Central Nervous System Tumors

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21 Central Nervous System Tumors

Ashwatha Narayana, MD, Lawrence Recht, MD, Philip H. Gutin, MD

Primary central nervous system (CNS) tumors accounted for an estimated 21,810 new cases diagnosed in the year 2008 in the United States,¹ and for an estimated 13,810 deaths for the same year. The incidence of brain tumors has been slowly increasing at an average rate of 1.1% per year.² However, the death rate has been decreasing over time, and the 5-year relative survival rate for primary brain tumors has improved from 24% during 1975 through 1977 to 35% during 1996 through 2003.¹ There is an early peak of 2 to 3 per 100,000 in the annual age-specific incidence of primary brain tumors in children up to the age of 4 years. A decline occurs between 15 and 24 years, followed by a steady rise, reaching a plateau of 21 per 100,000 between 75 and 79 years of age.³ Several histopathologically different tumors arise in the brain, reflecting the diversity of phenotypically distinct cells within the CNS, that have a capacity for neoplastic transformation.⁴ Malignant gliomas are considered first in this chapter. Many of the principles of brain tumor management are discussed in this section. Tumors that are most common in children but that are also seen in adult patients are reviewed in Chapter 54 and are only briefly presented here. The chapter closes with a discussion on the management of metastatic brain tumors, which constitute the most common type of brain tumor encountered.

Malignant Glioma

Epidemiologic Statistics

Malignant gliomas make up 35% to 45% of primary brain tumors, and of these, nearly 85% are glioblastoma multiforme (GBM).⁴ The incidence of anaplastic astrocytoma (AA) peaks in children younger than 10 years of age and then remains constant in each subsequent decade of life. In contrast, GBM is uncommon before the age of 20 years, whereas the rate of occurrence increases dramatically after the age of 40.³ The incidence of malignant gliomas has increased at least twofold among the elderly during the previous two decades.⁵

Current knowledge of the molecular biology and genetics of the astrocytic neoplasms has been well summarized.⁶ Two genetic pathways, a progression pathway and a de novo pathway, that lead to GBM development have been described (Fig. 21-1). Although primary and secondary GBMs are histologically indistinguishable, it is well accepted that distinct molecular aberrations and pathways lead to the formation of primary (de novo) versus secondary GBMs. Primary GBMs are thought to arise in a de novo manner, without any malignant precursor lesion. Amplification of the epidermal growth factor receptor (EGFR) is thought to be a critical event in the molecular cause of primary GBMs. Secondary GBMs, on the other hand, are thought to arise as a result of the malignant transformation of lower grade gliomas, with overexpression of platelet-derived growth factor, fibroblast growth factor–2, and cyclin-dependent kinase 4, as well as p53 mutations and loss of Rb playing major roles in such transformations. Loss of PTEN has been implicated in both pathways, although it is much more common in the pathogenesis of primary GBM.

FIGURE 21-1 • Genetics of gliomas pathway.

Several hereditary syndromes are associated with an increased risk of brain tumors (Fig. 21-2). Neurofibromatosis-1 is the most common familial tumor syndrome associated with brain tumors.⁷ With the exception of Turcot syndrome, all are inherited in an autosomal dominant pattern. In addition to the association between hereditary syndromes and brain tumors, certain families of brain tumor patients have aggregations of brain tumors and extraneural malignancies. Germ-line p53 mutations have been frequently identified in glioma patients with multifocal lesions, a different second primary malignancy, and a family history of cancer.

FIGURE 21-2 • Hereditary syndromes associated with brain tumors.

Although some environmental factors have been linked with brain tumor development, they do not appear to be responsible for most brain tumors.⁸ Apart from a predisposing genetic syndrome that is present in less than 5% of patients with brain tumors, the only other firmly established cause is ionizing radiation. Radiation-induced gliomas have been reported, and 25% of such cases have arisen in children with acute lymphoblastic leukemia who received prophylactic cranial irradiation and chemotherapy.

Anatomy

The brain is divided into supratentorial and infratentorial compartments by the tentorium cerebelli. The supratentorial compartment includes the cerebral hemispheres and the sellar, pineal, and diencephalic regions, whereas the infratentorial compartment includes the midbrain, pons, medulla, and cerebellum. The cerebral hemispheres are connected by the corpus callosum and are divided into the frontal, parietal, occipital, and temporal lobes. The frontal lobes are concerned with behavior organization, planning and association, and speech; the parietal lobes with motor, sensory, and complex intellectual functions; the occipital lobes with vision; and the temporal lobes with behavior, memory, speech, emotion, and auditory-visual pathways.⁹ Most malignant gliomas arise in the cerebral hemispheres, and the lobar distribution is directly related to the amount of white matter present in each region.

The brain is housed within the bony calvarium, made up of the frontal, ethmoid, parietal, sphenoid, temporal, and occipital bones. The posterior margin of the lesser wings of the sphenoid marks the anterior aspect of the lateral cerebral (Sylvian) fissure, the junction of the frontal and temporal lobes of the brain. The base of the skull can be approximated on the surface of the patient by a line, called the orbitomeatal or Reid baseline, which extends from the infraorbital rim to the external auditory meatus.⁹

Pathologic Conditions

Neuropathologists have not agreed on a uniform classification system for brain tumors. However, the fourth edition of the World Health Organization (WHO) classification of tumors of the CNS, published in 2007, is based on the consensus of an international working group of pathologists and geneticists.¹⁰ It is the standard for the definition of brain tumors for clinical oncology and cancer research communities worldwide. According to this classification, CNS tumors are classified as follows: (1) tumors of neuroepithelial tissue, (2) germ cell tumors, (3) tumors of cranial and paraspinal nerves, (4) tumors of the sellar region, (5) tumors of the meninges, (6) lymphomas and hemopoietic neoplasms, and (7) metastatic tumors (Table 21-1).

Table 21-1 World Health Organization Classification of Primary Central Nervous System Tumors

Major Classification of Tumors	WHO Grade
Astrocytic Tumors
Pilocytic astrocytoma	I
Diffuse astrocytoma	II
Anaplastic astrocytomas	III
Glioblastoma	IV
Gliosarcoma	IV
Oligodendroglial Tumors
Oligodendroglioma	II
Anaplastic oligodendroglioma	III
Oligoastrocytic Tumors
Oligoastrocytoma	II
Anaplastic oligoastrocytoma	III
Ependymal Tumors
Ependymoma	II
Anaplastic ependymoma	III
Choroid Plexus Tumors
Choroid plexus papilloma	II
Atypical choroid plexus papilloma	III
Tumours of the pineal region
Pineocytoma	I
Pineoblastoma	IV
Neuronal and Mixed Neuronalglial Tumors
Anaplastic ganglioglioma	III
Tumors of the Pineal Region
Pineocytoma	I
Pineoblastoma	IV
Embryonal Tumors
Medulloblastoma	IV
CNS primitive neuroectodermal tumors (PNETs)	IV
Tumors of the Cranial and Paraspinal Nerves
Schwannoma	I
Neurofibroma	I
Meningeal Tumors
Meningeoma	I
Anaplastic meningioma	II
Hemangioblastoma	I
Tumors of the Sellar Region
Craniopharyngioma	I
Pituicytoma	I

Reliance on a pathologic classification of brain tumors is a requisite for treatment. Indeed, histopathologic examination is more important than anatomic staging in determining the clinical behavior and prognosis of these tumors. Tumor classification is based on histologic evidence of differentiation; however, expression of histologic features may vary widely within tumors of a given type, particularly diffuse gliomas. This regional heterogeneity makes interpretation of small biopsy samples difficult; this is especially true of astrocytomas. Unfortunately, these difficulties can have significant implications on the diagnosis and grading of these tumors.

Histologic grading is a means of predicting the biologic behavior of a neoplasm. In the clinical setting, tumor grade is a key factor influencing the choice of therapies, particularly determining the use of adjuvant radiation and specific chemotherapy protocols. The WHO classification of tumors of the nervous system includes a grading scheme that ranges across a wide variety of neoplasms rather than a strict histologic grading system.¹⁰ Grade I applies to lesions with low proliferative potential and the possibility of cure following surgical resection alone. Neoplasms designated grade II are generally infiltrative in nature and, despite low-level proliferative activity, often recur. Some type II tumors tend to progress to higher grades of malignancy, for example, low-grade diffuse astrocytomas that transform to AA and glioblastoma. Similar transformation occurs in oligodendroglioma and oligoastrocytoma. The designation WHO grade III is generally reserved for lesions with histologic evidence of malignancy, including nuclear atypia and brisk mitotic activity. The designation WHO grade IV is assigned to cytologically malignant, mitotically active, necrosis-prone neoplasms. Examples of grade IV neoplasms include glioblastoma, medulloblastoma, and lymphoma.

Astrocytic gliomas, which are the most common primary brain tumors, arise from astrocytes, the supporting cells of the brain and spinal cord. The cytoplasmic processes that extend from the astrocytes contain a characteristic filamentous protein, glial fibrillary acidic protein (GFAP), which provides an immunohistochemical marker for these tumors. The WHO defines diffusely infiltrative astrocytic tumors with cytologic atypia alone as grade II (diffuse astrocytoma), those also showing anaplasia and mitotic activity as grade III (AA), and tumors additionally showing microvascular proliferation or necrosis as WHO grade IV (Fig. 21-3). Necrosis may be of any type; perinecrotic palisading need not be present.

FIGURE 21-3 • Pathologic conditions of malignant glioma.

A, Anaplastic astrocytoma showing hypercellularity and pleomorphic nuclei. Tumor necrosis is absent. (Hematoxylin and eosin; original magnification ×250.) B, Glioblastoma multiforme with the hallmark features of necrosis with peripheral pseudopalisading of neoplastic nuclei. (Hematoxylin and eosin; original magnification ×250.)

Clinical Presentation

The presenting symptoms and signs of brain tumors are divided into those associated with a mass effect and increased intracranial pressure and those that are focal. The most common presenting symptom is headache, and approximately 20% of patients with supratentorial tumors present with seizures. Alterations in personality, mood, mental capacity, and concentration are frequently seen early in the clinical course.⁴ The focal neurologic symptoms and signs observed with supratentorial brain tumors are summarized in Table 21-2.

Table 21-2 Focal Symptoms

Anatomic Region	Symptoms or Signs or Both
Frontal lobe	Personality change
	Slowing of contralateral hand movements
	Contralateral spastic hemiplegia
	Mood elevation
	Difficulty in adapting to new situations
	Loss of initiative
	Dysphagia + lip, tongue, and hand movements
	Apraxia (if dominant lobe involved)
Bifrontal involvement	Bilateral hemiparesis
	Spastic bulbar palsy
	Impairment of intellect
	Lability of mood
	Dementia
	Primitive grasp, suck, and snout reflex
Temporal lobe	Impairment of recent memory
	Homonymous quadrantanopsia
	Auditory hallucination
	Aggressive behaviour
Non-dominant lobe	Minor perceptual problem
Non-dominant lobe	Spatial disorientation
Dominant lobe	Dysnomia
	Impaired perception of verbal command
	Fluent-Wernicke-like aphasia
Parietal lobe	Mild hemiparesis
	Mild to severe sensory loss
	Homonymous hemianopsia
	Visual inattention
Non-dominant lobe	Perceptual abnormalities
	Anosognosia
	Apraxia for self-dressing
Dominant lobe	Alexia
	Dysgraphia
	Other forms of apraxia
Occipital lobe	Contralateral homonymous hemianopsia
Occipital lobe	Visual aberrations
Bilateral occipital involvment	Cortical blindness
Thalamus or basal ganglia or both	Herniation syndrome
	Contralateral sensory abnormalities
	Intermittent contralateral paresthesia
	Neuropathic pain syndrome
	Contralateral intention tremor
	Semiballistic-like movement disorder
	Hydrocephalus due to trapping of lateral horn of ventricle

Routes of Spread

Malignant gliomas form as an expansile mass that conforms to the barriers of the cortical convolutions, deep nuclear structures, and adjacent myelinated nerve fibers.¹¹ Microscopic examination typically shows a gradient of infiltrating tumor cells that decreases with the distance from the periphery of the mass. As they enlarge, malignant gliomas extend directly into adjacent lobes, infiltrate throughout the ipsilateral cerebral hemisphere, and disseminate along anatomically defined nerve fiber pathways. In some cases, individual cells, facilitated by the accompanying edema, may infiltrate for long distances from the main tumor mass. Multicentric gliomas are found in less than 5% of patients. Dissemination by seeding through the cerebrospinal fluid pathways occurs in approximately 10% of cases, but is usually a late event, often appearing at a time when its effects are inconsequential compared with those of the recurrent primary tumor mass. Metastases rarely arise outside the CNS.

Diagnostic Studies

Magnetic resonance imaging (MRI) is the modality of choice for diagnosis and evaluation of intracranial neoplasms. It is the ideal modality for initial preoperative diagnosis, including tumor extent, treatment planning, and image-guided therapies because of its multiplanar capability, anatomic detail, and superior resolution.¹²^,¹³ The ability to characterize tissue allows for improved assessment of fatty, hemorrhagic, cystic, necrotic, and vascular components, as well as mass effect and location. In malignant gliomas, on T1-weighted sequence enhanced with gadolinium contrast, the tumor appears as an irregular, ringlike configuration that may surround a central area of necrosis (Fig. 21-4). On T2-weighted fluid-attenuation image recovery (FLAIR) images, the changes that reflect edema extend beyond the boundaries of contrast enhancement that may harbor microscopic extension. In fact, tumor may even be found in normal-appearing brain beyond the T2-weighted abnormality.

FIGURE 21-4 • Axial magnetic resonance image of high-grade astrocytoma of right frontal lobe with fluid-attenuation image recovery sequence and T-weighted image with contrast.

Imaging studies are performed within the first 48 hours after surgical resection to determine the presence of residual tumor and to provide a baseline for subsequent treatment. Enhancement resulting from surgical trauma may be indistinguishable from residual tumor even after a complete surgical resection. Postsurgical enhancement develops as early as the fifth postoperative day, peaks after 2 weeks, and may persist for months.¹⁴ Corticosteroids, which act to re-establish the blood-brain barrier, also have a profound effect on the area of enhancement, and diminution in the area of enhancement may be due to corticosteroids alone. To determine a radiographic response to therapy, patients should be on the same or a lower dose of corticosteroids than the dose at the time of the pretreatment scan.

Lacking with conventional MRI is an assessment of physiologic and functional information about the tumor. The gadolinium enhancement, as seen on T1-weighted MRI, reflects regions where there has been a breakdown of the blood-brain barrier. This may not be a reliable indicator of high-grade tumor because of the presence of nonenhancing tumor or contrast-enhancing necrosis.¹⁵ Similarly, T2-defined volume either overestimates or underestimates the microscopic or nonenhancing disease in a majority of patients. New MRI techniques, such as MR perfusion, MR diffusion, MR spectroscopy (MRS), and functional MRI (fMRI), can provide further physiologic characterization of the tumor related to hemodynamics, cellularity, and metabolism, respectively, and may be used to assess response to therapy.¹⁶

MRS is a noninvasive method to evaluate the malignancy of gliomas based on metabolite levels such as N-acetylaspartate (NAA), choline (Cho) compounds, total creatine (Cr), and lactate (Lac), or metabolite ratios such as Cho/NAA and Cho/Cr (Fig. 21-5). Spectroscopy also holds great promise in aiding target definition for radiotherapy treatment planning and evaluation of response to therapy and tumor recurrence.¹⁷ With the advantage of measuring tumor regional variations in abnormalities of metabolite levels, MRS has recently been used as an in vivo molecular imaging technique that assists in targeting and predicts response to radiation therapy for patients with brain gliomas.

FIGURE 21-5 • Single voxel spectroscopy on a patient with high-grade brainstem glioma.

In addition to MRS, brain fMRI has gained potential in clinical application recently as it can image the eloquent cortices, such as the motor cortex, the Broca area, the Wernicke area, and the visual cortex, which are difficult to identify on anatomic MRI. Incorporation of fMRI information into the radiotherapy treatment process can possibly allow a radiation oncologist to properly plan and deliver an adequate radiation dose while avoiding damage to the adjacent functional cortices in the treatment of gliomas.¹⁸

Dynamic MRI techniques can be used to measure important features of tumor vascularity in vivo, including the density and permeability of capillaries. Increased vessel numbers lead to higher regional cerebral (i.e., tumor) blood volume, which can be measured relative to healthy brain tissue by perfusion MRI techniques. Thus, relative cerebral blood volume provides analysis of capillary density in gliomas (Fig. 21-6). In adult astrocytomas, relative cerebral blood volumes correlate well with histopathologic grade and survival. A relative cerebral blood volume value of more than 1.75 is associated with the presence of high-grade tumor and with reduced survival in patients with gliomas.¹⁹

FIGURE 21-6 • Perfusion imaging in a patient with recurrent glioblastoma. A-F represent images taken before and 10 months after therapy, demonstrating decrease in contrast enhancement in T1 images (B and D); rCBV in perfusion imaging (B and E) and K^trans in diffusion imaging (C and F) sequences.

Staging

There is no accepted staging system for gliomas. The American Joint Committee on Cancer (AJCC) proposed a staging scheme for primary brain tumors based on tumor (T) and metastasis (M) (dissemination within and rarely outside the CNS) as well as grade (G). Because this system was not generally adapted to clinical use, it was removed from the 1997 AJCC staging manual and since then has not been used.

Prognostic Factors

A major contribution of the cooperative group brain tumor studies has been the identification of pretreatment characteristics that affect the outcome in patients with malignant gliomas. A nonparametric recursive partitioning technique was applied to an analysis of 1578 patients accrued to three successive Radiation Therapy Oncology Group (RTOG) trials.²⁰ Age, histologic appearance, Karnofsky performance status (KPS), mental status, duration of symptoms, neurologic functional class, extent of surgery, and radiation dose were identified as significant partitioning covariates. As shown in Table 21-3, six patient classes were defined with median survival times ranging from 4.6 to 58.6 months and 2-year survival rates of 4% to 76%. These classes were used to define favorable (classes I and II, 12% of the patients evaluated), intermediate (classes III and IV, 43%), and poor (classes V and VI, 45%) prognosis subgroups. A subsequent reanalysis of the data in glioblastoma patients showed no statistical difference between class V and VI with a median survival time of 7.5 months.²¹ This information is important for interpreting correctly the results of studies comparing different treatment regimens and for assessing the potential of new therapeutic methodologies.

Table 21-3 Malignant Glioma Recursive Partitioning Analysis Classification

Class	Definition
I	Age <50, anaplastic astrocytoma, and normal mental status
II	Age ≥50, KPS 70-100, anaplastic astrocytoma, and at least 3 months from time of first symptoms to initiation treatment
III	—Age <50, anaplastic astrocytoma and abnormal mental status
III	—Age <50, glioblastoma multiforme and KPS 90-100
IV	—Age <50, glioblastoma multiforme, KPS <90
	—Age ≥50, KPS 70-100, anaplastic astrocytoma and 3 months or less from time of first symptoms to start of treatment
	—Age >50, glioblastoma multiforme, surgical resection, and good neurologic function
V	—Age ≥50, KPS 70-100, glioblastoma multiforme, either surgical resection and neurologic function that inhibits the ability to work or biopsy only followed by at least 54.4 Gy of RT
V	—Age ≥50, KPS <70, normal mental status
VI	—Age ≥50, KPS <70, abnormal mental status
VI	—Age ≥50, KPS 70-100, glioblastoma multiforme, biopsy only, receiving less than 54.4 Gy of RT

Standard Therapeutic Approaches

Surgery

The combination of surgery, radiation therapy, and chemotherapy represents the standard approach to the treatment of malignant gliomas. Generally, surgery is performed through an open craniotomy. The goals of surgery are to provide a histologic diagnosis, to alleviate intracranial hypertension and focal neurologic deficits resulting from a mass effect, and to permit rapid corticosteroid dose tapering.²² Furthermore, a large tumor mass left in the brain can serve as a nidus for cerebral edema after radiotherapy. The influence of surgical resection in malignant gliomas has been controversial. The aim of palliation of symptoms was always clear, but the survival advantage was debated. However the evidence suggests that patients with more complete resections designed to minimize the volume of residual tumor live longer and have an improved functional status compared with those who undergo a biopsy or partial resection only. An analysis of an RTOG database of 645 patients with malignant gliomas revealed a median survival of 11.3 months with total resection, 10.4 months with subtotal resection, and 6.6 months with biopsy alone.²³ However, tumor size was not found to be a predictor of survival. Unfortunately, there are no well-conducted randomized clinical trials in high-grade gliomas that have tested the extent of surgical resection. A poorly done study on 30 elderly patients with radiologically obvious malignant glioma randomized to biopsy alone versus resection showed a borderline survival benefit with resection.²⁴ Advances in neurosurgery, including diagnostic ultrasound, lasers, ultrasonic tissue aspirators, cortical mapping, functional imaging, and computer-assisted stereotactic laser techniques, have improved the ability of neurosurgeons to radically remove intracranial tumors.²²

A closed-needle biopsy, using computed tomography (CT)- or MRI-coupled stereotactic techniques, may be indicated in many clinical settings. A biopsy is preferred for tumors located in functionally important or inaccessible areas of the brain. In addition, surgical resection is not practical for patients with significant tumor infiltration across the midline and around the ventricular system, or for those with diffuse, nonfocal lesions.²²

Radiation Therapy

Randomized trials conducted by the Brain Tumor Cooperative Group (BTCG) and the Scandinavian Glioblastoma Study Group (SGSG) provided seminal evidence that external-beam irradiation favorably affects the outcome of malignant gliomas. BTCG trials 6901 and 7201 demonstrated a significant survival advantage for irradiated patients who received 50 to 60 Gy to the whole brain (in single daily fractions of 1.7-2.0 Gy, 5 days per week) either alone or with chemotherapy compared with those treated with either resection and supportive care only (P = 0.001) or with chemotherapy alone (P < 0.01).²⁵^,²⁶ The median survival of patients receiving 60 Gy was 2.3 times longer than that observed for nonirradiated patients. Nearly 30% of irradiated patients in the SGSG trial maintained a full or partial working capacity, whereas the nonirradiated patients progressively deteriorated, and none regained their original performance level.²⁷ Randomized trials of postoperative radiotherapy in gliomas is shown in Fig. 21-7. These studies were so convincing that virtually all patients with malignant gliomas receive adjuvant radiation therapy.

FIGURE 21-7 • Pooled results of postoperative radiotherapy versus no radiotherapy in gliomas.

Chemotherapy

Until recently, the role of adjuvant chemotherapy in high-grade gliomas remained controversial. Historically, the nitrosoureas, especially carmustine (bis-chloroethyl-nitrosourea [BCNU]), was the most active single agent and no other drug or drug combination had been found to be more effective with the exception of the procarbazine, lomustine (CCNU), and vincristine (PCV) regimen.²⁸ However, a retrospective analysis of RTOG data and a phase III trial conducted at the Medical Research Council (MRC) showed no benefit in survival with the PCV regimen. Similarly, no benefit of chemotherapeutic agents like tirapazamine, topotecan, paclitaxel (Taxol), interferon-β, and thalidomide were noted when used with standard radiation in RTOG phase II trials.²⁸

Introduction of temozolomide has redefined the role of chemotherapy in gliomas and represents the new standard of care. It is a derivative of dacarbazine and an inactive prodrug that undergoes hydrolysis to active metabolite monomethyl triazeno imidazole carboximide when absorbed and results in methylation of guanine at the O6 and N7 positions at the deoxyribonucleic acid. It has several advantages over conventional chemotherapy agents. These include oral administration, rapid absorption, 100% bioavailability, ability to cross the blood-brain barrier, linear pharmacokinetics, and minimal delayed myelosuppression. A large, multicenter phase II trial done in recurrent gliomas refractory to PCV chemotherapy treated with temozolomide showed a 35% response rate (RR) and a 6-month progression-free survival (PFS) rate of 46%, and was subsequently Food and Drug Administration–approved for relapsed AA.²⁹ Based on these responses, the European Organisation for Research and Treatment of Cancer (EORTC) conducted a phase III trial of 60 Gy of radiation with or without temozolomide at 75 mg/m²/day followed by six cycles of adjuvant therapy with temozolomide at 200 mg/m² for 5 days per month in 543 patients.³⁰ With a median follow-up of 28 months, the median overall survival improved from 12.1 to 14.6 months and the 2-year overall survival improved from 10.4% to 26.5% with the addition of temozolomide therapy.

Current focus of clinical development involves targeted therapies in glioma. Several agents have shown confirmed activity and are currently being investigated for integration in the initial management of malignant gliomas. These include antiangiogenic agents, tyrosine kinase blockers, inhibitors of Ras/MAPK pathways, and histone deacetylase inhibitors.³¹

Techniques of Radiotherapy

Most malignant gliomas are unifocal at the time of initial presentation, and after treatment the majority recur at or within 1 to 2 cm of their original location.³² Thus, limited treatment portals are used for malignant gliomas. Intracranial metastases that appear after partial brain irradiation do not affect the ultimate outcome, because they are nearly always accompanied by relapse at the primary tumor site. Whole-brain radiation therapy (WBRT) is commonly recommended for patients with multifocal tumors, but even for these lesions, relapses occur most frequently in the sites of known disease.³²

The conventional dose schedule is 59.4 to 60 Gy, given in single daily fractions of 1.8 to 2.0 Gy, 5 days per week. With this scheme, approximately 25% of patients with GBM and 50% of those with AA exhibit a significant radiographic response. Rapid fractionation schemes (such as 30-40 Gy in 10-15 fractions of 2.67-3.0 Gy each) may be appropriate for some elderly or poor-performance-status patients with GBM who have relatively short survival expectancies.

The gross target volume (GTV) represents a three-dimensional (3-D) reconstruction of the location of the tumor, determined by merging data from contrast-enhanced CT scans and MRI studies. The integration of MRI into CT-based treatment planning provides complementary information for accurately defining the GTV. Little agreement exists as to the definition of the clinical target volume (CTV) or the planning target volume (PTV). A shrinking field approach is used in RTOG trials. The initial PTV (PTV1) encompasses the enhancing lesion (GTV) and edema (CTV) with a 2-cm margin. After 46 Gy of a conventionally fractionated treatment course, the PTV (PTV2) is reduced to include only the enhancing lesion with a 2.5 cm margin. Using the extent of edema to define the CTV has some limitations. The identification of peritumoral edema is subjective, and its volume may vary with corticosteroid dosage. An analysis of the patterns of failure using the RTOG-defined PTVs demonstrated that nearly all relapses occurred within the reduced PTV2 at the site of the enhancing tumor.³³ Based on these data, we define the CTV by adding a margin of approximately 2.5 cm around the T1 contrast or a 1.5-cm margin around the FLAIR series. The PTV is determined by adding an additional 0.3- to 0.5-cm margin to the CTV to account for treatment uncertainties.

Patients are fixed in a custom-designed immobilization device, and are simulated and treated in the supine or prone position, depending on tumor location. Field arrangements and beam energy are selected after consideration of the location of the tumor within the brain and the geometry of the PTV. Lateral opposed fields are used only when extensive bilateral tumor involvement is present. This technique is suboptimal for most lesions because a substantial volume of normal brain tissue will be irradiated to the same dose as the tumor. Three-dimensional conformal radiation therapy (3D-CRT) is ideally suited for the treatment of brain tumors. Three-dimensional treatment plans are designed directly from CT (and MRI) image data sets, and the target volume and surrounding normal tissues are displayed using the beam’s-eye view technique. The use of multiple 3-D–planned nonaxial coplanar and noncoplanar fields reduces the volume of normal brain tissue treated to high doses. This approach allows higher than traditional doses to be safely administered to tumors located proximal to critical structures.

Intensity-modulated radiation therapy (IMRT) is an advanced form of 3D-CRT that uses inverse planning and computer-controlled radiation dose deposition. The advantage of precision delivery of radiation enables dose escalation and sparing of normal tissues. The brain IMRT treatment planning consists of immobilization using an Aquaplast face mask. A CT simulation with intravenous contrast is done with the acquisition of 1.5- to 3-mm thickness images. The previously obtained MRI data is superimposed on the CT images using the fusion program. GTV, CTV, and PTV are defined as in a 3D-CRT plan. All normal structures are outlined in three dimensions. User-defined constraints, including maximum and minimum dose constraints both for the PTV and the normal structures, are prescribed. As in 3D-CRT, noncoplanar beams are used. The plan consists of an intensity profile that is created for each beam. This is translated to leaf motion of the dynamic multileaf collimator using the inverse planning algorithm (Fig. 21-8). We have seen that the use of IMRT decreases the dose to the critical structures like optic nerves and brainstem when compared with the 3-D conformal plan.³⁴ There is evidence that use of IMRT decreases the dose to the cochlea in children with medulloblastoma when used for the posterior fossa boost.

FIGURE 21-8 • Intensity-modulated radiation therapy treatment plan for a patient with high-grade glioma of right parietal region.

Special Issues With Radiation Management

Volume of Radiation

In the BTCG 8001 trial, patients were randomized to receive either 6000 cGy WBRT or 4300 cGy WBRT with 1720 cGy boost. No difference in survival or recurrence was noted.³⁵ In a Japanese trial, patients were randomized to 4000 cGy WBRT with 1800 cGy boost or 5600 cGy local field radiation alone.³⁶ Again, the 2-year survival rate was no different in this study (43% versus 39%), indicating that large-volume irradiation is unnecessary in high-grade gliomas.

Dose of Radiation

Radiation dose is another important consideration. In an MRC phase III trial, 444 patients were randomized to either 45 Gy in 20 fractions or 60 Gy in 30 fractions (1 : 2 randomization). A benefit of 60 Gy was seen in terms of 1-year survival (29% versus 39%) and the median survival (9 versus 11 months).³⁷ In the RTOG phase III trial, patients received either 60 Gy WBRT or 60 Gy WBRT with a 10 Gy boost (Fig. 21-9). There was no benefit with the boost in terms of the median survival (9.3 versus 8.2 months).³⁸ Researchers at the University of Michigan reported dose escalation to 80 Gy and 90 Gy with 3D-CRT and showed no difference in patterns of relapse or survival, indicating the absence of benefit with dose escalation beyond 60 Gy in malignant gliomas.³⁹

FIGURE 21-9 • Overall survival as a function of radiation dose.

Radiation Sensitizers

Multiple randomized trials conducted by the RTOG, the Brain Tumor Study Group (BTSG), and others have failed to show any survival benefit with misonidazole or other agents when compared with radiation therapy alone. Difluoromethylornithine, an inhibitor of polyamine synthesis, has not shown any benefit in a phase III clinical trial.⁴⁰ Efaproxiral (RSR13), a synthetic allosteric modifier of hemoglobin, showed a median survival of 12.3 months when used along with 60-Gy radiation therapy in a phase II study, and is being presently tested in a phase III trial.⁴¹

Two halogenated pyrimidine analogues, bromodeoxyuridine (BUdR) and iododeoxyuridine, have been tested and in randomized trials have failed to show any benefit. Northern California Oncology Group data had shown a median survival of 252 weeks with BUdR with concomitant radiation and chemotherapy in AA compared with 82 weeks without BUdR.⁴² However, an RTOG trial of 60 Gy in 30 fractions combined with PCV chemotherapy with or without BUdR in 189 patients of AA had to be prematurely closed because of lack of benefit (1-year survival 68% versus 82%) and higher toxicity.⁴³

Altered Fractionation

Again, multiple randomized trials conducted by RTOG, EORTC, and others have failed to show any survival benefit with hyperfractionation when compared with conventional radiation therapy alone.⁴⁴ Similarly, several trials using different accelerated fractionation regimens have been reported; none have shown a survival benefit over conventional irradiation. An EORTC trial involving 60 Gy given in either conventional fractionation or with three fractions of 2 Gy given in a single day, 4 hours apart, in 340 patients showed no difference in survival or any increased toxicity.⁴⁵ Doses of 64 and 70.4 Gy in 1.6-Gy, twice-daily fractions with BCNU tested in an RTOG trial showed no benefit.⁴⁶ Shortening the treatment time has again failed to show any improvement.⁴⁷ A Johns Hopkins trial of 30 Gy in 10 fractions followed by 2 weeks rest and then another 21 Gy in 7 fractions to reduced fields in 219 patients showed a survival similar to RTOG recursive partitioning analysis (RPA) groups I through VI patients.⁴⁸

Brachytherapy

An earlier BTSG trial that randomized malignant glioma patients to 60 Gy radiation with or without iodine-125 (I-125) seed implant to 50 Gy showed a survival benefit with the addition of brachytherapy (median survival of 13 versus 16 months).⁴⁹ Since the information was presented as an abstract only and never published, it remains difficult to establish that this approach clearly improves survival. However, a randomized trial done at Princess Margaret Hospital that randomized patients to 50-Gy external-beam radiation with or without temporary I-125 seed implant to 60 Gy did not show any survival benefit (median survival of 13.2 versus 13.8 months).⁵⁰

Stereotactic Radiosurgery

Several retrospective trials have indicated that there is a possible survival advantage with the addition of a stereotactic radiosurgery (SRS) boost to high-grade gliomas. The RTOG conducted a randomized trial of conventional radiotherapy to 60 Gy and BCNU alone or preceded by a radiosurgery boost to 15 to 24 Gy in patients with GBM measuring 4 cm or less.⁵¹ However, the results were disappointing. The median survival (14 versus 13.7 months), 2-year survival (22% versus 18%), and 3-year survival (16% versus 8%), were similar with or without the boost. There was no improvement in any RPA class. No increased toxicities were seen with the addition of the SRS boost. Failures were still predominantly local (>90%).

Normal Tissue Reactions

Several adverse neurologic reactions may be observed in patients receiving cranial irradiation. They are classified into acute reactions, early-delayed reactions, and late-delayed injuries. With daily fractions of 1.8 to 2.0 Gy, the acute reaction most often presents as mild headache and nausea, beginning within a few hours after the first treatment and becoming progressively less severe with each succeeding fraction.⁵² The pathogenesis is thought to be increased cerebral edema caused by radiation-induced permeability changes in the blood-brain barrier. Corticosteroids may prevent or relieve most symptoms. Thus, if symptoms of increased intracranial pressure are present, patients undergoing cranial irradiation should be pretreated with corticosteroids (i.e., dexamethasone, 8-16 mg per 24 hours), administered for at least 48 to 72 hours before beginning treatment.

The early-delayed reaction (also called radiation encephalopathy) is characterized by transient, self-limited neurologic deterioration, somnolence, or focal encephalopathy.⁵² Early-delayed encephalopathy occurs in 15% to 40% of patients with primary or metastatic brain tumors. This reaction, which begins within 1 to 12 weeks after the completion of radiation therapy, usually peaks by 8 weeks after treatment and resolves spontaneously within the subsequent 4 months. Patients complain of headache, lethargy, and an exacerbation of their neurologic symptoms. At times, corticosteroid therapy and intensive medical support may be required. Declines in long-term memory within 1 to 2 months after irradiation followed by recovery 4 to 8 months later have also been observed.

The early-delayed reaction is thought to result from transient demyelination, resulting from damage to proliferating oligodendrocytes, and temporary changes in the blood-brain barrier. CT and MRI studies during this period may show apparent tumor enlargement, increased tumor enhancement, and edema, and in some cases new enhancement may appear. These changes appear to relate to intralesional reactions, indicative of tumor response, or localized perilesional edema and demyelination. It is important to recognize that the appearance of new findings during the early post-treatment interval does not always indicate that the tumor has recurred or that a change in therapy is warranted.

Late-delayed radiation injuries vary in their appearance and severity from asymptomatic white matter changes to cerebral atrophy, hemorrhagic vascular telangiectasia, neurobehavioral impairment, pituitary-hypothalamic dysfunction, and potentially fatal necrosis. Rarely, therapeutic irradiation can cause an occlusive arterial cerebrovasculopathy or secondary neoplasia.

Approximately 3% to 9% of patients irradiated for brain tumors develop clinically detectable focal radiation necrosis.⁵³ Radiation necrosis may appear as early as 3 months after treatment, but usually develops within 1 to 2 years after treatment is completed. The breakdown of white matter may induce marked edema and mass effect. The symptoms of focal necrosis frequently recapitulate those of the tumor, leading the clinician to suspect recurrence. MRI may show a contrast-enhancing mass with extensive white matter alterations on T2-weighted images. Histopathologic findings are generally limited to the white matter and include focal coagulation necrosis and demyelination. Endothelial cell atypia and a unique form of fibrinoid necrosis of small arterial vessels are characteristic features that suggest the underlying pathophysiology.

Radiation necrosis is uncommon at doses less than 60 Gy with conventionally fractionated irradiation. The probability of necrosis increases with larger daily fraction sizes (2.2-2.5 Gy).³⁷ For patients treated with hyperfractionated irradiation (twice-daily fractions of 1.2 Gy), the incidence of necrosis increased from 4.6% for 64.8 Gy to 19.2% for 81.6 Gy. Individual host factors, including the use of chemotherapy, may alter sensitivity and increase the risk of injury.

Because neither the symptoms nor the radiographic findings clearly distinguish tumor from necrosis, the clinical diagnosis of radiation necrosis may be difficult to confirm. ¹⁸Fluorodeoxyglucose–positron emission tomography (¹⁸FDG-PET), ²⁰¹T1–single photon emission computed tomography (²⁰¹Tl-SPECT), perfusion imaging, and MRS studies may help to differentiate necrosis from recurrent tumor. However, many patients have a mixture of necrosis and tumor. Thus, a biopsy may be required to confirm the diagnosis, especially when the injury occurs at or near the tumor site.

Corticosteroids may improve or stabilize the neurologic symptoms associated with the effects of radiation injury. Surgical resection is frequently beneficial to patients with favorably situated focal necrotic lesions who deteriorate neurologically and become steroid-dependent. There is no evidence that anticoagulation may lead to clinical improvement when surgery is not feasible. However, recent reports suggest a role for bevacizumab in the management of radiation-induced brain necrosis.⁵⁴

Diffuse white matter injury develops in at least 40% of patients irradiated for intracranial neoplasms.⁵² The T2-weighted MRI images reveal hyperintensity of the periventricular white matter. Cerebral cortical atrophy occurs in 17% to 50% of patients treated for brain tumors. Enlarged cerebral sulci and ventricular dilatation are seen on neuroimaging studies. The abnormalities that accompany white matter change and cerebral atrophy are discernible within the first year after irradiation and persist or progress thereafter. They tend to be more severe with larger treatment volumes, higher doses, older age, longer intervals after irradiation, and chemotherapy. Clinical features range from mild lassitude or personality change to incapacitating dementia. Some patients with cerebral atrophy may also develop gait abnormalities and urinary incontinence suggestive of the syndrome of normal pressure hydrocephalus. Many patients with radiographic changes have no symptoms, but in those who do, the degree of impairment correlates approximately with the severity of the MRI appearance.

Decreased levels of intellectual function have been observed in adults after cranial irradiation. Certain cognitive functions, such as memory, may be more susceptible to decline than others.⁵² Impairment is most pronounced in those who have had chemotherapy and WBRT. Intellectual decline is first discernible within 4 to 6 months after treatment and becomes more pronounced by 2 to 3 years of follow-up. Memory loss may prevent patients from returning to their premorbid occupation. However, an analysis⁵⁵ found that 60% of long-term survivors irradiated for gliomas were employed at occupations comparable to those they had held before treatment. Patients treated with partial brain irradiation tended to have a higher KPS, superior memory function, and a better employment history compared with those who received WBRT.

Neuropsychologic testing of patients treated for a variety of brain tumors who failed to retain their premorbid social or occupational levels of function demonstrated that newly learned tasks requiring attention and immediate problem-solving ability were performed poorly. In contrast, tests that evaluated long-term memory and overlearned material were generally consistent with premorbid levels.⁵³ IQ testing alone is a less sensitive indicator of changes in cognitive function in adults. Prompt neuropsychologic intervention when necessary and early return to work after treatment may lead to improvement in or recovery of cognitive function.

Outcome

The median survival times using conventional radiation therapy alone or with chemotherapy for patients with GBM is 10 to 14 months, whereas the 2-year survival rate is only 10% to 25%.³⁰ The median survival for patients with AA is 36 months, and the 3-year survival rate is approximately 50%.

Low-Grade Astrocytoma

Incidence

Low-grade astrocytomas make up 5% to 15% of adult primary brain tumors and 67% of low-grade gliomas, the remainder of low-grade gliomas being mixed oligoastrocytomas (19%) and oligodendrogliomas (13%).⁴ Unlike the incidence of their malignant counterparts, the incidence of low-grade astrocytomas decreases with increasing age. They are most common between the ages of 20 and 40 years and rarely occur after the age of 50.

Anatomy

Low-grade astrocytomas in adults typically involve the cerebral hemispheres. Among 995 cases of supratentorial astrocytomas culled from the literature, 42% were located in the frontal lobes, 37% in the temporal, 5% in the parietal, and 10% in more than one lobe, whereas 6% presented at other sites.⁴

Pathologic Conditions

Astrocytomas are well-differentiated tumors that display increased cellularity compared with normal brain tissue and have mild to moderate nuclear pleomorphism (see Fig. 21-3). Microcysts are frequently present, a feature that distinguishes astrocytomas from reactive gliosis.⁵⁴ The majority of low-grade astrocytomas are classified as grade II in the WHO classification. Juvenile pilocytic astrocytomas are classified as grade 1 in the WHO system (see Table 21-1).

The various astrocytoma subtypes, including the fibrillary, protoplastic, gemistocytic, and pilocytic forms, are distinguished by their intracytoplasmic fibrillary processes, demonstrated by staining for GFAP (Fig. 21-10). Fibrillary astrocytomas, the most common subtype, and protoplasmic astrocytomas have been referred to as “ordinary” astrocytomas and share a similar prognosis. Over time, at least 50% of these tumors transform into more anaplastic lesions. Gemistocytic astrocytomas are composed of large, plump astrocytes with abundant eosinophilic cytoplasm. Because gemistocytes commonly transform into highly anaplastic cells, they behave in an aggressive fashion and should be treated as anaplastic gliomas.

FIGURE 21-10 • Low-grade astrocytoma showing mildly increased cellularity with uniform cells and nuclei. (Hematoxylin and eosin; original magnification ×250.)

Pilocytic astrocytomas typically occur in the first two decades of life but also arise in adults. They are composed of fusiform cells with unusually long, wavy processes called Rosenthal fibers. Mitosis is rarely seen. Endothelial proliferation may be present, but does not signify malignancy.⁵⁶ Pilocytic astrocytomas have a long natural history and rarely dedifferentiate into tumors with more malignant histologic appearances.

Although low-grade astrocytomas are often similar in their histologic appearance, their biologic behavior may vary considerably. In one study, a Ki-67 labeling index (LI) of more than 10% was associated with higher histologic grade and poorer survival, and this value was more significant than histologic grading.⁵⁷ These data suggest that patients with a high LI may be considered for more aggressive treatment programs.

Clinical Presentation

About two thirds of adult patients with low-grade astrocytomas present with seizures but are otherwise neurologically intact.⁴ Others exhibit a slowly progressive neurologic syndrome consisting of headache, vomiting, motor deficit, visual or sensory loss, language disturbance, or personality change. Symptoms may be present for months or years before a diagnosis is made. Seizures are associated with a better survival, whereas the presence of functional deficits predicts a poorer outcome.

Routes of Spread

Pilocytic astrocytomas are well circumscribed and grow by expansion, whereas the nonpilocytic tumors diffusely infiltrate adjacent tissues in a pattern similar to that of malignant gliomas. One variant, called gliomatosis cerebri and found in the second and third decade of life, may involve considerable areas of the cerebral hemispheres, cerebellum, and brainstem. The widespread nature of this lesion has been regarded as evidence for multifocal astrocytic neoplastic transformation.

Diagnostic Studies

Pilocytic astrocytomas appear on imaging as discrete, enhancing lesions. The classic appearance is a large cyst with an enhancing mural nodule. Ordinary astrocytomas appear as diffuse, poorly defined, low-density, nonenhancing lesions.¹⁶ Approximately 40% of ordinary astrocytomas enhance on imaging, and calcification is found in 10% of cases.¹²^,¹⁶ MRI typically shows low signal intensity changes on T1-weighted images, high signal intensity on T2, and an absence of enhancement (Fig. 21-11).

FIGURE 21-11 • Axial magnetic resonance image of low-grade astrocytoma of right temporal region with fluid-attenuation image recovery sequence.

Prognostic Factors and Grouping

Bauman and associates have proposed a grouping system for predicting the survival for patients with low-grade gliomas using RPA based on a database of 401 patients.⁵⁸ Age, KPS, and presence or absence of contrast enhancement were used as prognostic indicators. Group I (KPS <70 and age >40) had the worst median survival, at 12 months. Group II (KPS >70, age >40 and contrast enhancement present) had a median survival of 46 months. Group III (KPS >70, age >40 and contrast enhancement absent or KPS <70 and age <40) had a median survival of 87 months. Group IV (KPS >70, age 18-40) had the best median survival of 128 months.