17 Central Nervous System Tumors Volker W. Stieber, Kevin P. McMullen, Michael T. Munley,

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17 Central Nervous System Tumors

Volker W. Stieber, Kevin P. McMullen, Michael T. Munley, and Edward G. Shaw

V. W. Stieber, MD, Assistant Professor;

K. P. McMullen, MD, Assistant Professor;

M. T. Munley, PhD, Associate Professor;

E. G. Shaw, MD, Professor and Chairman

Department of Radiation Oncology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston- Salem, NC 27157-1030, USA

17.1

Introduction

The central nervous system (CNS) is comprised of the brain and spinal cord and their coverings and may be affected by both primary and metastatic tumors. The outcomes of treatment are highly vari- able, dependent on diagnosis. Patients with benign diseases are often able to live out their natural life span, while those with malignant tumors frequently have survival measured in weeks or months. It is incumbent upon the clinician to use an appropriate treatment technique for all patients with CNS disease in order to minimize the chance of significant acute toxicities (or late toxicities in survivors) and maximize the therapeutic benefit.

17.2

Natural History

17.2.1

Anatomy of the Brain

Knowledge of the basic topographical and functional anatomy of the brain is important for accurate communication of tumor location within the CNS as well as defining areas of functional eloquence that need to be considered when planning therapy.

Generally, the brain can be considered to have three major divisions: the cerebrum, cerebellum and brain stem. When considering tumor location it is also common to distinguish between supratentorial (cerebral hemispheres and midline structures) and infratentorial (cerebellum, lower brain stem).

The longitudinal cerebral fissure divides the cerebrum into two hemispheres, Each hemisphere is the separated by the major sulci into six lobes: frontal, parietal, occipital and temporal, and the midline central and limbic lobes (Fig. 17.1).

The prominent central sulcus (of Rolando) separates the frontal lobe from the parietal lobe. The

CONTENTS

17.1 Introduction 425 17.2 Natural History 425 17.2.1 Anatomy of the Brain 425 17.2.2 Epidemiology 427 17.2.2.1 Primary CNS Tumors 427 17.2.2.2 Tumors Metastatic to the CNS 428 17.3 Workup and Staging 430 17.4 General Management 431 17.4.1 Medical Management 431 17.4.2 Surgical Management 431 17.4.3 Radiation Therapy 432

17.4.3.1 Definitive Radiation Therapy 432 17.4.3.2 Palliative Radiation Therapy 432 17.5 General Concepts of Modern Radiation Therapy Technique 434

17.5.1 Principles of Imaging-Based Treatment Planning 434

17.5.2 Target Volumes and Organs at Risk Specifications 434 17.5.3 Dose Reporting 436

17.5.4 Intensity-Modulated Radiation Therapy 436 17.6 Simulation Procedures 437

17.6.1 General Concepts of Positioning, Immobilization and Simulation 437

17.6.2 Specific Examples of Treatment Techniques 439 17.6.2.1 Pituitary Region 439

17.6.2.2 Meningiomas 440 17.6.2.3 Temporal Lobe Lesions 441 17.6.2.4 Frontal or Parietal Lobe Lesions 441 17.6.2.5 Central and Thalamic Lesions 442 17.6.2.6 Posterior Fossa 442

17.6.2.7 Whole Brain Irradiation 443 17.6.2.8 Craniospinal Irradiation 444 17.6.2.9 Spinal Tumors 446

17.7 Simulation Films and Portal Films 447 17.8 Dose Prescriptions 447

17.8.1 Primary CNS Tumors 447 17.8.2 Metastatic CNS Tumors 448 17.9 Future Directions 448 References 449

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parietal–occipital fissure separates parietal lobe from occipital lobe. The lateral fissure (of Sylvius) defines the temporal lobe boundaries. The cerebral hemispheres are connected by the corpus callosum, beneath which are the midline structures (third ventricle, pineal body, and midbrain) and the deep paramedian structures (lateral ventricles, caudate nucleus, lentiform nucleus, thalamus, and hypo- thalamus).

A basic understanding of the functional anatomy of the cerebral hemispheres can be approached in three ways. The first is a regional or “lobe-by-lobe”

consideration of function. The occipital lobe is primarily involved with vision and its dependent functions. The temporal lobe processes sound, vestibu- lar sensations, sights, smells, and other perceptions into complex “experiences” important for memory.

Wernicke’s area is located on the posterior portion of the superior temporal gyrus and plays a critical role in receptive speech. The parietal lobe, specifi- cally the postcentral gyrus, is critically involved in somatosensory function. Sensory integration (body image) and Gnostic (perceptive) functions also reside within the parietal lobe. The frontal lobe is associated with higher level cognitive functions such as reasoning and judgment. The frontal lobe also contains the primary motor cortex (pre- central gyrus) and Broca’s area (inferior third of the frontal gyrus), important in expressive speech. The limbic lobe mediates memories, drives, and stimuli.

It affects visceral functions central to emotional expression, such as sexual drive. Finally, the central lobe (insula) is important in visceral sensation and motility.

The second approach to functional neuroanatomy is the schema of Brodmann, which numbers areas

of structural specialization (Brodmann 1908a,b).

These numbered areas, in some cases, correspond to the functional location of important primary sensory and motor areas. The 52 numbered areas provide both an anatomical and functional “road map” of the brain by which tumor location can be described (Fig. 17.2).

The final and most eloquent method to describe functional neuroanatomy is through various techniques of functional mapping (Fig. 17.3).

While classic mapping utilizes microelectrode stimulation of the cortical surface directly, new non-invasive techniques such as functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and magnetoencephalography (MEG) are increasingly being integrated into clinical practice (Babiloni et al. 2004; Barnes et al.

1997; Choi et al. 2005). These procedures allow for precise mapping of function in an individual and can accurately predict deficits related to injury of a given area by tumor or therapy.

Fig. 17.2. Location of the major motor, sensory, and speech areas of the cerebral cortex with reference to Brodmann’s area numbers

Fig. 17.1. a Lateral surface of the brain including cerebral hemisphere, cerebellum, and brainstem. The major sulci divide the cerebral cortex into four lateral lobes: frontal, parietal, occipital, and temporal. b Medial surface of the left brain demonstrating midline structures of the central and limbic lobes

a b

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17.2.2

Epidemiology

17.2.2.1

Primary CNS Tumors

The incidence rate of all primary non-malignant and malignant (including pilocytic astrocytomas) brain and CNS tumors is 14.1 cases per 100,000 person-years (6.8 per 100,000 person-years for benign and borderline tumors and 7.3 per 100,000 person-years for malignant tumors). The overall incidence rates increased from 13.5 per 100,000 person-years in 1997 to 14.7 per 100,000 person- years in 2001 (CBTRUS 2004). The rate is higher in females (14.3 per 100,000 person-years) than males (13.9 per 100,000 person-years). An estimated 41,130 new cases of primary non-malignant and malignant brain and CNS tumors were expected to be diagnosed in 2004 (CBTRUS 2004). The worldwide incidence rate of primary malignant brain and CNS tumors, age-adjusted using the world standard pop- ulation, is 3.6 per 100,000 person-years in males and

2.5 per 100,000 person-years in females. The incidence rates are higher in more developed countries (males 5.9 per 100,000 person-years; females 4.1 per 100,000 person-years) than in less developed countries (males 2.8 per 100,000 person-years; females 2.0 per 100,000 person-years) (Ferlay et al. 2001).

The incidence rate of childhood primary non-malignant and malignant brain and CNS tumors is 4.0 cases per 100,000 person-years. The rate is higher in males (4.2 per 100,000 person-years) than females (3.8 per 100,000 person-years) (CBTRUS 2004). An estimated 18,500 deaths in 2005 will be attrib- uted to primary malignant brain and CNS tumors (American Cancer Society 2005).

The majority of primary CNS tumors (31%) are located within the frontal, temporal, parietal, and occipital lobes of the brain. Tumors in other loca- tions in the cerebrum, ventricle, cerebellum, and brainstem account for 3, 2, 4, and 2% of all tumors, respectively. Other tumors of the brain account for 16% of all tumors. Tumors of the meninges repre- sent 24% of all tumors. The cranial nerves and the spinal cord/cauda equina account for 6% and 4% of

Fig. 17.3a–c. Cortical surface electrode mapping of the speech area in a patient undergoing resection of recurrent glioma. a Exposed cortical surface. b Mapping array in place. c Resec- tion cavity with electrode number 5 demarcating speech area.

Patient had normal speech postoperatively

a b

c

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all tumors, respectively. The pituitary and pineal glands account for about 7% of tumors. Olfactory tumors of the nasal cavity and other CNS tumors, NOS (not otherwise specified), each account for less than 1% of tumors (CBTRUS 2004).

The overall incidence of primary spinal cord tumors is approximately 10–19% that of all primary brain tumors (Connoly 1982). The incidence ratio of intracranial to intraspinal tumors is up to four times higher in pediatric patients than in adults, the frequency of specific spinal cord tumors being quite different from that of their counterpart brain tumors. The incidence ratios of intracranial to intraspinal astrocytomas, ependymomas and meningiomas are approximately 10:1, 3:1, and 18:1, respectively (Sasanelli et al. 1983). Schwannoma and meningioma account for approximately 60%

of primary spinal tumors, with schwannoma being slightly more frequent; both types occur primarily in adults. Regional differences are also noted. Glio- mas constitute 46% of primary intracranial tumors but only 23% of spinal tumors. Most primary spinal gliomas are ependymomas with a predilection for the cauda equina.

In 2000, the World Health Organization (WHO) updated their comprehensive classification of primary CNS neoplasms (International Agency for Research on Cancer 2000). Table 17.1 shows the WHO’s pathological classification system of common primary CNS tumors. The most frequently reported histology is a predominately benign tumor, meningioma, which accounts for over 29% of all tumors, followed closely by glioblastomas and astrocytomas. The predominately benign nerve sheath tumors and pituitary tumors account for 8% and 6% of all tumors, respectively. Acoustic neuromas account for 54% of all nerve sheath tumors. Gliomas are tumors that arise from glial cells, and include astrocytomas, glioblastomas, oligodendrocytomas, ependymomas, mixed gliomas, malignant gliomas NOS, and neuroepithelial tumors. The broad cate- gory glioma represents 42% of all tumors (CBTRUS 2004). Of gliomas, 61% occur in the frontal, temporal, parietal, and occipital lobes of the brain. Glio- blastomas account for the majority of gliomas, while astrocytomas and glioblastomas account for three- quarters of gliomas (CBTRUS 2004). Table 17.2 shows a comparison of different grading systems that have been used to classify the malignant gliomas. The most common spinal cord intramedullary tumors are those that are derived from glial precur- sors (astrocytes, ependymocytes, and oligodendro- cytes) (Preston-Martin 1990).

17.2.2.2

Tumors Metastatic to the CNS

Metastatic brain tumors are the most common intracranial neoplasms in adults and are a significant cause of morbidity and mortality. The estimate of the incidence rate of metastatic brain tumors varies from 8.3–11 per 100,000 (Percy et al. 1972; Walker et al. 1985). In two cohorts of patients who were diagnosed with colorectal, lung, breast, or kidney carcinoma or melanoma, brain metastases were diagnosed in 8.5–9.6% of patients (Barnholtz-Sloan et al. 2004; Schouten et al. 2002). The cumulative incidence was estimated at 16.3–19.9% in patients with lung carcinoma, 6.5–9.8% in patients with renal carcinoma, 6.9–7.4% in patients with melanoma, 5.0–5.1% in patients with breast carcinoma, and 1.2–1.8% in patients with colorectal carcinoma.

The spine is the most common site of bony metastases overall, with a reported incidence in cancer patients of 40% (Byrne 1992). Malignant spinal cord compression (MSCC) from epidural metastases occurs in 5–10% of cancer patients and in up to 40%

of patients with preexisting nonspinal bone metastases (Bilsky et al. 1999; Byrne 1992; Healey and Brown 2000; Wong et al. 1990). Of those with bony spinaldisease, 10–20% develop symptomatic spinal cord compression, resulting in between 14,100 and 28,200 cases per year (Gerszten and Welch 2000;

Loblaw et al. 2003; Schaberg and Gainor 1985).

The overall incidence of MSCC within 5 years of death from cancer is 2.5% (Loblaw et al. 2003).

Symptoms depend on location of the compression and can involve the spinal cord at any level. The incidence of MSCC by vertebral level is 10–16% cervical, 35–40% in T1-6, 44–55% in T7-12 and 20% lumbar (Gilbert et al. 1978; Patchell et al. 2003; Pigott et al. 1994). Metastatic lesions present initially at multiple, noncontiguous levels in 10–38% of cases (Gilbert et al. 1978; O’Rourke et al. 1986; Ruff and Lanska 1989).

The histology of MSCC follows the incidence pat- terns of malignant disease, with the most common histological diagnoses (breast, lung and prostate) accounting for approximately half of all cases (American Cancer Society 2005; Byrne 1992).

Approximately 25% of all patients with MSCC have breast cancer, 15% lung cancer, and 10% prostate carcinomas. Overall, 5.5% of breast cancer patients, 2.6% of lung cancer patients, 7.2% of prostate cancer patients, and 0.8% of colorectal cancer patients experience a MSCC (Loblaw et al. 2003). Other commonly reported histological diagnoses in adults

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Table 17.1. World Health Organization Classification of Tumors of the Nervous System (International Agency for Research on Cancer 2000)

Tumors of neuroepithelial tissue Astrocytic tumors

Diffuse astrocytoma

• Fibrillary astrocytoma

• Protoplasmatic astrocytoma

• Gemistocytic astrocytoma Anaplastic astrocytoma Glioblastoma

• Giant cell glioblastoma

• Gliosarcoma Pilocytic astrocytoma

Pleomorphic xanthoastrocytoma Subependymal giant cell astrocytoma Oligodendroglial tumors

Oligodendroglioma

Anaplastic oligodendroglioma Mixed gliomas

Oligoastrocytoma

Anaplastic oligoastrocytoma Ependymal tumors

Ependymoma

• Cellular

• Papillary

• Clear cell

• Tanycytic

Anaplastic ependymoma Myxopapillary ependymoma Subependymoma

Choroid plexus tumors Choroid plexus papilloma Choroid plexus carcinoma Glial tumors of uncertain origin Astroblastoma

Gliomatosis cerebri

Chordoid glioma of the third ventricle Neuronal and mixed neuronal–glial tumors

Gangliocytoma

Dysplastic gangliocytoma of cerebellum (Lhermitte–Duclos)

Desmoplastic infantile astrocytoma/ganglioglioma

Dysembryoplastic neuroepithelial tumor Ganglioglioma

Anaplastic ganglioglioma Central neurocytoma Cerebellar liponeurocytoma

Paraganglioma of the filum terminale Neuroblastic tumors

Olfactory neuroblastoma (Esthesioneu- roblastoma)

Olfactory neuroepithelioma

Neuroblastomas of the adrenal gland and sympathetic nervous system Pineal parenchymal tumors Pineocytoma

Pineoblastoma

Pineal parenchymal tumor of intermediate differentiation

Embryonal tumors Medulloepithelioma Ependymoblastoma Medulloblastoma

• Desmoplastic medulloblastoma

• Large cell medulloblastoma

• Medullomyoblastoma

• Melanotic medulloblastoma Supratentorial primitive neuroectodermal tumor (PNET)

• Neuroblastoma

• Ganglioneuroblastoma Atypical teratoid/rhabdoid tumor Tumors of peripheral nerves Schwannoma (neurilemmoma, neuri- noma)

Cellular Plexiform Melanotic Neurofibroma Plexiform Perineurioma

Intraneural perineurioma Soft tissue perineurioma

Malignant peripheral nerve sheath tumor (MPNST)

Epithelioid

MPNST with divergent mesenchymal and/or epithelial differentiation Melanotic

Melanotic psammomatous Tumors of the meninges Tumors of meningothelial cells Meningioma

• Meningothelial

• Fibrous (fibroblastic)

• Transitional (mixed)

• Psammomatous

• Angiomatous

• Microcystic

• Secretory

• Lymphoplasmacyte-rich

• Metaplastic

• Clear cell

• Chordoid

• Atypical

• Papillary

• Rhabdoid

• Anaplastic meningioma

Mesenchymal, non-meningothelial tumors

Lipoma Angiolipoma Hibernoma

Liposarcoma (intracranial) Solitary fibrous tumor

Table 17.1. World Health Organization Classification of Tumors of the Nervous System (International Agency for Research on Cancer 2000)

Fibrosarcoma

Malignant fibrous histiocytoma Leiomyoma

Leiomyosarcoma Rhabdomyoma Rhabdomyosarcoma Chondroma Chondrosarcoma Osteoma Osteosarcoma Osteochondroma Hemangioma

Epithelioid hemangioendothelioma Hemangiopericytoma

Angiosarcoma Kaposi sarcoma

Primary melanocytic lesions Diffuse melanocytosis Melanocytoma Malignant melanoma Meningeal melanomatosis Tumors of uncertain histogenesis Hemangioblastoma

Lymphomas and hemopoietic neo- plasms

Malignant lymphomas Plasmacytoma Granulocytic sarcoma Germ cell tumors Germinoma

Embryonal carcinoma Yolk sac tumor Choriocarcinoma Teratoma

• Mature

• Immature

• Teratoma with malignant transforma- tion

Mixed germ cell tumors Tumors of the sellar region Craniopharyngioma

• Adamantinomatous

• Papillary Granular cell tumor

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Table 17.2. Grading of astrocytic tumors. A given tumor may not fall under the same designation in all three systems (Daumas-Duport et al. 1988; Huntington et al. 1965; International Agency for Research on Cancer 2000)

WHO designation WHO

grade

Kernohan grade

St. Anne/

Mayo grade

St. Anne/Mayo grade criteria

Pilocytic astrocytoma I I (excluded) (n/a)

Astrocytoma II I, II 1 0 criteria present*

2 1 criterion present: usually nuclear atypia

Anaplastic astrocytoma III II, III 3 2 criteria present: usually nuclear atypia and mitosis

Glioblastoma multiforme IV III, IV 4 3–4 criteria present: usually the above and/or endothelial proliferation and/or necrosis

*Criteria include nuclear atypia, mitosis, endothelial proliferation and necrosis

include, by order of cumulative incidence, multiple myeloma, nasopharynx, renal cell, melanoma, small-cell lung, lymphoma and cervix (Byrne 1992;

Loblaw et al. 2003; Schiff et al. 1998).

17.3

Workup and Staging

For CNS tumors, both benign and malignant, MRI with and without contrast remains the gold standard for imaging (Ricci and Dungan 2001). The preferred slice thickness of MRI is 5 mm or less with a 2.5-mm or lower slice sampling. T1-weighted images with contrast allow excellent visualization of contrast-enhancing tumors such as meningiomas, glioblastoma multiforme and brain metastases. T2- weighted images demonstrate areas of edema that reflect involvement by infiltrative low- or high- grade gliomas. T1-weighted FLAIR images are also useful in this regard. MRI fusion or registration with the treatment planning computed tomography (CT) scan should be utilized for target definition; this is described in the section Principles of Imaging-Based Treatment Planning. Other imaging studies such as MRI spectroscopy, fMRI, PET scans, and single photon emission tomography (SPECT) scans better reflect biological characteristics of CNS tumors, such as tumor metabolism, proliferation, oxygenation and blood flow, and function of surrounding normal brain. Functional and biological imaging data are currently incorporated into decisions as to whether ablative procedures such as surgery, radiosurgery, or brachytherapy can be safely considered. Also, PET scans and MRI spectroscopy may allow for differentiating active tumor versus radionecrosis after radiation therapy. The integration of MR spectroscopy and PET imaging into radiation therapy treatment planning is a current

topic of research (Munley et al. 2002; Nuutinen et al. 2000; Pirzkall et al. 2000).

CNS tumors rarely metastasize outside the CNS but may spread within it. For example, medullo- blastomas, primitive neuroectodermal tumors, anaplastic ependymomas, choroids plexus carcinomas, pineoblastomas, germ cell tumors, and lymphomas may involve the cerebrospinal fluid (CSF), leptomen- inges (i.e., coverings of the brain), or spinal cord.

Studies that stage the extent of these tumors include MRI of the entire neural axis and CSF cytology.

In patients who present emergently, CT can be obtained rapidly, and provide information on ventricular obstruction, hemorrhage or edema, although imaging of the parenchyma is inferior to MRI. Lumbar puncture should be avoided if at all possible until intracranial pressure has nor- malized, due to the risk of herniation and death.

The most important modality in the workup of suspected MSCC is gadolinium-enhanced MRI of the entire spinal axis. With the exception of a primary paraspinal or neuraxis tumor, MSCC occurs most often in the setting of disseminated disease from a distant primary tumor site. A potential pit- fall in the initial evaluation of a patient with suspected spinal cord compression is imaging only the symptomatic area of the spine. Frequently, patients with lower body or extremity symptoms, and/or radicular pain in the lumbar distribution present for evaluation and management with only partial spine imaging. However, 25% of patients have spinal cord compression verified at multiple levels by MRI, and approximately two-thirds of these have involvement of different regions of the spine (Husband et al. 2001). When a sensory level is present on patient evaluation, it may be two or more segments different from the actual lesion on MRI in 28% of patients, and four or more levels distant from the lesion in 21% of patients (Husband et al. 2001).

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17.4

General Management

Multimodality therapy for CNS tumors routinely takes the form of medical treatment followed by surgical resection for durable decompression and to obtain a tissue diagnosis. Patients who are medically inoperable, refuse surgery, or have multiple and/or unresectable lesions often receive whole brain radiation therapy for palliation of their symptoms.

17.4.1

Medical Management

Medical treatment generally consists of steroids with or without mannitol (Sarin and Murthy 2003). Both drugs have previously been shown to decrease peritumoral brain edema by different mechanisms of action (Bell et al. 1987). Mannitol is used in steroid refractory patients. A common regimen of mannitol is 20–25% solution given intra- venously (i.v.) over approximately 30 min dosed at 0.5–2.0 g/kg (Quinn and DeAngelis 2000). Patients who present with emergent symptoms from intracranial malignancy are typically treated with dexamethasone. Response to therapy is usually noted within 12–18 h of administration, and over 80% of patients show dramatic improvement by 3–4 days after initiation of therapy (French 1966; Long et al. 1966). A common regimen in patients receiving radiation therapy is high-dose dexamethasone (10–

25 mg i.v.) followed by maintenance on oral steroids (4–6 mg p.o. every 6 h), with tapering initiated at the clinician’s discretion, usually over 1–2 months fol- lowing the completion of radiation therapy (Sarin and Murthy 2003; Vecht et al. 1994; Wolfson et al. 1994). In the setting of MSCC from solid tumors, dexamethasone has been shown to improve rates of surviving with intact gait function (Kalkanis et al.

2003; Sorensen et al. 1994).

Given the concerns over the incidence of steroid- induced toxicity with steroid dosing longer than 21 days in duration, higher doses and longer tapering schedules should be based on the physician’s assess- ment of symptom severity and response (Heimdal et al. 1992; Sorensen et al. 1994; Weissman et al.

1991). Side effects of intermediate- to long-term steroid use include: hyperglycemia; insomnia; emotional lability; thrush; gastric irritation, ulceration and possibly perforation; proximal muscle wast- ing; weight gain and adiposity (moon facies, buf- falo hump, centripetal obesity), osteoporotic com-

pression fractures; and aseptic necrosis of the hip joints (Bilsky and Posner 1993). Select patients with MSCC may not require steroids during treatment (Maranzano et al. 1996). This management strategy may be considered reasonable if a patient is at high risk of complication from steroids due to underlying medical comorbidities such as peptic ulcer disease, uncontrolled diabetes, or other medical problems that may cause severe or life-threatening problems if steroids are initiated.

Stabilization of the patient in status epilepticus in order to perform imaging and make management decisions is critical (Working Group on Status Epilepticus and Epilepsy Foundation of America 1993). After securing the airway and stabilizing the patient, seizure activity must be ter- minated as rapidly as possible. Phenytoin and rapid onset/short-acting benzodiazepines are commonly used to quickly control seizure activity. Recom- mended initial regimens include 0.1 mg/kg at 2 mg/

min lorazepam or 0.2 mg/kg diazepam at 5 mg/

min. Phenytoin infusion of 15–20 mg/kg at 50 mg/

min or less in adults is indicated for seizure activity refractory to benzodiazepines or after truncation of seizures with diazepam (Working Group on Status Epilepticus and Epilepsy Foundation of America 1993). Failure to control seizures can potentially lead to physical injuries, airway com- promise and secondary brain hypoxia/injury, or coma (Epilepsy Foundation of America 1993;

Quinn and DeAngelis 2000). However, there is no evidence to support routine use of prophylactic anticonvulsants for patients diagnosed with a brain tumor (Forsyth et al. 2003; Glantz et al. 1996).

17.4.2

Surgical Management

Surgical resection and/or placement of a shunt is often required for emergent management of brain tumors causing life threatening hydrocephalus, mass effect, or profound neurological impairment and may relieve symptoms enough that other treatment modalities may be considered as alternate or adjunctive management strategies. Symptoms are usually related to mass effect, so resection or debulking are often the only logical choices if medical therapy fails to provide improvement in neurological symptoms. Rapid surgical decompression is the treatment of choice for such problems when surgery can be safely performed based on patient performance status or tumor location. If no neurosurgical team is available, transfer

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of the patient should be initiated while medical mea- sures are undertaken to stabilize the patient.

Laminectomy has historically been the standard surgery for MSCC, with most series in the literature showing no benefit to laminectomy-treated patients over patients managed with radiation therapy (Byrne 1992; Gilbert et al. 1978; Loblaw and Laperriere 1998; Young et al. 1980). In real- ity, many patients with spinal cord compression are not surgical candidates and are best treated with steroids and radiation therapy as their primary modality. Even patients with very poor initial performance or mobility/continence status can be helped by receiving emergent radiation therapy. A randomized trial evaluating the benefit of adding surgical decompression to the radiotherapeutic management of symptomatic metastatic spinal cord compression showed that patients who underwent decompressive surgery had a significantly improved median time of gait retention and ability to regain gait function (Patchell et al. 2003). Overall survival was not significantly different. These data indicate that all patients presenting with MSCC of short duration should be evaluated by a neurosurgeon for emergent decompression prior to initiating radiation therapy.

17.4.3

Radiation Therapy

17.4.3.1

Definitive Radiation Therapy

Radiation therapy is a mainstay of the management of most malignant and a significant number of benign primary CNS tumors. Table 17.3 provides an overview of the most common primary CNS tumors and literature-based guidelines for treatment. For tumors treated with a “shrinking-field” technique, ICRU (International Commission on Radiation Unit) definitions of treatment volumes for both the initial and boost fields are given, together with general dosing guidelines. Selected outcome endpoints are provided along with the appropriate references. A more detailed description of treatment technique is provided for selected tumors later in the chapter.

17.4.3.2

Palliative Radiation Therapy

The fact that 60–70% of patients who present with brain metastases have multiple lesions makes

radiotherapy the primary modality for palliation in the majority of cases (Hazuka et al. 1993;

Patchell 2003). Many patients will respond dra- matically to medical therapy and radiation in the emergent setting with an improvement in their performance status, particularly if their symptoms are largely caused by edema. With this in mind, radiation therapy dosing schedules for the treatment of emergent patients can be tailored to patient parameters such as initial response to steroids, extent of extracranial disease, primary site and purported response of primary to systemic therapy. Two randomized trials comparing radiotherapy with or without surgical resection in the management of a solitary brain metastasis have documented a survival advantage with the addition of surgery over radiation alone (Patchell et al.

1990; Vecht et al. 1993). A third randomized trial was negative (Mintz et al. 1996). There is no level-I evidence demonstrating any survival benefit from operating on patients with multiple metastases.

However, patients with multiple lesions and severe neurological symptoms from a dominant metastasis that is unresponsive to medical therapy may benefit from a craniotomy for reasons described above. An improvement in the patient’s performance status may then allow further aggressive therapy with external beam radiation therapy and/

or radiosurgery. Leukemic brain infiltration causing acute mental status changes and/or impending herniation is a rare entity treated with whole-brain radiation therapy.

Patients with malignant glioma who require emergent treatment are typically treated with regimens similar to those used for brain metastases.

Surgical debulking is the mainstay of emergent treatment, as is the initiation of steroid therapy.

Patients who are unable to undergo surgical debulking may be treated with a short course of whole- brain radiation similar to that used for brain metastases.

Although no randomized trials exist comparing radiotherapy over best supportive care or medical therapy alone, every published series for MSCC has shown efficacy of radiation therapy in helping patients relieve pain and retain/regain lost function.

Morbidity is generally low and well tolerated even by patients with a poor performance status. Approxi- mately 89% of patients who are ambulatory prior to radiation therapy can expect to retain gait function, while an average of 39% of paretic patients and only 10% of paraplegic patients will remain ambulatory (Loblaw et al. 2003).

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Table 17.3. Suggested definitions of ICRU volumes by diagnosis, based on magnetic resonance imaging and dose ranges (in Gray; Gy) delivered to these volumes. GTV gross tumor volume, CTV clinical target volume, GTV gross tumor volume, +C with contrast, MS median survival, DFS disease-free survival, OS overall survival, LC local control. The numbers in subscript denote years DiagnosisDefinition of initial treatment field (CTV)Usual dose to CTVDefinition of final field (to GTV)Usual dose to GTVDose to craniospinal axis (if indicated)MSDFS5OS1OS5LC5Selected references WHO grade- I glioma(n/a)(n/a)Enhancing tumor (T1+C); 1 cm margin 45–50.4 Gy(n/a)95%95%Brown et al. (2004) WHO grade- II gliomaEnhancing tumor (T1 + C); Edema (T2/FLAIR) 2 cm margin

45 GyEnhancing tumor (T1+C); 2 cm margin 50.4–54 Gy(n/a)37– 50%58– 73%

Karim et al. (1996, 2002);Shaw et al. (2002) WHO grade- III gliomaEnhancing tumor (T1+C); edema (T2/FLAIR); 2-cm margin

45–50.4 GyEnhancing tumor (T1+C); 2-cm margin 59.4 GyLeptomeningeal spread on MRI: 30–39.6 Gy. Bulky disease: 55.8–59.4 Gy 17.5–58.6 months38%Prados et al. (2004); Scott et al. (1998); Tortosa et al. (2003) WHO grade- IV gliomaEnhancing tumor (T1+C); edema (T2/FLAIR); 2-cm margin

45–50.4 GyEnhancing tumor (T1+C); 2-cm margin 59.4–64.8 GyLeptomeningeal spread on MRI: 30–39.6 Gy. Bulky disease: 55.8–59.4 Gy

17.5– 17.1 months28– 70%0–14%Shaw et al. (2003) Menin- gioma, benign/ atypical

(n/a)(n/a)Enhancing tumor (T1+C); 1-cm margin 52.2–64.8 Gy(n/a)48– 89%58– 85%

Condra et al. (1997); Goldsmith et al. (1994);Stafford et al. (1998) Meningi- oma, malignant

Enhancing tumor (T1+C); edema (T2/FLAIR); 2-cm margin 45–50.4 GyEnhancing tumor (T1+C); 2-cm margin 55.8–59.4 Gy(n/a)1.5 yearsPerry et al. (1999) Pituitary adenoma(n/a)(n/a)Enhancing tumor (T1+C); 0.7–1 cm margin

45–50.4 Gy (non-functioning); 45–54 Gy (functioning) (n/a)90–95% (33–95% biochemical control) Stieber and deGuzman (2003) Ependy- momaEnhancing tumor (T1+C); edema (T2/FLAIR); 2-cm margin

45 GyEnhancing tumor (T1+C); 2-cm margin 50.4–55.8 GyNegative CSF: 30 Gy. Posi- tive CSF: 36 Gy. Gross lepto- meningeal spread on MRI: 39.6 Gy. Bulky disease: 54 Gy 67– 100%95–100%Stieber et al. (2005) Chordoma, chondrosarcoma

Enhancing tumor (T1 + C); tumor bed; 2-cm margin 50.4 GyEnhancing tumor (T1+C); 2-cm margin

59.4–70.2 Gy(n/a)36– 72%75– 80%40–75%Stieber et al. (2005) Central neurocytoma(n/a)(n/a)FLAIR changes; 1-cm margin50.4–55.8 Gy(n/a)98%98%Rades et al. (2003b, 2005) Vertebral hemangioma

Enhancing vascular lesion Entire involved vertebral body ≥1 cm margin (n/a)(n/a)36–45 Gy(n/a)82%Rades et al. (2003a) Brain metas- tasesWhole brain30–37.5 Gy (adjuvant 40–50.4 Gy)

(n/a)(n/a)(n/a)3.8–7.1 months12– 32%

Gaspar et al. (1997, 2000) Spinal cord metastasisEnhancing tumor (T1+C); tumor bed; surgical track, including scar; One vertebral body above and below

30–37.5 Gy(n/a)(n/a)(n/a)3.3–4.2 months

Patchell et al. (2003) Leukemic brain infiltration

Whole brain24–30 Gy in 1.8–3.0 Gy fractions

(n/a)(n/a)18 Gy9 monthsSanders et al. (2004)

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17.5

General Concepts of Modern Radiation Therapy Technique

17.5.1

Principles of Imaging-Based Treatment Planning The current standard of care for radiation therapy of primary CNS tumors is to use CT- and MRI-based 3-D treatment planning. CT simulation is still necessary, since most commercial treatment planning systems perform dose calculations from CT data sets. Fusion of a MRI scan data set (see below) with the treatment planning CT scan allows for optimum definition of the extension of the tumor and accurate delineation of surrounding structures of interest including the optic apparatus. MRI scans are essential to define treatment-planning volumes based on the reports of the ICRU 50 (International Commission on Radiation Units and Measurements I 1993) and ICRU 62 (International Commission on Radiation Units and Measurements I 1999), which are described in detail in the section on target volume definition, below (Table 17.3). Imaging of tumor biology or physiology may provide additional information for radiation therapy treatment planning. Functional MRI scans that image cerebral blood flow can show regions of normal brain function, e.g., motor strip, expressive and receptive language areas (Ricci and Dungan 2001). With three-dimensional MR spectroscopy, the choline-to-N-acetylaspartate ratio or index (CNI) appears to be both sensitive and specific at differentiating tumor from normal tissue when the proper threshold is selected (McKnight et al. 2002). [¹¹C]-Methionine PET imaging also shows promise in improving the anatomical delineation of low-grade gliomas (Nuutinen et al. 2000). Currently, the main utility of these functional and metabolic imaging studies is to better define the anatomical

extent of the tumor for radiation therapy treatment planning. Biological or physiological data are not yet imported and incorporated into the planning process, but ultimately will be when so-called “bioanatomic”

radiation therapy treatment planning becomes widely available (Carson et al. 2003; Morris et al. 2001).

All diagnostic information, but particularly MRI scans (including T2 and FLAIR images) and CT scans, as well as clinical and surgical findings, should be combined to define the tumor volume and critical structures. Depending on diagnosis, some patients may enjoy survival measured in years rather than months, so it is especially critical to respect dose- tolerances of normal structures in order to limit late toxicities. Normal tissues to be contoured include, at a minimum, the eyes (including lacrimal glands and lenses), optic nerves, optic chiasm, pituitary gland, brainstem, and temporal lobes. Using dose–volume histograms (DVHs), dose to the tumor can be maxi- mized and normal tissue dose minimized by analyz- ing competing treatment plans.

Table 17.4 shows normal tissue tolerance of critical normal intracranial structures to radiation therapy.

Comparison of dose tolerances to the doses required to control disease demonstrated clearly that at the

“standard” treatment doses of 54–60 Gy the prob- ability of causing serious toxicity is quite low as long as care is taken with planning. Beam energies of no less than 6 MV should be used in order to spare surrounding structures, most notably the temporal lobes. A very good balance between depth dose and penumbra width is provided by 10-MV photons.

17.5.2

Target Volumes and Organs at Risk Specifications Treatment planning is based on the three-dimensional volumes of interest described by the Inter-

Table 17.4. Normal tissue tolerance of intracranial organs at risk. All doses are in cGy at conventional fractionation (Emami et al. 1991)

Organ TD5/5 (Volume) TD50/5 (Volume) Endpoint

1/3 2/3 3/3 1/3 2/3 3/3

Brain 6000 5000 4500 7500 6500 6000 Necrosis, infarction

Brainstem 6000 5300 5000 6500 Necrosis, infarction

Optic nerve 6000 Blindness

Optic chiasm 5400 Blindness

Eye (lens) 1000 Cataracts

Eye (retina) 4500 Blindness

Lacrimal gland 3000 Dry eye syndrome

Ear (mid/external) 3000 3000 5500 4000 4000 4000 Acute serous otitis 5500 5500 5500 6500 6500 6500 Chronic serous otitis

Pituitary <4500 6000 Panhypopituitarism

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national Commission on Radiation Units and Measurements (ICRU) (International Com- mission on Radiation Units and Measure- ments I 1993, 1999). Figure 17.4 shows a graphi- cal representation of these volumes as described below.

Based on the ICRU 50 and 62 reports, gross tumor volume (GTV) represents the grossly vis- ible disease burden (International Commission on Radiation Units and Measurements I 1993, 1999). For grade-IV astrocytoma (glioblastoma multiforme) this is a T1-enhancing abnormality on MRI.

If there is no residual abnormality after a surgical resection, the tumor resection cavity is defined to be the GTV. Surrounding edema is not considered part of the GTV. The clinical target volume (CTV) is sub- clinical microscopic malignant disease, often seen as T2 or FLAIR abnormality (which does include edema) on MRI (International Commission on Radiation Units and Measurements I 1993).

Suggested definitions of and doses to be delivered to GTV and CTV are given in Table 17.3 by histological diagnosis.

The planning target volume (PTV) is also referred to as “dosimetric margin”. The dosimetric margin of the PTV takes two additional margins into consideration (International Commission on Radiation Units and Measurements I 1999). The PTV1 is the CTV plus a dosimetric margin; the smaller PTV2 is the GTV plus dosimetric margin. The internal margin is defined so as to take into account variations in size, shape, and position of the CTV in relation to anatomical reference points. The set-up margin is added to take into account uncertainties in patient–

beam positioning. Segregating the internal margin and the set-up margin reflects the differences in the source of uncertainties. The internal margin is due mainly to physiological variations that are difficult or impossible to control, such as (potential) fluctua- tions in the mass effect from cerebral edema which may occur over the course of treatment. In contrast, the set-up margin is added because of uncertainties related mainly to technical factors that can be reduced by more accurate positioning and immobilization of the patient (such as stereotactic positioning), as well as improved mechanical stability of the machine. The addition of uniform margins that take into account all types of uncertainties would generally lead to an excessively large PTV, which could result in exceeding normal tissue tolerances.

Thus, the balance between disease control and risk of complications may require an evaluation based on the experience and the judgment of the clinician in order to avoid serious treatment-related complications. The PTV may therefore be reduced in areas near critical structures. Dosimetric margins as low as 3–5 mm may be acceptable with appropriate immobilization devices. The target is usually considered to be appropriately treated if the PTV is enclosed within the 95–105% isodose line. For plans emphasizing homogeneous dose delivery, typically no more than 20% of the PTV should exceed 110%

of the prescription dose.

Organs at risk (OARs) are critical normal structures that are at risk for significant toxicity in the judgment of the treating physician. Such OARs are normal tissues, of which the radiation sensitivity and proximity to the CTV may significantly influ-

Fig. 17.4. Diagrammatic representation of ICRU 50 and 60 volumes. Abbreviations are deﬁ ned in the text. Solid arrows expansion of one volume to deﬁ ne another. The gross tumor volume (GTV; orange) expands to the planning target volume (PTV)2 (red).

The clinical target volume (CTV; blue) expands to the PTV1 (green)