penetrate the BBB is the nitrosoureas. These include BCNU (carmustine) and CCNU (lomustine), which are lipid soluble and cell cycle specific. These drugs are given in high doses and typically used to treat glioblastoma multiforme and anaplastic astrocytoma; however, often these high-grade tumors invade and destroy the BBB.

BCNU can also be administered in the form of wafers placed by the neurosurgeon directly into the brain tumor. An initial study for recurrent malignant gliomas found that patients’ tumors responded to the treatment. This report was followed by an upfront study for glioblastoma. The US Food and Drug Administration (FDA) granted approval for these wafers (Gliadel) for newly diagnosed high-grade glioma in 2002.

Temozolomide is an orally available chemotherapeutic agent introduced in the 1990s for the treatment of malignant gliomas. Initial results in treating recurrent anaplastic astrocytoma and glioblastoma were so successful that the drug was approved for the treatment of recurrent brain tumors by the FDA. For recurrent tumors the drug is administered orally 5 days per month. Temozolomide was then tested for the upfront treatment of glioblastoma. This occurred in a multicenter study in which the drug was given daily as part of the initial treatment with radiation therapy, followed by five doses per month for maintenance treatment. Survival increased substantially with this regimen, and as a result the FDA approved the use of temozolomide as part of first-line treatment of newly diagnosed high-grade glioma in 2005. The CATNON trial, just completed in 2017, demonstrated temozolomide chemotherapy was associated with significant survival benefits in patients with newly diagnosed anaplastic glioma.

Another major breakthrough in chemotherapy for brain tumors was the finding that the antiangiogenesis monoclonal antibody Avastin (Bevacizumab) improved the progression-free survival and tumor images on MRIs of patients with glioblastoma. The drug targets vascular endothelial growth factor (VEGF) and is administered intravenously. In 2017, the FDA granted full approval for the use of Avastin in the treatment of adults with recurrent glioblastoma. It is usually administered in combination with another chemotherapy agent such as irinotecan.

Radiation therapy

Radiation therapy can be used alone or in conjunction with surgery or chemotherapy to treat malignant brain tumors. It is typically chosen as a treatment option for tumors that are too large or inaccessible for surgical resection and to eradicate residual neoplastic cells after a surgical debulking. Radiotherapy consists of the delivery of high-powered photons, with energies in a much greater range than that of standard x-rays, as an external beam focused directly at the tumor site. The external beam is transmitted to the tumor through a linear accelerator or a cobalt machine that uses cobalt isotopes as the radiation source. External beam radiation is the most widely used form of radiation treatment.

Conventional radiation therapy, as described previously, is fractionated into small doses delivered over a period of weeks. Often, if a large fraction is to be delivered, the dose is divided and given in multiple small doses; this is called hyperfractionation . The aim is to decrease the damage done to healthy surrounding tissue. Studies are investigating the use of a few high ablative doses of radiation known has hypofractionation radiotherapy. Preliminary findings suggest hypofractionation improves tumor growth control and may offer an increase in antitumor immune response as compared with hyperfractionation radiotherapy. ^,

Conformal radiation is the use of high-dose external beam radiation, produced by a linear accelerator, to precisely match or “conform” to the tumor shape. This method attempts to deliver a uniform amount of radiation to the tumor and minimize irradiation of healthy brain tissue.

Radiosurgery involves relatively high-dose hypofractionated radiation beams directed at small tumor areas through the use of computer imaging. This type of treatment includes the Gamma Knife, linear accelerators, and the Cyberknife, which are discussed later.

The radiation oncologist determines the dosage, frequency, and method of radiation delivery, depending on tumor type, location, growth rate, and other medical issues for each patient. A typical course of radiation therapy will last 6 weeks. Patients are irradiated for just 1 to 5 minutes, 5 days a week. The radiation is intended to destroy the malignant cells and preserve healthy ones; however, some rapidly growing cells, such as skin tissue and mucosa, are killed, also producing the common side effects known to radiation.

Radiation therapy has considerable limitations and disadvantages. There is an accepted maximum lifetime dosage of radiation that the brain and body can tolerate. As doses come close to this limit, the risk of radiation necrosis increases. Because the brains of young children are particularly vulnerable to radiation, other therapies, such as chemotherapy, are used until the developing brain is more tolerant of radiation. Metastatic lesions have invaded multiple organs or body systems; therefore a more systemic treatment such as chemotherapy is most effective for this type of brain cancer.

Stereotactic radiosurgery

Stereotactic radiosurgery is defined as delivery of a high dose of ionizing radiation, in a single fraction, to a small, precisely defined volume of tissue. ^, The high-energy accelerators involved improve the physical effect of radiation by allowing energy to travel more precisely in a straight line and penetrate deeper before dissipating. The goal is to arrest tumor growth by disrupting the tumor’s DNA. This technique has been shown to be most beneficial for treating centrally located lesions less than 3 cm in size and for patients with increased surgical risk factors. Advantages of stereotactic radiosurgery are as follows:

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  It is a noninvasive procedure using local anesthesia and sedation to place the stereotactic frame.

  
  
• 2.
  

  It avoids risks of general anesthesia and immediate postoperative risks such as bleeding, CSF leak, and infection.

  
  
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  It lowers treatment cost and shortens hospital stays.

Stereotactic radiosurgery is used to treat benign, malignant, and metastatic tumors; vascular malformations; and functional disorders. The primary modes of administration for stereotactic radiosurgery include the Gamma Knife, linear accelerators, and the Cyberknife. The radiosurgery team consists of a neurosurgeon, radiation oncologist, medical physicist, oncology nurse, dosimetrist, and radiation therapist.

The Gamma Knife was first introduced in Sweden in 1968 and is now used worldwide at more than 300 sites ( Fig. 25.3 ). The Gamma Knife uses 201 discrete sources of cobalt 60, which are focused precisely to one point in three-dimensional space within the cranium. The Gamma Knife is typically used for deeply embedded small tumors, often metastatic, that require precise delivery of radiation. ^,

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