Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved
Chapter 77
Brain metastases{ 1
JAIME GA´LLEGO PE´REZ-LARRAYA1,2* AND JERZY HILDEBRAND2 (deceased) Department of Neurology and Neurosurgery, Clinic of the University of Navarra, University of Navarra, Pamplona, Spain 2
Fdration de Neurologie Mazarin, Groupe Hospitalier Piti-Salptrire, Paris, France
INTRODUCTION Despite better prevention and treatment advances achieved during the last decades, cancer is still a major public health concern and remains one of the leading causes of death worldwide (Lopez et al., 2006). The central nervous system (CNS) is a frequent target for metastases from systemic cancer. The most common location of CNS metastases is the brain parenchyma, followed by the leptomeningeal space. Parenchymal metastases differ from leptomeningeal disease in clinical presentation, treatment modalities, and prognosis. However, their combination is common: on one hand, superficial brain lesions may invade the subarachnoid space, and on the other hand, primary leptomeningeal carcinomatosis often invades the brain parenchyma via perivascular Virchow–Robin spaces. This chapter deals only with metastases restricted to the brain parenchyma.
INCIDENCE AND PRIMARY TUMORS The exact incidence of metastatic brain tumors is unknown. Most epidemiologic studies may underestimate their true incidence, in part because some brain metastases remain asymptomatic, in part because even symptomatic lesions are often ignored in severely ill patients with advanced primary disease (Gavrilovic and Posner, 2005). Autopsy and clinical studies suggest that brain metastases occur in 10–30% of adult patients with systemic malignancies (Posner and Chernik, 1978; Schouten et al., 2002), thus representing by far the most frequent neurologic complication of systemic cancer
and the most common type of brain tumor in adults. They exceed the number of primary brain tumors at least fourfold. The incidence of brain metastases is thought to be rising in the last few decades due to a combination of factors other than population aging. First, improvements in and wider use of neuroimaging have resulted in an increased and earlier detection of clinically silent metastases. For example, routine brain scans are performed during the staging evaluation in neurologically asymptomatic patients with newly diagnosed lung cancer (Shi et al., 2006) or metastatic melanoma (Gavrilovic and Posner, 2005). Second, more effective treatments for systemic disease have extended survival of cancer patients, leading to a larger population at risk for brain metastases. Third, some highly effective anticancer agents poorly cross the blood–brain barrier (BBB), and are thereby unable to eradicate dormant micrometastases in patients with controlled systemic disease. Every malignant tumor is able to metastasize to the brain. However, only a limited number account for the vast majority of brain metastases. In adults, three tumors, lung and breast carcinomas and malignant melanoma, account for up to 75% of brain metastases (Nussbaum et al., 1996; DeAngelis and Posner, 2009). In children and very young adults, the primary tumors most likely to metastasize to the brain are sarcomas (osteogenic sarcoma, rhabdomyosarcoma, and Ewing’s sarcoma) and germ cell tumors (Kebudi et al., 2005). Lung cancers are the most common source of brain metastases, accounting for at least one half of the cases
*Correspondence to: Jaime Ga´llego Pe´rez de Larraya, M.D., Ph.D., Department of Neurology and Neurosurgery, Clı´nica Universidad de Navarra, Universidad de Navarra, Avd. Pı´o XII, 36, Pamplona 31008, Spain. Tel: þ34-948-255400, Fax: þ34-948296500, E-mail: [email protected] {
This chapter is dedicated to the memory of Professor Jerzy Hildebrand
1144 J. GA´LLEGO PE´REZ-LARRAYA AND J. HILDEBRAND (Soffietti et al., 2006). Patients with small-cell lung candestruction of the CNS structures, and by ischemia cer (SCLC), which accounts for only 15% of all lung can(DeAngelis and Posner, 2009). Through mass effect cers, are at special risk as up to 50% of them eventually and obstruction of cerebrospinal fluid (CSF) circulation, develop brain metastases (Seute et al., 2004). Among brain metastases may also cause intracranial hypertennon-small-cell lung cancers (NSCLC), adenocarcinomas sion, obstructive hydrocephalus, brain herniations, and metastasize to the brain more frequently than squamous false localizing signs such as sixth nerve palsy. cell carcinomas (Shi et al., 2006). Most symptoms and signs caused by brain metastases Breast cancer is the second most common source, evolve progressively over days to weeks. But some have responsible for about 15% of all brain metastases a stroke-like onset caused by tumor hemorrhage, tumor (Soffietti et al., 2006; DeAngelis and Posner, 2009). emboli, or acute rise in intracranial pressure. However, The risk is increased in estrogen receptor-negative in the authors’ experience, the mechanism of acute neuand HER2/neu-positive tumors. Patients with HER2/ rologic deficit remains often unexplained and could be neu-positive breast cancer are treated with trastuzumab related to acute worsening of edema. (Herceptin®), and in that group the incidence of brain Brain metastases may be located in all sites of the metastases is high. This may be due to increased patient brain, and are multiple in about 50% of the cases survival and to the fact that trastuzumab, which does not (Nussbaum et al., 1996). Therefore, any new neurologic cross the BBB, is unable to eradicate micrometastases manifestation occurring in a patient with cancer should (Stemmler et al., 2007). raise the possibility of a metastatic brain tumor. Certain Melanoma represents the third most common cause features, however, are particularly common. They of brain metastases, accounting for 5–10% of the cases, include headache, seizures, focal signs, cognitive and despite its comparably low incidence (Majer and behavioral changes, and gait disorders. Samlowski, 2007). But its propensity to form brain Headache is the most common presenting symptom, metastases is very high, and 50% of patients dying of occurring in approximately 50% of the patients (Forsyth melanoma have brain lesions (Amer et al., 1978). and Posner, 1993). It is more common in patients with Genitourinary tract cancers, mainly renal carcinoma, multiple and/or posterior fossa lesions. Headache and colorectal cancers come respectively as the fourth caused by brain metastases is usually mild but increases and fifth sources of brain metastases. In patients with in intensity and duration with time. Typically, it appears prostate cancer, small-cell or neuroendocrine carcinoin the early morning, worsens with maneuvers that mas represent less than 1% of the tumors, but are responincrease intracranial pressure such as straining, sible for 26% of brain metastases caused by prostate bending, or coughing, and may be accompanied by malignancies (Flannery et al., 2010). drowsiness, nausea, and vomiting. However, this “typiIn up to 15% of the patients with histologically cal” presentation occurs in only one-quarter to one-third proven brain metastases, physical examination and labof the patients. In the majority of the cases headaches oratory investigations fail to identify the site of the priresemble primary disorders such as tension-type headmary tumor in the early course of the disease (Nussbaum aches, and occasionally migraine (Forsyth and Posner, et al., 1996). During follow-up most of these patients are 1993). Thus headache characteristics, other than recent eventually found to have lung cancer (Ruda et al., 2001). worsening, fail to predict reliably the presence of brain metastases, unless focal deficits or papilledema coexist (Argyriou et al., 2006). Nowadays, papilledema CLINICAL FINDINGS is found in less than 10% of the patients due to earlier diagnosis of brain tumors (Young et al., 1974; Approximately two-thirds of brain metastases become DeAngelis and Posner, 2009). symptomatic in the course of the malignant disease Seizures occur as the first manifestation of brain (Cairncross et al., 1980). Most of them are diagnosed metastases in 20% of the patients and appear during in patients with already known systemic cancer the course of the disease in a similar percentage of cases (metachronous presentation) or found during diagnostic (Lynam et al., 2007). Patients with multiple lesions or procedure of the malignant disease (synchronous premetastatic melanoma have an increased seizure risk sentation). The discovery of brain metastases before that (Oberndorfer et al., 2002). Metastasis-related seizures of the underlying cancer (precocious presentation) is are essentially focal with or without secondary generalless common but this situation may prevail in departization, and thus have a localizing value. The most ments of neurosurgery and neurology. characteristic presentation is sensorimotor focal fits Tumor tissue plus the surrounding vasogenic edema with Jacksonian progression pattern. Postseizure palsy and, in some cases, intratumor hemorrhage produce and dysphasia are common in patients with underlying focal neurologic signs by compression rather than
BRAIN METASTASES tumor and may last longer than 24 hours (DeAngelis and Posner, 2009). The differential diagnosis of tumorrelated focal seizures and nonepileptic fluctuation of focal deficits such as worsening of aphasia or focal weakness is often very difficult in patients with language or other cognitive disorders including memory impairment. Nonconvulsive status epilepticus, which may be caused by unknown brain metastases, is another challenging but less common diagnostic issue (Blitshteyn and Jaeckle, 2006). Focal neurologic deficits such as weakness of one limb or hemiparesis with or without sensory changes, language disorders, and deficits of visual fields are common presenting signs occurring in up to 40% of the patients (Kaal et al., 2005). Cognitive decline, including memory impairment or lack of concentration, and behavioral disturbances ranging from personality changes to depression are extremely frequent. They have been reported in up to two-thirds of patients with brain metastases (Young et al., 1974; Mehta et al., 2003; Chang et al., 2007), but are largely underdiagnosed because they may be subtle, are reported more often by family members than by the patient himself, and may occur in absence of other neurologic signs. Gait disorders may be the initial manifestation of brain metastases even in the absence of lower limb weakness. They are typically caused by multiple, bilateral, small size metastases (Fig. 77.1). The patients usually complain of unsteadiness, and their gait is characterized by short steps and moderate widening of lower limbs.
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PATHOPHYSIOLOGYAND PATHOLOGY The metastatic process is a highly selective and nonrandom phenomenon, governed by a cascade of molecular and genetic changes (Chiang and Massague, 2008). The propensity to generate brain metastases differs not only between tumor types but also between cells of a single tumor. Not all cells of a given tumor are able to reach the CNS, and of those that do, not all will survive in the brain (Nathoo et al., 2005). Therefore primary tumors and their corresponding brain metastases can be biologically different, even when they appear pathologically similar (Morita et al., 1998). This seed (the metastasis) and soil (the brain) phenomenon is complex and not yet fully understood. It consists of a series of linked sequential steps: (1) cell detachment from the primary tumor by downregulation of adhesion molecules (Bremnes et al., 2002), and invasion of the host tissue through upregulation of matrixdegrading enzymes such as metalloproteases (Egeblad and Werb, 2002); (2) entry into the bloodstream through more permeable tumor-induced endothelial cells (Chang et al., 2000); (3) escape from destruction in the circulation, mainly by the immune system (natural killer cells) (Nieswandt et al., 1999) but also by mechanical forces; (4) arrest and early extravasation from brain microvessels (Kienast et al., 2010), favored by specific adhesion to brain endothelial cells (Pasqualini and Arap, 2002); and (5) survival and proliferation in the brain tissue by production of appropriate growth factors and promotion of angiogenesis or vessel co-option (Marchetti et al., 2003; Kienast et al., 2010). Cell predisposition to
Fig. 77.1. Contrast-enhanced T1-weighted MRI of a 67-year-old man with multiple brain metastases originating from lung adenocarcinoma. Unsteady gait was the only presenting sign. Note the ring-like enhancement of the largest lesion with central necrosis. (Reproduced courtesy of Prof. D. Bale´riaux.)
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metastasize is determined by genetic alterations, and changes that predict brain metastases from lung (Kikuchi et al., 2006) and breast cancer (Albiges et al., 2005) have been identified. Every step of this cascade is relatively inefficient and must be accurately completed for the final development of a brain metastasis. This explains why only a very tiny percentage of primary tumor cells is able to form viable brain metastases (Liotta and Kohn, 2003). Brain metastases are solid, usually rounded and well circumscribed space-occupying lesions (Wesseling et al., 2007). When present, the infiltration of the brain does not exceed 1 mm, except in metastases from SCLC and melanoma which may show a diffuse infiltration (Baumert et al., 2006). Distant infiltration may account for tumor recurrence after local therapy. Because tumor growth disrupts the BBB, brain metastases are often surrounded by vasogenic edema. Its extent, however, is not always proportional to the size of the malignant lesion. Large and rapidly growing metastases may contain central necrosis. Metastases of adenocarcinomas may contain collections of mucoid material (Wesseling et al., 2007). Microbleeds are common, and can be due either to invasion of blood vessel walls or to associated neovascularization. Large bleeds occur in up to 50% of metastases of melanoma and choriocarcinoma, followed by renal, thyroid, and testicular tumors (Mandybur, 1977). Metastases of lung cancers bleed in about 5% of the cases, but are a leading cause of tumor hemorrhage because of their high frequency. A recent study has shown an unexpectedly high rate of intratumoral hemorrhage in patients with metastases of breast or prostate cancers (Navi et al., 2010), but this observation is unusual and may reflect local experience. The histological appearance of brain metastases is generally similar to that of the primary tumor, even though they may differ biologically and genetically. In patients with unknown primary cancer and uninformative histological examination, appropriate immunostaining can suggest the nature and the location of the primary tumor (Becher et al., 2006). Brain metastases tend to develop at the junction between gray and white matter (Delattre et al., 1988; Hwang et al., 1996). Melanoma metastases are more likely than other metastatic tumors to invade the gray matter. Although direct extension into the CNS occasionally occurs from local tumors, most brain metastases reach the brain through hematogenous spread, and are believed to be entrapped in small size terminal arteries (Kienast et al., 2010). This mechanism may explain the propensity of brain metastases to develop in watershed zones of the cerebral circulation. The distribution of brain metastases, however, is roughly proportional to brain volume and blood flow: 80% are located in
the cerebral hemispheres, 15% in the cerebellum, and 5% in the brainstem. One study indicates that tumors arising in the pelvis, mainly prostate or uterine cancers, or colorectal cancer have a special affinity for the cerebellum (Delattre et al., 1988). The reason for this predilection is unknown. Based on imaging and autopsy data, one-half of patients with brain metastases have a single lesion (Posner and Chernik, 1978; Nussbaum et al., 1996), and an additional 20% two or three metastatic lesions (Delattre et al., 1988). Metastases from renal and colorectal tumors are often single, whereas lung cancers and melanoma are more likely to generate multiple lesions (Delattre et al., 1988).
DIAGNOSTIC PROCEDURES In patients with known cancer the purpose of diagnostic examinations is to identify and locate brain metastases. In individuals not known to have a malignant disease and in whom neuroimaging suggests brain metastases, the aim is to rule out other brain diseases, and to determine the nature and the location of the primary tumor.
Patients with known cancer Magnetic resonance imaging (MRI) is the best technique for detecting brain metastases, although there are no pathognomonic MRI features. MRI is superior to computed tomography (CT), even with double-dose delayed contrast, in visualizing small metastases and posterior fossa lesions (Schellinger et al., 1999). MRI has indeed a higher resolution, superior tissue contrast, and no bone artifacts. Furthermore, its versatile and multiplanar capabilities are useful in differential diagnosis and in planning surgery or stereotactic radiosurgery. Standard MRI includes T1WI (T1-weighted imaging) with and without contrast agent, T2WI (T2-weighted imaging), and FLAIR (fluid-attenuated inversion recovery) sequences. Most brain metastases generate low or intermediate intensity signal on T1WI. An increased intensity may correspond to a recent hemorrhage or to melanin deposit. Peritumoral edema appears as an area of decreased intensity. Brain metastases that reach a certain volume are enhanced after injection of paramagnetic contrast agent. Most brain metastases are spherical and sharply delineated. They may show peripheral ring enhancement with a nonenhancing core corresponding to central necrosis (Fig. 77.1). The enhancement is more conspicuous with magnetization transfer suppression (Knauth et al., 1996) and triple contrast dose (Sze et al., 1998), which may reveal very small lesions but also lead to false-positive findings. Conversely, treatment of the primary tumor with antiangiogenic agents may decrease
BRAIN METASTASES contrast enhancement of metastatic brain lesions (Karimi et al., 2009). T2WI and FLAIR sequences usually demonstrate an area of increased intensity encompassing both the tumor and the surrounding edema. The extent of edema is better appreciated on T2WI and FLAIR than on T1WI. Diffusion-weighted MRI (DW-MRI) is especially useful in the differential diagnosis of ring-enhancing cerebral lesions. It shows high-intensity signal in abscesses (restricted diffusion, low signal on apparent coefficient diffusion (ADC) map), compared to low-intensity signal (unrestricted diffusion, high signal on ADC map) in cystic or necrotic tumors (Fig. 77.2). Solid brain metastases can appear as hyperintense lesions (restricted diffusion) depending on their cellularity, in which case DW-MRI is unable to differentiate metastatic lesions from acute or subacute ischemic stroke (Geijer and Holtas, 2002).
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Perfusion MRI often shows an elevated relative cerebral blood volume (rCBV) in both metastatic and primary tumors. However, beyond the contrast-enhancing margins of the lesion, rCBV is usually increased in infiltrating primary tumors and decreased by edema in minimally invasive metastases (Law et al., 2002). The MRI spectroscopy profile of solid metastases is characterized by increased choline peak, and decreased or even absent N-acetylaspartate and creatine levels. In metastases with necrotic areas, elevated lactate and lipid peaks may be found (Fig. 77.3). These findings are not specific and are also seen in primary tumors. Likewise in rCBV study, peritumoral measurements may help to differentiate primary from secondary brain tumors, thanks to their different infiltration capacity. Spectroscopic imaging demonstrates elevated choline levels in the peritumoral region of gliomas but not of metastases (Law et al., 2002).
Fig. 77.2. Cerebral lesions with ring-enhancing appearance on contrast-enhanced T1- weighted image (upper images of panels (A) and (B)). The lesion in panel (A) is a breast adenocarcinoma metastasis, and its core is characterized by high signal on apparent diffusion coefficient (ADC) map (unrestricted diffusion). The lesion on panel (B) is an abscess, and its core is hypointense on ADC map (restricted diffusion). (Reproduced courtesy of Prof. M. Lemort.)
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Fig. 77.3. MRI spectroscopy of a brain metastasis, with increased choline peak, decreased N-acetylaspartate and creatine levels, and elevated lipid peak corresponding to necrosis. Cho, choline; Cr, creatine; NAA, N-acetylaspartate; Lip, lipids. (Reproduced courtesy of Dr. R. Guillevin.)
CT scan with and without iodine contrast is used when MRI is not available or when its use is prohibited by the presence of magnetic material. On nonenhanced CT scan, brain metastases appear as hypo- or isodense mass lesions, except when there is intratumoral bleeding or calcification. Lesion density is increased after contrast injection. Brain positron emission tomography (PET) using 18 F-fluorodeoxyglucose (18 F-FDG) or amino acid tracers can be useful to differentiate hypometabolic postradiation focal necrosis from hypermetabolic malignant lesion (Hustinx et al., 2005).
When MRI or CT scan show, in an appropriate clinical setting, multiple mass lesions located near the gray–white matter junction and surrounded by an often disproportionate edema, the diagnosis of brain metastases is usually accepted without pathological confirmation. However, diagnostic biopsy may be indicated in certain circumstances such as: (1) atypical neuroimaging, (2) controlled systemic malignancy without evidence of pulmonary tumor, (3) primary cancer with low propensity to form CNS metastases, and (4) high risk of vascular or infectious brain lesion.
BRAIN METASTASES 1149 In brain metastases without leptomeningeal involvePrimary brain gliomas and primary CNS lymphoma ment, CSF changes are characterized only by an (PCNSL) with atypical radiological presentation may be increased protein level. But lumbar puncture for CSF extremely difficult to differentiate from brain metastaanalysis may be hazardous and is not recommended. ses despite progress made in DW-MRI, perfusion MRI, EEG is helpful to support the diagnosis of epileptic and MR spectroscopy (see diagnostic procedures), and seizures especially in patients with confusion, language definite diagnosis may require biopsy. or memory disorders, and unreliable history. But its Hemorrhage caused by a small and previously uniinterpretation is often complicated by nonepileptiform dentified metastasis may closely resemble primary brain abnormalities due to the underlying tumor. hematoma. In some patients the definite diagnosis is made only after a prolonged follow-up. In most ischemic lesions the shape, the location, and Patients not known to have cancer the lack of early contrast enhancement helps to differenIn patients without obvious cancer, the identification of tiate vascular from malignant disease. But in cases with the primary tumor is part of the diagnostic procedure. delayed neuroimaging, contrast enhancement and The major dilemma is how far to pursue systemic invesedema may mislead the diagnosis. Occasionally, systigations, which may delay potentially curative treatment temic tumors may generate emboli made of malignant such as radiosurgery and jeopardize its efficacy. The cells and/or mucin (mucin-secreting cancers) plus fibrin, which occlude cerebral arteries of various sizes and diagnostic work-up before considering surgery should cause symptomatic stroke. In these patients, malignant consist of at least a clinical examination including fullmass may develop subsequently on the site of the ischebody skin scrutiny, chest and abdomen CT, and wholebody 18 F-FDG PET if accessible. Chest CT is the most mic territory (Nielsen and Posner, 1983). fruitful and simple examination (van de Pol et al., Brain abscesses are rare (1/100 000 per year), but 1996), as about 60% of patients with brain metastases their incidence is increased after neurosurgical procehave primary or metastatic lung tumor. CT of abdomen dures (bacteria) and in immunosuppressed patients and pelvis occasionally shows an unsuspected cancer. (fungi such as aspergillus). In about 15% of the cases brain abscesses are cryptogenic, and in patients Whole-body 18 F-FDG PET scan is a sensitive tool for without identified infectious source, inflammatory labdetecting systemic cancer, but its specificity in differenoratory changes are subtle or even absent, making the tiating malignant from benign or inflammatory lesions is relatively low (Lan et al., 2008). When these examinadiagnosis difficult. Nowadays DW-MRI allows the distions are inconclusive brain tumor resection or stereotinction between infectious and malignant disease tactic biopsy is recommended. Both procedures help (Fig. 77.2). Also in tuberculomas, inflammatory tests to establish histological diagnosis and orient to the locaare often unable to distinguish tuberculous from neotion of the primary tumor (Becher et al., 2006). In addiplastic lesions. Most CSF analysis shows only an increased protein level because concomitant tuberculous tion, neurosurgery may be the first therapeutic step. meningitis is present in less than 10% of the patients Specific serum tumor markers such as a-fetoprotein (Arseni, 1958). and b-human chorionic gonadotrophin for germ cell tumors, and other markers including CA 15.3 for breast, Due to migration, neurocysticercosis is no longer CA 19.9 for pancreatic, and CA 125 for ovarian carcilimited to endemic areas (Latin America, Africa, and noma may help to orient the diagnosis of the primary Eastern Europe). Multiple brain cysts occasionally cancer. mimic metastatic lesions. The diagnosis is based on the occurrence of chronic seizures and serologic criteria. Two viral CNS diseases may have a pseudotumoral DIFFERENTIAL DIAGNOSIS presentation: herpes simplex encephalitis (HSE) and Up to 10% of structural brain lesions seen in cancer progressive multifocal leukoencephalopathy (PML). patients may not be metastatic, and correspond to priBoth diseases may be diagnosed with polymerase chain mary tumors, vascular, infectious, granulomatous, or reaction. However, the diagnosis may be challenging in demyelinating lesions (Patchell et al., 1990). They are HSE patients with minimal infectious signs, and in more likely to occur in patients with specific risk factors patients with PML who can mount an inflammatory for these complications, in individuals with controlled reaction allowing enhancement of MRI lesions. systemic cancer without evidence of primary or metaSarcoidosis is a systemic disease characterized by static pulmonary lesions, and in tumors with low propennoncaseous granulomas which involve leptomeninges sity to invade the CNS. In patients who have undergone and cerebral parenchyma in up to 10% of the patients. prior brain irradiation, clinical and radiological features Occasionally, parenchymal location is the only obvious of necrosis may resemble tumor progression. manifestation of the disease and may be mistaken for
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a neoplastic lesion. The diagnosis may require biopsy, and is sometimes made on surgical material. Recent multiple sclerosis plaques are contrastenhanced and may be occasionally mistaken for brain metastases. However, in our experience, the most likely diagnostic error is PCNSL, because in both diseases the lesions are multiple and have, typically, a periventricular location. Brain lesions due to late-delayed toxicity of radiation therapy usually appear over 1 year following treatment, and therefore are not frequent in patients with brain metastases. The most common complication is diffuse leukoencephalopathy, causing cognitive and gait disorders which may mimic tumor progression. The main risk factors for this pathology are age, vascular risk factors, and concomitant chemotherapy. Focal radionecrosis is uncommon in patients treated with whole-brain irradiation using 30 Gy delivered in 10 days. But it occurs in up to 10% of individuals treated with stereotactic irradiation. Radiation-induced meningioma or glioma develop after a delay of 10–15 years.
TREATMENT Several therapeutic options are available to treat brain metastases. Their choice is guided by following factors: 1. 2. 3.
the extent, control, and pathology of the primary tumor the size, location, and number of brain metastases prior anticancer treatments.
A meta-analysis of the RTOG studies defined four independent prognostic factors for survival of patients with brain metastases: (1) age, (2) extent of systemic
disease, (3) one versus several brain metastases, and (4) performance status (PS). Median survival of patients with four favorable factors was 7 months, whereas patients with only one favorable factor survived only 3 months (Diener-West et al., 1989). Treatment of brain metastases cannot be considered in isolation as in about half of the patients death is caused by extraneural lesions. In most patients with widespread and uncontrolled cancer, the survival is unlikely to be significantly prolonged even by the most effective therapy of the cerebral disease. In such patients the primary aim of treatment of brain metastases is to improve or stabilize the neurologic deficit and the quality of life, with minimal inconvenience and morbidity. Whole-brain radiation therapy (WBRT) and corticosteroids usually fulfill these requirements. For example, in melanoma patients on fotemustine (a nitrosourea derivative) (Mornex et al., 2003) or in SCLC patients on teniposide (a podophyllotoxin) (Postmus et al., 2000), WBRT significantly prolongs the time to progression of brain metastases. By contrast, in patients in whom the primary tumor is either undiagnosed or well controlled, who have a PS of 70% or more, and between one and three brain metastases, both quality of life and survival are primarily related to the treatment of malignant brain lesions. In such patients aggressive treatment of CNS-disease is warranted and several options summarized in the therapeutic algorithm are available (Fig. 77.4).
External whole-brain radiation therapy WBRT is a mainstay of treatment and is used at some stage in malignant brain disease in most patients. The standard dose is 30 Gy delivered in 10 daily fractions.
Fig. 77.4. Treatment algorithm in brain metastases. SCLC, small-cell lung cancer; PS, performance status; ChT, chemotherapy; SRS, stereotactic radiosurgery; WBRT, whole-brain radiation therapy.
BRAIN METASTASES There is no clear evidence to support that modified dose or fractionation schedule results in significantly better control of brain disease, longer median survival, or better cognitive outcome (Borgelt et al., 1980; Kurtz et al., 1981). Also there is no evidence that particular dose or fractionation should be based either on tumor pathology or radiosensitivity of the primary tumor, but this may be due to the limited number of studies explicitly addressing the issue. The main indications for WBRT are as follows: ●
●
●
●
●
As already mentioned, patients with poor outcome: advanced age, uncontrolled systemic cancer, low PS (
Chapter 77
Brain metastases{ 1
JAIME GA´LLEGO PE´REZ-LARRAYA1,2* AND JERZY HILDEBRAND2 (deceased) Department of Neurology and Neurosurgery, Clinic of the University of Navarra, University of Navarra, Pamplona, Spain 2
Fdration de Neurologie Mazarin, Groupe Hospitalier Piti-Salptrire, Paris, France
INTRODUCTION Despite better prevention and treatment advances achieved during the last decades, cancer is still a major public health concern and remains one of the leading causes of death worldwide (Lopez et al., 2006). The central nervous system (CNS) is a frequent target for metastases from systemic cancer. The most common location of CNS metastases is the brain parenchyma, followed by the leptomeningeal space. Parenchymal metastases differ from leptomeningeal disease in clinical presentation, treatment modalities, and prognosis. However, their combination is common: on one hand, superficial brain lesions may invade the subarachnoid space, and on the other hand, primary leptomeningeal carcinomatosis often invades the brain parenchyma via perivascular Virchow–Robin spaces. This chapter deals only with metastases restricted to the brain parenchyma.
INCIDENCE AND PRIMARY TUMORS The exact incidence of metastatic brain tumors is unknown. Most epidemiologic studies may underestimate their true incidence, in part because some brain metastases remain asymptomatic, in part because even symptomatic lesions are often ignored in severely ill patients with advanced primary disease (Gavrilovic and Posner, 2005). Autopsy and clinical studies suggest that brain metastases occur in 10–30% of adult patients with systemic malignancies (Posner and Chernik, 1978; Schouten et al., 2002), thus representing by far the most frequent neurologic complication of systemic cancer
and the most common type of brain tumor in adults. They exceed the number of primary brain tumors at least fourfold. The incidence of brain metastases is thought to be rising in the last few decades due to a combination of factors other than population aging. First, improvements in and wider use of neuroimaging have resulted in an increased and earlier detection of clinically silent metastases. For example, routine brain scans are performed during the staging evaluation in neurologically asymptomatic patients with newly diagnosed lung cancer (Shi et al., 2006) or metastatic melanoma (Gavrilovic and Posner, 2005). Second, more effective treatments for systemic disease have extended survival of cancer patients, leading to a larger population at risk for brain metastases. Third, some highly effective anticancer agents poorly cross the blood–brain barrier (BBB), and are thereby unable to eradicate dormant micrometastases in patients with controlled systemic disease. Every malignant tumor is able to metastasize to the brain. However, only a limited number account for the vast majority of brain metastases. In adults, three tumors, lung and breast carcinomas and malignant melanoma, account for up to 75% of brain metastases (Nussbaum et al., 1996; DeAngelis and Posner, 2009). In children and very young adults, the primary tumors most likely to metastasize to the brain are sarcomas (osteogenic sarcoma, rhabdomyosarcoma, and Ewing’s sarcoma) and germ cell tumors (Kebudi et al., 2005). Lung cancers are the most common source of brain metastases, accounting for at least one half of the cases
*Correspondence to: Jaime Ga´llego Pe´rez de Larraya, M.D., Ph.D., Department of Neurology and Neurosurgery, Clı´nica Universidad de Navarra, Universidad de Navarra, Avd. Pı´o XII, 36, Pamplona 31008, Spain. Tel: þ34-948-255400, Fax: þ34-948296500, E-mail: [email protected] {
This chapter is dedicated to the memory of Professor Jerzy Hildebrand
1144 J. GA´LLEGO PE´REZ-LARRAYA AND J. HILDEBRAND (Soffietti et al., 2006). Patients with small-cell lung candestruction of the CNS structures, and by ischemia cer (SCLC), which accounts for only 15% of all lung can(DeAngelis and Posner, 2009). Through mass effect cers, are at special risk as up to 50% of them eventually and obstruction of cerebrospinal fluid (CSF) circulation, develop brain metastases (Seute et al., 2004). Among brain metastases may also cause intracranial hypertennon-small-cell lung cancers (NSCLC), adenocarcinomas sion, obstructive hydrocephalus, brain herniations, and metastasize to the brain more frequently than squamous false localizing signs such as sixth nerve palsy. cell carcinomas (Shi et al., 2006). Most symptoms and signs caused by brain metastases Breast cancer is the second most common source, evolve progressively over days to weeks. But some have responsible for about 15% of all brain metastases a stroke-like onset caused by tumor hemorrhage, tumor (Soffietti et al., 2006; DeAngelis and Posner, 2009). emboli, or acute rise in intracranial pressure. However, The risk is increased in estrogen receptor-negative in the authors’ experience, the mechanism of acute neuand HER2/neu-positive tumors. Patients with HER2/ rologic deficit remains often unexplained and could be neu-positive breast cancer are treated with trastuzumab related to acute worsening of edema. (Herceptin®), and in that group the incidence of brain Brain metastases may be located in all sites of the metastases is high. This may be due to increased patient brain, and are multiple in about 50% of the cases survival and to the fact that trastuzumab, which does not (Nussbaum et al., 1996). Therefore, any new neurologic cross the BBB, is unable to eradicate micrometastases manifestation occurring in a patient with cancer should (Stemmler et al., 2007). raise the possibility of a metastatic brain tumor. Certain Melanoma represents the third most common cause features, however, are particularly common. They of brain metastases, accounting for 5–10% of the cases, include headache, seizures, focal signs, cognitive and despite its comparably low incidence (Majer and behavioral changes, and gait disorders. Samlowski, 2007). But its propensity to form brain Headache is the most common presenting symptom, metastases is very high, and 50% of patients dying of occurring in approximately 50% of the patients (Forsyth melanoma have brain lesions (Amer et al., 1978). and Posner, 1993). It is more common in patients with Genitourinary tract cancers, mainly renal carcinoma, multiple and/or posterior fossa lesions. Headache and colorectal cancers come respectively as the fourth caused by brain metastases is usually mild but increases and fifth sources of brain metastases. In patients with in intensity and duration with time. Typically, it appears prostate cancer, small-cell or neuroendocrine carcinoin the early morning, worsens with maneuvers that mas represent less than 1% of the tumors, but are responincrease intracranial pressure such as straining, sible for 26% of brain metastases caused by prostate bending, or coughing, and may be accompanied by malignancies (Flannery et al., 2010). drowsiness, nausea, and vomiting. However, this “typiIn up to 15% of the patients with histologically cal” presentation occurs in only one-quarter to one-third proven brain metastases, physical examination and labof the patients. In the majority of the cases headaches oratory investigations fail to identify the site of the priresemble primary disorders such as tension-type headmary tumor in the early course of the disease (Nussbaum aches, and occasionally migraine (Forsyth and Posner, et al., 1996). During follow-up most of these patients are 1993). Thus headache characteristics, other than recent eventually found to have lung cancer (Ruda et al., 2001). worsening, fail to predict reliably the presence of brain metastases, unless focal deficits or papilledema coexist (Argyriou et al., 2006). Nowadays, papilledema CLINICAL FINDINGS is found in less than 10% of the patients due to earlier diagnosis of brain tumors (Young et al., 1974; Approximately two-thirds of brain metastases become DeAngelis and Posner, 2009). symptomatic in the course of the malignant disease Seizures occur as the first manifestation of brain (Cairncross et al., 1980). Most of them are diagnosed metastases in 20% of the patients and appear during in patients with already known systemic cancer the course of the disease in a similar percentage of cases (metachronous presentation) or found during diagnostic (Lynam et al., 2007). Patients with multiple lesions or procedure of the malignant disease (synchronous premetastatic melanoma have an increased seizure risk sentation). The discovery of brain metastases before that (Oberndorfer et al., 2002). Metastasis-related seizures of the underlying cancer (precocious presentation) is are essentially focal with or without secondary generalless common but this situation may prevail in departization, and thus have a localizing value. The most ments of neurosurgery and neurology. characteristic presentation is sensorimotor focal fits Tumor tissue plus the surrounding vasogenic edema with Jacksonian progression pattern. Postseizure palsy and, in some cases, intratumor hemorrhage produce and dysphasia are common in patients with underlying focal neurologic signs by compression rather than
BRAIN METASTASES tumor and may last longer than 24 hours (DeAngelis and Posner, 2009). The differential diagnosis of tumorrelated focal seizures and nonepileptic fluctuation of focal deficits such as worsening of aphasia or focal weakness is often very difficult in patients with language or other cognitive disorders including memory impairment. Nonconvulsive status epilepticus, which may be caused by unknown brain metastases, is another challenging but less common diagnostic issue (Blitshteyn and Jaeckle, 2006). Focal neurologic deficits such as weakness of one limb or hemiparesis with or without sensory changes, language disorders, and deficits of visual fields are common presenting signs occurring in up to 40% of the patients (Kaal et al., 2005). Cognitive decline, including memory impairment or lack of concentration, and behavioral disturbances ranging from personality changes to depression are extremely frequent. They have been reported in up to two-thirds of patients with brain metastases (Young et al., 1974; Mehta et al., 2003; Chang et al., 2007), but are largely underdiagnosed because they may be subtle, are reported more often by family members than by the patient himself, and may occur in absence of other neurologic signs. Gait disorders may be the initial manifestation of brain metastases even in the absence of lower limb weakness. They are typically caused by multiple, bilateral, small size metastases (Fig. 77.1). The patients usually complain of unsteadiness, and their gait is characterized by short steps and moderate widening of lower limbs.
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PATHOPHYSIOLOGYAND PATHOLOGY The metastatic process is a highly selective and nonrandom phenomenon, governed by a cascade of molecular and genetic changes (Chiang and Massague, 2008). The propensity to generate brain metastases differs not only between tumor types but also between cells of a single tumor. Not all cells of a given tumor are able to reach the CNS, and of those that do, not all will survive in the brain (Nathoo et al., 2005). Therefore primary tumors and their corresponding brain metastases can be biologically different, even when they appear pathologically similar (Morita et al., 1998). This seed (the metastasis) and soil (the brain) phenomenon is complex and not yet fully understood. It consists of a series of linked sequential steps: (1) cell detachment from the primary tumor by downregulation of adhesion molecules (Bremnes et al., 2002), and invasion of the host tissue through upregulation of matrixdegrading enzymes such as metalloproteases (Egeblad and Werb, 2002); (2) entry into the bloodstream through more permeable tumor-induced endothelial cells (Chang et al., 2000); (3) escape from destruction in the circulation, mainly by the immune system (natural killer cells) (Nieswandt et al., 1999) but also by mechanical forces; (4) arrest and early extravasation from brain microvessels (Kienast et al., 2010), favored by specific adhesion to brain endothelial cells (Pasqualini and Arap, 2002); and (5) survival and proliferation in the brain tissue by production of appropriate growth factors and promotion of angiogenesis or vessel co-option (Marchetti et al., 2003; Kienast et al., 2010). Cell predisposition to
Fig. 77.1. Contrast-enhanced T1-weighted MRI of a 67-year-old man with multiple brain metastases originating from lung adenocarcinoma. Unsteady gait was the only presenting sign. Note the ring-like enhancement of the largest lesion with central necrosis. (Reproduced courtesy of Prof. D. Bale´riaux.)
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metastasize is determined by genetic alterations, and changes that predict brain metastases from lung (Kikuchi et al., 2006) and breast cancer (Albiges et al., 2005) have been identified. Every step of this cascade is relatively inefficient and must be accurately completed for the final development of a brain metastasis. This explains why only a very tiny percentage of primary tumor cells is able to form viable brain metastases (Liotta and Kohn, 2003). Brain metastases are solid, usually rounded and well circumscribed space-occupying lesions (Wesseling et al., 2007). When present, the infiltration of the brain does not exceed 1 mm, except in metastases from SCLC and melanoma which may show a diffuse infiltration (Baumert et al., 2006). Distant infiltration may account for tumor recurrence after local therapy. Because tumor growth disrupts the BBB, brain metastases are often surrounded by vasogenic edema. Its extent, however, is not always proportional to the size of the malignant lesion. Large and rapidly growing metastases may contain central necrosis. Metastases of adenocarcinomas may contain collections of mucoid material (Wesseling et al., 2007). Microbleeds are common, and can be due either to invasion of blood vessel walls or to associated neovascularization. Large bleeds occur in up to 50% of metastases of melanoma and choriocarcinoma, followed by renal, thyroid, and testicular tumors (Mandybur, 1977). Metastases of lung cancers bleed in about 5% of the cases, but are a leading cause of tumor hemorrhage because of their high frequency. A recent study has shown an unexpectedly high rate of intratumoral hemorrhage in patients with metastases of breast or prostate cancers (Navi et al., 2010), but this observation is unusual and may reflect local experience. The histological appearance of brain metastases is generally similar to that of the primary tumor, even though they may differ biologically and genetically. In patients with unknown primary cancer and uninformative histological examination, appropriate immunostaining can suggest the nature and the location of the primary tumor (Becher et al., 2006). Brain metastases tend to develop at the junction between gray and white matter (Delattre et al., 1988; Hwang et al., 1996). Melanoma metastases are more likely than other metastatic tumors to invade the gray matter. Although direct extension into the CNS occasionally occurs from local tumors, most brain metastases reach the brain through hematogenous spread, and are believed to be entrapped in small size terminal arteries (Kienast et al., 2010). This mechanism may explain the propensity of brain metastases to develop in watershed zones of the cerebral circulation. The distribution of brain metastases, however, is roughly proportional to brain volume and blood flow: 80% are located in
the cerebral hemispheres, 15% in the cerebellum, and 5% in the brainstem. One study indicates that tumors arising in the pelvis, mainly prostate or uterine cancers, or colorectal cancer have a special affinity for the cerebellum (Delattre et al., 1988). The reason for this predilection is unknown. Based on imaging and autopsy data, one-half of patients with brain metastases have a single lesion (Posner and Chernik, 1978; Nussbaum et al., 1996), and an additional 20% two or three metastatic lesions (Delattre et al., 1988). Metastases from renal and colorectal tumors are often single, whereas lung cancers and melanoma are more likely to generate multiple lesions (Delattre et al., 1988).
DIAGNOSTIC PROCEDURES In patients with known cancer the purpose of diagnostic examinations is to identify and locate brain metastases. In individuals not known to have a malignant disease and in whom neuroimaging suggests brain metastases, the aim is to rule out other brain diseases, and to determine the nature and the location of the primary tumor.
Patients with known cancer Magnetic resonance imaging (MRI) is the best technique for detecting brain metastases, although there are no pathognomonic MRI features. MRI is superior to computed tomography (CT), even with double-dose delayed contrast, in visualizing small metastases and posterior fossa lesions (Schellinger et al., 1999). MRI has indeed a higher resolution, superior tissue contrast, and no bone artifacts. Furthermore, its versatile and multiplanar capabilities are useful in differential diagnosis and in planning surgery or stereotactic radiosurgery. Standard MRI includes T1WI (T1-weighted imaging) with and without contrast agent, T2WI (T2-weighted imaging), and FLAIR (fluid-attenuated inversion recovery) sequences. Most brain metastases generate low or intermediate intensity signal on T1WI. An increased intensity may correspond to a recent hemorrhage or to melanin deposit. Peritumoral edema appears as an area of decreased intensity. Brain metastases that reach a certain volume are enhanced after injection of paramagnetic contrast agent. Most brain metastases are spherical and sharply delineated. They may show peripheral ring enhancement with a nonenhancing core corresponding to central necrosis (Fig. 77.1). The enhancement is more conspicuous with magnetization transfer suppression (Knauth et al., 1996) and triple contrast dose (Sze et al., 1998), which may reveal very small lesions but also lead to false-positive findings. Conversely, treatment of the primary tumor with antiangiogenic agents may decrease
BRAIN METASTASES contrast enhancement of metastatic brain lesions (Karimi et al., 2009). T2WI and FLAIR sequences usually demonstrate an area of increased intensity encompassing both the tumor and the surrounding edema. The extent of edema is better appreciated on T2WI and FLAIR than on T1WI. Diffusion-weighted MRI (DW-MRI) is especially useful in the differential diagnosis of ring-enhancing cerebral lesions. It shows high-intensity signal in abscesses (restricted diffusion, low signal on apparent coefficient diffusion (ADC) map), compared to low-intensity signal (unrestricted diffusion, high signal on ADC map) in cystic or necrotic tumors (Fig. 77.2). Solid brain metastases can appear as hyperintense lesions (restricted diffusion) depending on their cellularity, in which case DW-MRI is unable to differentiate metastatic lesions from acute or subacute ischemic stroke (Geijer and Holtas, 2002).
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Perfusion MRI often shows an elevated relative cerebral blood volume (rCBV) in both metastatic and primary tumors. However, beyond the contrast-enhancing margins of the lesion, rCBV is usually increased in infiltrating primary tumors and decreased by edema in minimally invasive metastases (Law et al., 2002). The MRI spectroscopy profile of solid metastases is characterized by increased choline peak, and decreased or even absent N-acetylaspartate and creatine levels. In metastases with necrotic areas, elevated lactate and lipid peaks may be found (Fig. 77.3). These findings are not specific and are also seen in primary tumors. Likewise in rCBV study, peritumoral measurements may help to differentiate primary from secondary brain tumors, thanks to their different infiltration capacity. Spectroscopic imaging demonstrates elevated choline levels in the peritumoral region of gliomas but not of metastases (Law et al., 2002).
Fig. 77.2. Cerebral lesions with ring-enhancing appearance on contrast-enhanced T1- weighted image (upper images of panels (A) and (B)). The lesion in panel (A) is a breast adenocarcinoma metastasis, and its core is characterized by high signal on apparent diffusion coefficient (ADC) map (unrestricted diffusion). The lesion on panel (B) is an abscess, and its core is hypointense on ADC map (restricted diffusion). (Reproduced courtesy of Prof. M. Lemort.)
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Fig. 77.3. MRI spectroscopy of a brain metastasis, with increased choline peak, decreased N-acetylaspartate and creatine levels, and elevated lipid peak corresponding to necrosis. Cho, choline; Cr, creatine; NAA, N-acetylaspartate; Lip, lipids. (Reproduced courtesy of Dr. R. Guillevin.)
CT scan with and without iodine contrast is used when MRI is not available or when its use is prohibited by the presence of magnetic material. On nonenhanced CT scan, brain metastases appear as hypo- or isodense mass lesions, except when there is intratumoral bleeding or calcification. Lesion density is increased after contrast injection. Brain positron emission tomography (PET) using 18 F-fluorodeoxyglucose (18 F-FDG) or amino acid tracers can be useful to differentiate hypometabolic postradiation focal necrosis from hypermetabolic malignant lesion (Hustinx et al., 2005).
When MRI or CT scan show, in an appropriate clinical setting, multiple mass lesions located near the gray–white matter junction and surrounded by an often disproportionate edema, the diagnosis of brain metastases is usually accepted without pathological confirmation. However, diagnostic biopsy may be indicated in certain circumstances such as: (1) atypical neuroimaging, (2) controlled systemic malignancy without evidence of pulmonary tumor, (3) primary cancer with low propensity to form CNS metastases, and (4) high risk of vascular or infectious brain lesion.
BRAIN METASTASES 1149 In brain metastases without leptomeningeal involvePrimary brain gliomas and primary CNS lymphoma ment, CSF changes are characterized only by an (PCNSL) with atypical radiological presentation may be increased protein level. But lumbar puncture for CSF extremely difficult to differentiate from brain metastaanalysis may be hazardous and is not recommended. ses despite progress made in DW-MRI, perfusion MRI, EEG is helpful to support the diagnosis of epileptic and MR spectroscopy (see diagnostic procedures), and seizures especially in patients with confusion, language definite diagnosis may require biopsy. or memory disorders, and unreliable history. But its Hemorrhage caused by a small and previously uniinterpretation is often complicated by nonepileptiform dentified metastasis may closely resemble primary brain abnormalities due to the underlying tumor. hematoma. In some patients the definite diagnosis is made only after a prolonged follow-up. In most ischemic lesions the shape, the location, and Patients not known to have cancer the lack of early contrast enhancement helps to differenIn patients without obvious cancer, the identification of tiate vascular from malignant disease. But in cases with the primary tumor is part of the diagnostic procedure. delayed neuroimaging, contrast enhancement and The major dilemma is how far to pursue systemic invesedema may mislead the diagnosis. Occasionally, systigations, which may delay potentially curative treatment temic tumors may generate emboli made of malignant such as radiosurgery and jeopardize its efficacy. The cells and/or mucin (mucin-secreting cancers) plus fibrin, which occlude cerebral arteries of various sizes and diagnostic work-up before considering surgery should cause symptomatic stroke. In these patients, malignant consist of at least a clinical examination including fullmass may develop subsequently on the site of the ischebody skin scrutiny, chest and abdomen CT, and wholebody 18 F-FDG PET if accessible. Chest CT is the most mic territory (Nielsen and Posner, 1983). fruitful and simple examination (van de Pol et al., Brain abscesses are rare (1/100 000 per year), but 1996), as about 60% of patients with brain metastases their incidence is increased after neurosurgical procehave primary or metastatic lung tumor. CT of abdomen dures (bacteria) and in immunosuppressed patients and pelvis occasionally shows an unsuspected cancer. (fungi such as aspergillus). In about 15% of the cases brain abscesses are cryptogenic, and in patients Whole-body 18 F-FDG PET scan is a sensitive tool for without identified infectious source, inflammatory labdetecting systemic cancer, but its specificity in differenoratory changes are subtle or even absent, making the tiating malignant from benign or inflammatory lesions is relatively low (Lan et al., 2008). When these examinadiagnosis difficult. Nowadays DW-MRI allows the distions are inconclusive brain tumor resection or stereotinction between infectious and malignant disease tactic biopsy is recommended. Both procedures help (Fig. 77.2). Also in tuberculomas, inflammatory tests to establish histological diagnosis and orient to the locaare often unable to distinguish tuberculous from neotion of the primary tumor (Becher et al., 2006). In addiplastic lesions. Most CSF analysis shows only an increased protein level because concomitant tuberculous tion, neurosurgery may be the first therapeutic step. meningitis is present in less than 10% of the patients Specific serum tumor markers such as a-fetoprotein (Arseni, 1958). and b-human chorionic gonadotrophin for germ cell tumors, and other markers including CA 15.3 for breast, Due to migration, neurocysticercosis is no longer CA 19.9 for pancreatic, and CA 125 for ovarian carcilimited to endemic areas (Latin America, Africa, and noma may help to orient the diagnosis of the primary Eastern Europe). Multiple brain cysts occasionally cancer. mimic metastatic lesions. The diagnosis is based on the occurrence of chronic seizures and serologic criteria. Two viral CNS diseases may have a pseudotumoral DIFFERENTIAL DIAGNOSIS presentation: herpes simplex encephalitis (HSE) and Up to 10% of structural brain lesions seen in cancer progressive multifocal leukoencephalopathy (PML). patients may not be metastatic, and correspond to priBoth diseases may be diagnosed with polymerase chain mary tumors, vascular, infectious, granulomatous, or reaction. However, the diagnosis may be challenging in demyelinating lesions (Patchell et al., 1990). They are HSE patients with minimal infectious signs, and in more likely to occur in patients with specific risk factors patients with PML who can mount an inflammatory for these complications, in individuals with controlled reaction allowing enhancement of MRI lesions. systemic cancer without evidence of primary or metaSarcoidosis is a systemic disease characterized by static pulmonary lesions, and in tumors with low propennoncaseous granulomas which involve leptomeninges sity to invade the CNS. In patients who have undergone and cerebral parenchyma in up to 10% of the patients. prior brain irradiation, clinical and radiological features Occasionally, parenchymal location is the only obvious of necrosis may resemble tumor progression. manifestation of the disease and may be mistaken for
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a neoplastic lesion. The diagnosis may require biopsy, and is sometimes made on surgical material. Recent multiple sclerosis plaques are contrastenhanced and may be occasionally mistaken for brain metastases. However, in our experience, the most likely diagnostic error is PCNSL, because in both diseases the lesions are multiple and have, typically, a periventricular location. Brain lesions due to late-delayed toxicity of radiation therapy usually appear over 1 year following treatment, and therefore are not frequent in patients with brain metastases. The most common complication is diffuse leukoencephalopathy, causing cognitive and gait disorders which may mimic tumor progression. The main risk factors for this pathology are age, vascular risk factors, and concomitant chemotherapy. Focal radionecrosis is uncommon in patients treated with whole-brain irradiation using 30 Gy delivered in 10 days. But it occurs in up to 10% of individuals treated with stereotactic irradiation. Radiation-induced meningioma or glioma develop after a delay of 10–15 years.
TREATMENT Several therapeutic options are available to treat brain metastases. Their choice is guided by following factors: 1. 2. 3.
the extent, control, and pathology of the primary tumor the size, location, and number of brain metastases prior anticancer treatments.
A meta-analysis of the RTOG studies defined four independent prognostic factors for survival of patients with brain metastases: (1) age, (2) extent of systemic
disease, (3) one versus several brain metastases, and (4) performance status (PS). Median survival of patients with four favorable factors was 7 months, whereas patients with only one favorable factor survived only 3 months (Diener-West et al., 1989). Treatment of brain metastases cannot be considered in isolation as in about half of the patients death is caused by extraneural lesions. In most patients with widespread and uncontrolled cancer, the survival is unlikely to be significantly prolonged even by the most effective therapy of the cerebral disease. In such patients the primary aim of treatment of brain metastases is to improve or stabilize the neurologic deficit and the quality of life, with minimal inconvenience and morbidity. Whole-brain radiation therapy (WBRT) and corticosteroids usually fulfill these requirements. For example, in melanoma patients on fotemustine (a nitrosourea derivative) (Mornex et al., 2003) or in SCLC patients on teniposide (a podophyllotoxin) (Postmus et al., 2000), WBRT significantly prolongs the time to progression of brain metastases. By contrast, in patients in whom the primary tumor is either undiagnosed or well controlled, who have a PS of 70% or more, and between one and three brain metastases, both quality of life and survival are primarily related to the treatment of malignant brain lesions. In such patients aggressive treatment of CNS-disease is warranted and several options summarized in the therapeutic algorithm are available (Fig. 77.4).
External whole-brain radiation therapy WBRT is a mainstay of treatment and is used at some stage in malignant brain disease in most patients. The standard dose is 30 Gy delivered in 10 daily fractions.
Fig. 77.4. Treatment algorithm in brain metastases. SCLC, small-cell lung cancer; PS, performance status; ChT, chemotherapy; SRS, stereotactic radiosurgery; WBRT, whole-brain radiation therapy.
BRAIN METASTASES There is no clear evidence to support that modified dose or fractionation schedule results in significantly better control of brain disease, longer median survival, or better cognitive outcome (Borgelt et al., 1980; Kurtz et al., 1981). Also there is no evidence that particular dose or fractionation should be based either on tumor pathology or radiosensitivity of the primary tumor, but this may be due to the limited number of studies explicitly addressing the issue. The main indications for WBRT are as follows: ●
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As already mentioned, patients with poor outcome: advanced age, uncontrolled systemic cancer, low PS (
