Primary & Metastatic Brain Tumours


Primary Brain Tumours >

Brain Metastases >


Primary Brain Tumours

Intracranial neoplasms can arise from any of the structures or cell types present in the cranial vault, including the brain, meninges, pituitary gland, skull, and even residual embryonic tissue. Recent data suggest that the incidence of primary brain tumors is rising. The overall annual incidence of primary brain tumors in the United States is 9.5 cases per 100,000 population. Over 60% of primary brain tumors are gliomas, and at least two-thirds of these are clinically aggressive and high grade. Brain tumors represent 20% of all childhood malignancies and are the number two cause of cancer death in children after leukemia

Epidemiology

Gender
There is a slight predominance of primary brain tumors in males.

Age
Primary brain tumors have a bimodal distribution, with a small peak in the pediatric population and a steady increase in incidence with age, beginning at age 20 years and reaching a maximum of 20 cases per 100,000 population between the ages of 75 and 84 years.

Etiology and Risk Factors

The cause of primary brain tumors is unknown, although genetic and environmental factors may contribute to their development.

Genetic factors
Clear heritable factors play a minor role in the genesis of primary brain tumors; < 5% of glioma patients have a family history of brain tumour. Several inherited diseases, such as tuberous sclerosis, neurofibromatosis type I, Turcot’s syndrome, and Li-Fraumeni syndrome, predispose to the development of gliomas. However, these tumors tend to occur in children or young adults and do not account for the majority of gliomas, which appear in later years.

Environmental factors
Prior cranial irradiation clearly increases the risk of subsequent intracranial neoplasms. Certain environmental factors have been tentatively linked to the development of gliomas, but they apply to few patients. Severe head trauma, chronic exposure to petrochemicals, or employment in the aerospace industry may be predisposing factors.

Lifestyle characteristics Brain tumors are not associated with lifestyle characteristics, such as cigarette smoking or alcohol use.

Signs and Symptoms

Brain tumors produce both nonspecific and specific signs and symptoms.

Nonspecific symptoms include headache, which occurs in about half of patients, and symptoms of increased intracranial pressure, such as nausea and vomiting. Because of the widespread availability of CT and MRI, papilledema is now seen in < 10% of patients, even when symptoms of raised intracranial pressure are present.

Specific signs and symptoms are usually referable to the particular intracranial location of the tumour.

Lateralizing signs, including hemiparesis, aphasia, and visual field deficits, are present in ~ 50% of patients.

Seizures are a common presenting symptom, occurring in ~ 25% of patients with high-grade gliomas and at least 50% of patients with low-grade tumors. Seizures may be either generalized or partial.

Stroke-like presentation Hemorrhage into a tumour may present like a stroke, although the accompanying headache and alteration of consciousness usually suggest an intracranial hemorrhage rather than an infarct. Hemorrhage is usually associated with high-grade gliomas, occurring in 5%-8% of patients with glioblastoma multiforme. However, oligodendrogliomas have a propensity to bleed, and hemorrhage occurs in 7%-14% of these low-grade neoplasms.

Diagnosis

MRI
The diagnosis of a primary brain tumour is best made by cranial MRI. This should be the first test obtained in a patient with signs or symptoms suggestive of an intracranial mass. The MRI scan should always be obtained both with and without contrast material (gadolinium).

High-grade or malignant gliomas appear as contrast-enhancing mass lesions, which arise in white matter and are surrounded by edema.

Multifocal malignant gliomas are seen in ~ 5% of patients.

Low-grade gliomas typically are nonenhancing lesions that diffusely infiltrate brain tissue and may involve a large region of brain. Low-grade gliomas are usually best appreciated on T2-weighted MRI scans.

CT
A contrast-enhanced CT scan may be used if MRI is unavailable. CT may be false-negative in patients with a low-grade tumour and can have significant artifact through the posterior fossa, which may obscure a lesion in this area. Calcification, which may suggest the diagnosis of an oligodendroglioma, is often better appreciated on CT than on MRI.

Pathology

Glial tumors arise from astrocytes or oligodendrocytes and exist along a spectrum of varying malignancy.

The astrocytic tumors are graded, using a three-tier system, into astrocytoma, anaplastic astrocytoma, and glioblastoma multiforme. Grading is based on pathologic features, such as endothelial proliferation, cellular pleomorphism, and mitoses; the presence of necrosis establishes the diagnosis of glioblastoma multiforme.

Low-grade astroglial tumors (such as astrocytoma, pilocytic astrocytoma, and oligodendroglioma) and mixed glial and neuronal tumors (such as ganglioglioma) grow slowly but have a propensity to transform into malignant neoplasms over time. Transformation is usually associated with progressive neurologic symptoms and the appearance of enhancement on neurologic imaging studies.

The high-grade gliomas include glioblastoma, anaplastic astrocytoma, and anaplastic oligodendroglioma. These tumors are extremely invasive, with tumour cells often found up to 4 cm away from the primary tumour mass.

Ependymomas Intracranial ependymomas are relatively rare, accounting for < 2% of all brain tumors. They are most frequently seen in the posterior fossa or spinal cord, although they can also arise in the supratentorial compartment. Ependymomas are typically low grade histologically, but their high rate of recurrence indicates malignant behavior. Medulloblastomas are uncommon in adults but are one of the two most common primary brain tumors in children (the other being the cerebellar astrocytoma). Medulloblastomas arise in the cerebellum and are always high-grade neoplasms. Primitive neuroectodermal tumors (PNETs) are high-grade, aggressive tumors that usually occur in children. These include pineoblastoma and neuroblastoma. Histologically, they are identical to medulloblastomas, and there is controversy as to whether or not these two tumors are the same. However, by convention, medulloblastoma refers only to a tumour in the cerebellum, whereas PNET can occur throughout the supratentorial compartment. Extra-axial tumors The most common extra-axial tumour is the meningioma. Meningiomas are usually benign tumors that arise from residual mesenchymal cells in the meninges. They produce neurologic symptoms by compressing the underlying brain. Meningiomas rarely are malignant or invade brain tissue. Other extra-axial tumors include pituitary adenoma, craniopharyngioma, choroid plexis papilloma, and acoustic neuroma (vestibular schwannoma).

Staging and Prognosis

Staging is not applicable to most primary brain tumors because they are locally invasive and do not spread to regional lymph nodes or distant organs.

Staging with a fully enhanced spinal MRI and CSF evaluation is important for a few tumour types, such as medulloblastoma, ependymoma, and PNETs, because they can disseminate via the CSF.

Prognostic factors Prognosis is inversely related to several important factors, including pathologic grade, patient age, and overall clinical condition at diagnosis.

With conventional treatment, including surgical resection, radiotherapy, and chemotherapy, median survival is 3 years for patients with an anaplastic astrocytoma and 1 year for those with a glioblastoma multiforme. In a population of patients with low-grade tumors, including astrocytoma and oligodendroglioma, median survival is 5-10 years; most of these individuals die from malignant transformation of their original tumour. Patients ³ 40 years old with low-grade glioma generally have more aggressive disease; their median survival is usually < 5 years.

Treatment

Treatment of primary brain tumors consists of both initial supportive and definitive therapies.

Supportive Therapy
Supportive treatment focuses on relieving symptoms and improving the patient’s neurologic function. The primary supportive agents are anticonvulsants and corticosteroids.

Anticonvulsants
Anticonvulsants are administered to the ~ 20% of patients who have a seizure at presentation. Phenytoin (300-400 mg/d) is the most commonly used medication, but carbamazepine (600-1,000 mg/d), phenobarbital (90-150 mg/d), and valproic acid (750-1,500 mg/d) are equally efficacious. Doses of all of these anticonvulsants can be titrated to the appropriate serum levels to provide maximal protection.

Newer anticonvulsants, such as gabapentin (Neurontin), lamotrigine (Lamictal), and topiramate (Topamax), are also effective. Therapeutic serum levels of these drugs have not yet been established.

Prophylaxis
Many physicians give prophylactic anticonvulsants to all patients with an intracranial neoplasm to prevent seizures. However, prospective studies have failed to show the efficacy of prophylactic anticonvulsants for patients with brain tumors. Consequently, prophylactic anticonvulsants should not be administered, except during the perioperative period, when their use may reduce the incidence of postoperative seizures. Phenytoin and phenobarbital are the agents usually used for prophylaxis.

Corticosteroids
Corticosteroids reduce peritumoral edema, diminishing mass effect and lowering intracranial pressure. This produces prompt relief of headache and improvement of lateralizing signs. Dexamethasone is the corticosteroid of choice because of its minimal mineralocorticoid activity. The starting dose is ~ 16 mg/d, but this is adjusted upward or downward to reach the minimum dose necessary to control neurologic symptoms.

Long-term corticosteroid use is associated with hypertension, diabetes mellitus, a nonketotic hyperosmolar state, myopathy, weight gain, insomnia, and osteoporosis. Thus, steroid dose in brain tumour patients should be tapered as rapidly as possible once definitive treatment has begun. Most patients can stop taking steroids by the time they have completed cranial irradiation.

Definitive Therapy for Intracranial Tumours

Definitive treatment of intracranial tumors includes surgery, radiotherapy, and chemotherapy. The first step is to devise an overall therapeutic plan, which should outline the sequence and elements of multidisciplinary therapy.

Surgery
Various surgical options are available, and the surgical approach should be carefully chosen to maximize tumour resection while preserving vital brain structures and minimizing the risk of postoperative neurologic deficits. The goals of surgery include: (1) obtaining an accurate histologic diagnosis; (2) reducing tumour burden and associated mass effect caused by the tumour and/or peritumoral edema; (3) maintaining or reestablishing pathways for CSF flow; and (4) achieving potential “cure” by gross total removal.

Surgical Tools
A variety of tools are available to help the neurosurgeon achieve these goals, including stereotactic and image-based guidance systems and electrophysiologic brain mapping.

Stereotactic frames provide a rigid, three-dimensional (3D) coordinate system for accurate targeting of brain lesions identified on CT or MRI scans.

Stereotaxy is particularly well-suited for obtaining tissue for biopsy from tumors located in deep structures, such as the thalamus, basal ganglia, and brainstem, or in other sites where aggressive tissue removal would produce unacceptable neurologic deficits. A limitation of stereotactic biopsy is that small volumes of tissue are obtained, and tissue sampling errors may result in failure to reach a correct diagnosis. Stereotactic biopsy may be nondiagnostic in 3%-8% of cases and has a surgical morbidity of approximately 5%.

Stereotactic frames can also be used to perform predefined volumetric tumour resections and to plan accurate surgical approaches to avoid or minimize damage to eloquent areas of the brain.

Image-based guidance system “Frameless” or “image-guided” stereotactic systems use computer technology to coregister preoperative imaging studies with intraoperative head position, thereby establishing stereotactic accuracy without the need for a frame.

Fiducial markers are placed on the patient’s scalp prior to surgery, and an MRI or CT scan is performed. In the operating room, fiducial markers are “registered” by correlating scalp location with MRI location using an intraoperative computer. This allows the entire 3D MRI space to be reconstructed in relation to the head position. Following this, the pointer or “wand” can be used to navigate and define MRI landmarks on the patient during surgery. Such systems facilitate more complete tumour removal and safer resections.

Brain mapping, also termed cortical mapping, uses electrical stimulation of the cortical surface to define areas of functional cortex, such as primary motor, sensory, or speech cortex. By pinpointing the exact location of these areas prior to tumour resection, the surgeon can perform a more aggressive resection and still safely avoid these structures, thereby preserving neurologic function.

An analysis of surgical data from Children’s Cancer Group (CCG) trial 945 found that the extent of surgical resection was the only factor that predicted the length of progression-free survival (PFS) in children with high-grade astrocytomas. The trial compared two different chemotherapy regimens in 172 children following surgical resection of such tumors. An improved PFS rate (> 90%) was observed in children who underwent radical (85%) resection, as compared with children who had less radical resections (P = .006). For children treated with radical or gross total resection, the 5-year PFS rate was 35% ± 7%, as compared with 17% ± 4% in children who underwent lesser resections. The authors conclude that aggressive surgical resection of malignant astrocytomas should be considered a principal component of the treatment strategy whenever technically feasible (Wisoff JH, Boyett JM, Bergger MS, et al: J Neurosurg 89(1):52-59, 1998).

Tools such as functional MRI and magnetic source imaging may provide a means to perform this mapping prior to surgery, although intraoperative cortical stimulation remains the gold standard. Magnetic resonance spectroscopy provides metabolic or biochemical information about tumors, which may be useful in differentiating viable tumour from edema or necrosis. Taken as a whole, these imaging techniques enable the neurosurgeon to perform more complete removal of tumors with less morbidity.

Pathology-Based Surgical Approach
The surgical approach to an intracranial lesion is strongly influenced by the suspected or previously confirmed pathology. Guidelines for the management of the most common tumors are discussed below. These guidelines may be modified according to the individual tumour size, location, and characteristics.

Meningiomas and other extra-axial tumors Benign extra-axial tumors, such as meningiomas, usually have a well-defined plane separating them from the surrounding brain parenchyma. In general, total extirpation can be achieved by open craniotomy. Firm attachment of the tumour to the dura, cranial nerves, vascular structures, or skull base may make this impossible. Subtotal resections that preserve neural or vascular structures while reducing mass effect are often favored for extensive skull base tumors.

The surgical management of other benign extra-axial tumors, such as acoustic neuroma, pineocytoma, choroid plexus papilloma, and pituitary adenoma, closely parallels that of meningioma. Gross total resection is generally curative and should be attempted whenever safe.

Low-grade gliomas Gross total resection, whenever possible, is the goal of surgery for low-grade gliomas and mixed neuronal-glial tumors (eg, astrocytoma, oligodendroglioma, pilocytic astrocytoma, and ganglioglioma), as long-term survival is often better in patients who have undergone a gross total resection than in those who have had a subtotal resection (5 year survival rates > 80% for gross total resection vs ~ 50% for subtotal resection).

If a radiographically proven gross total resection is attained, postoperative radiation or chemotherapy can often be withheld until there is evidence of tumour progression (see “Radiation therapy” below). If a postoperative scan reveals a small but surgically accessible residual lesion, immediate reoperation should be considered, particularly in children.

When low-grade tumors are found in patients with medically refractory, chronic epilepsy, surgical management should be oriented toward curing the epilepsy, as well as toward total tumour removal.

Ependymomas Gross total resection is the goal of surgery whenever possible. Because ependymomas arise in the ventricular system, they can disseminate in the CSF, and CSF diversion is often necessary. Therefore, all patients should be assessed for “drop” metastases prior to surgery, and at regular intervals thereafter.

High-grade gliomas More extensive resections improve the quality of life and Karnofsky performance status (KPS) of patients with high-grade gliomas (glioblastoma multiforme, anaplastic astrocytoma, and anaplastic oliogodendroglioma) by reducing mass effect, edema, and steroid dependence. True gross resections prolong survival relative to subtotal or partial resections, but extensive subtotal resections do not appear to confer any survival advantage over biopsy alone or limited resections. For this reason, most neurosurgeons attempt to achieve maximal resections while minimizing risk to critical areas of the brain. Stereotactic biopsy may be favored when the tumour is deep-seated or is situated directly in eloquent cortex, or when multifocal disease is present.

Recurrent or progressive tumors When a brain tumour recurs or enlarges, reoperation is often necessary to reduce mass effect. Radiation necrosis following high-dose radiotherapy for gliomas can often cause severe mass effect and edema, which is alleviated by debulking. Although rarely curative, these procedures can improve quality of life and modestly extend survival.

The North Central Cancer Treatment Group (NCCTG), Radiation Therapy Oncology Group (RTOG) and Eastern Cooperative Oncology Group (ECOG) recently completed a randomized trial of low-dose radiation therapy (50.4 Gy in 28 fractions) vs a high-dose regimen (64.8 Gy in 36 fractions) in 203 adults with supratentorial low-grade glioma. Rates of survival at 2 and 5 years were better, although not significantly so, with low-dose radiotherapy. The 2-year actuarial incidence of grade 3-5 radiation necrosis was 1% with low-dose radiotherapy and 4.5% with the high dose (Shaw EW, Arusell R, Scheithauer B, et al: Proc Am Soc Clin Oncol 17:401a [abstract], 1998).

In general, reoperation is not considered in patients with a KPS £ 60 or in patients who are not candidates for adjuvant therapy following initial surgery.

Initial resection or reoperation followed by intracavitary administration of chemotherapy, immunotherapy, or gene therapy is being explored, but is still investigational. Carmustine (BCNU)-impregnated wafers (Gliadel) are the only form of intracavitary chemotherapy currently approved by the FDA for recurrent glioblastoma.

Radiation Therapy
Radiation therapy plays a central role in the treatment of brain tumors in adults. It is the most effective nonsurgical therapy for patients with malignant gliomas and also has an important role in the treatment of patients with low-grade gliomas.

Controversies
The recommended radiation dose, volume, and fractionation schedule for patients with astrocytomas are still debated. Opinions also vary as to the volume of brain tissue that should be irradiated for malignant gliomas.

Whole-brain vs partial-brain irradiation Whole-brain irradiation is reserved for multifocal lesions and lesions with significant subependymal or leptomeningeal involvement. This treatment philosophy is based on the accepted compromise that, in some cases, isolated tumour cells will be excluded from the radiation field, but that limited-field treatment results in less morbidity and appears to produce equal, albeit poor, overall survival.

Dose-response in low-grade gliomas Retrospective studies suggest a radiation dose-response in low-grade gliomas. However, selection bias may play a role in these retrospective studies.

Several recently completed randomized studies addressed the question of optimal timing and dose of radiotherapy in patients with low-grade gliomas. A recently completed American intergroup randomized trial compared 50.4 Gy vs 64.8 Gy of radiation in patients with low-grade glioma (see box on previous page). A European Organization for Research and Treatment of Cancer (EORTC) trial compared 45 vs 59.4 Gy of radiation in patients with low-grade astrocytoma (see box). Both studies confirmed the superiority or equivalent efficacy of the lower radiation dose.

In a randomized EORTC trial of 379 patients with low-grade astrocytoma, PFS rates were the same in patients randomized to receive 45 Gy as in those randomized to 59.4 Gy, 47% and 50%, respectively, at a median follow-up of 70 months. Overall survival rates were also similar, 58% and 59%, respectively (Karim ABMF, Maat B, Hatlevoll R, et al: Int J Radiat Oncol Biol Phys 36:549-556, 1996).

A second EORTC trial tested immediate vs delayed radiotherapy in individuals with low-grade glioma (see box ). While immediate radiotherapy significantly improved 5-year progression-free survival, overall survival was identical on the two treatment arms.

The EORTC recently presented the results of a randomized study of low-grade glioma (EORTC 22845) comparing immediate radiotherapy (54 Gy in 30 fractions) to delayed treatment (ie, no further treatment until radiographic and clinical evidence of progression). With a median follow-up of 4.6 years, the estimated 5-year progression-free survival was 44% in the immediate-radiotherapy group vs 37% in the delayed-treatment group (P = .02). However, overall survival was similar in the two groups (63% and 66%, respectively) (Karim ABMF, Cornu P, Afra D, et al: Proc Am Soc Clin Oncol 17:400a, 1998).

Recommended Treatment Approach for Low-Grade Astrocytomas

The role of postoperative radiotherapy in the management of incompletely resected low-grade astrocytomas has not been firmly established. However, based on the available data, the following principles appear to be reasonable.

  • A complete surgical resection of hemispheric astrocytomas should be attempted.

  • If a complete surgical resection has been attained, radiation therapy can be withheld until MRI or CT studies clearly indicate a recurrence that cannot be approached surgically.

  • When a complete surgical resection is not performed, postoperative radiation may be recommended, particularly if labeling studies indicate that the astrocytoma has a high proliferative potential. Some patients with incompletely resected low-grade gliomas can be followed and radiation therapy deferred until clinical or radiographic progression occurs.

  • Radiation therapy should be delivered, using a megavoltage machine, in 1.7- to 2-Gy daily fractions to a total dose £ 50 Gy. The treatment fields should include the primary tumour volume only, as defined by MRI, and should not encompass the whole brain.

  • In low-grade astrocytomas, radiation therapy can be expected to produce a 5-year survival rate of 50% and a 10-year survival rate of 20%.

The EORTC recently presented the results of a randomized study of low-grade glioma (EORTC 22845) comparing immediate radiotherapy (54 Gy in 30 fractions) to delayed treatment (ie, no further treatment until radiographic and clinical evidence of progression). With a median follow-up of 4.6 years, the estimated 5-year progression-free survival was 44% in the immediate-radiotherapy group vs 37% in the delayed-treatment group (P = .02). However, overall survival was similar in the two groups (63% and 66%, respectively) (Karim ABMF, Cornu P, Afra D, et al: Proc Am Soc Clin Oncol 17:400a, 1998).

Radiation Therapy for High-Grade Gliomas
An analysis of three studies of high-grade gliomas done by the Brain Tumor Study Group (BTSG) showed that postoperative radiotherapy doses > 50 Gy were significantly better in improving survival than no postoperative treatment, and that 60 Gy resulted in significantly prolonged survival compared with 50 Gy. On the other hand, an American intergroup protocol, which randomized patients to receive 60 Gy of whole-brain irradiation, with or without a local boost of 10 Gy, demonstrated no survival benefit in the group receiving treatment with a total radiation dose of 70 Gy. These results may have been confounded by the competing morbidity of whole-brain radiotherapy when given at a dose of 60 Gy.

Based on these data, a standard dose for high-grade histologies is considered to be 60 Gy in 30-33 fractions, which corresponds to a dose just above the threshold for radionecrosis. Approximately half of patients with anaplastic astrocytomas exhibit radiographic evidence of response following 60 Gy of radiation, as compared with 25% of patients with glioblastoma multiforme. Complete radiographic response is rare in either case.

Alternatives to Conventional Radiotherapy
The results of standard radiation treatment in patients with malignant gliomas are poor. Patients with glioblastoma multiforme have a median survival of 9-12 months, while patients with anaplastic astrocytomas survive a median of 3 years. In an attempt to improve these poor results, a number of new approaches have been tried, including hyperfractionated radiotherapy (HFRT), focal dose escalation with interstitial brachytherapy, and radiosurgery. Newer experimental treatments include the use of radiosensitizers and boron neutron capture therapy (BNCT).

HFRT is the delivery of radiation in multiple (usually twice) daily fractions in order to increase the total dose given over the same period of time, as compared with standard radiotherapy. As the dose is fractionated, the differential sparing of normal structures allows for the delivery of significantly higher biological doses to the tumour while maintaining normal tissue doses at or below tolerance levels. The multiple daily treatments must be separated by sufficient time to permit full repair of radiation-induced damage between treatments. For normal CNS tissues, this interval has not been precisely defined but is generally considered to be at least 6 hours.

HFRT regimens have been used in the treatment of pediatric and adult supratentorial and brainstem malignant gliomas. To date, trials have failed to show an improvement in survival when higher total doses are delivered. However, doses as high as 72 Gy have been no more toxic than 60 Gy given in a routine fractionation scheme.

Accelerated fractionation In this fractionation scheme, patients are treated more than once daily but with conventional-size fractions of 1.6-2.0 Gy per fraction. The goal is to complete treatment in a shorter time.

To date, trials have not indicated a survival advantage for accelerated fractionation, but no increased toxicity has been observed. Further increases in total dose may be possible with this approach.

Brachytherapy is the placement of radioactive isotopes directly into the volume to be treated. Stereotactic techniques are employed to precisely place the radioactive seeds and calculate dose. The tumour receives the highest dose, and surrounding tissues are spared, due to the rapid fall-off in dose with distance from the sources.

Focal irradiation with brachytherapy has resulted in modestly improved local control and survival in selected patients with recurrent or primary glioblastoma multiforme. Brachytherapy may be appropriate for treating lesions that are £ 4 cm in patients with performance status ³ 70% and no subependymal spread. However, it has largely been replaced by radiosurgery.

Radiosurgery Over the last several years, there has been growing interest in the use of radiosurgery in the treatment of primary and recurrent malignant brain tumors. Radiosurgery is currently performed with one of three technologies: high-energy photons produced by linear accelerators, the Gamma Knife (AB Elekta, Stockholm, Sweden) or, less frequently, charged particles, such as protons or other ions produced by cyclotrons or synchrotrons.

The survival rates, patterns of recurrence, and rates of complications (including radionecrosis) of radiosurgery and brachytherapy are similar. Radiosurgery may be a more appealing approach than brachytherapy for the management of highly focal malignant gliomas because it is a noninvasive, single-day procedure that can usually be performed in an outpatient setting.

Radiosurgery is a relatively safe, effective means for improving both local control and survival in patients with newly diagnosed glioblastoma multiforme. Patient age and tumour volume are highly predictive of outcome. However, randomized trials are needed to further evaluate both the efficacy of stereotactic radiosurgery as a primary adjuvant modality for glioblastoma multiforme and the relative prognostic significance of patient and tumour characteristics. There appears to be no significant advantage to radiosurgery as a primary therapy for anaplastic astrocytoma or low-grade gliomas.

Radionecrosis
Both brachytherapy and sterotactic radiosurgery can induce focal radionecrosis. This complication produces symptoms of mass effect in about 50% of patients with malignant glioma, requiring resection to remove the necrotic debris. (Fewer than 5% of patients with other lesions [eg, brain metastases] require reoperation for radionecrosis.) Occasionally, treatment with corticosteroids can control the edema around the radionecrotic area, but often the patient becomes steroid-dependent, with all of the attendant complications of chronic steroid use. Radionecrosis can be a significant limitation of the focal radiotherapy techniques.

Recommended Approach for Extra-Axial Tumors

Surgery alone is curative in the vast majority of patients with benign tumors. However, in certain settings, a complete resection is impossible. Postoperative radiotherapy prevents further growth of many of these lesions.

CT-based treatment planning, or 3D conformal radiation therapy, is a relatively new method of treatment planning that utilizes CT information and powerful computer technology to optimize delivery of external-beam radiotherapy to tumors. Recent studies have shown that conformal radiation therapy improves local control rates by eliminating marginal misses and decreases the late effects of radiotherapy by reducing the volume of normal brain irradiated.

Pituitary adenomas For pituitary adenomas that persist or recur after surgery, 45 Gy is delivered in 25 fractions to the radiographic boundaries of the tumour. Coronal-enhanced MRI is critical for treatment planning since CT often does not visualize the skull base and the entire extent of disease.

The most common indication for radiotherapy is invasion of the cavernous sinus or the suprasellar space. Macroadenomas (> 1.5 cm) have a higher recurrence rate following surgery than do microadenomas. Most pituitary lesions do not grow following therapy, and hormonally active tumors usually demonstrate a hormonal response in 1-3 years. Following radiation therapy, 20%-50% of patients develop panhypopituitarism, requiring hormone replacement therapy. Other significant complications (ie, damage to the visual apparatus) are rare today.

Meningiomas are readily curable with complete surgical resection. However, base of skull lesions and lesions involving a patent venous sinus often are not resected completely. For some patients with these lesions, a course of postoperative radiotherapy is indicated. In general, 54 Gy is delivered in 30 fractions to the radiographic tumour region utilizing 3D treatment planning. Radiosurgery may also be useful in treating meningiomas, and doses of 13-18 Gy are associated with a high rate of control at 10 years following therapy.

Acoustic neuroma has classically been considered a surgical disease. Following total resection, recurrence rates are < 5%. When only subtotal resection is possible, disease recurs in at least 60% of patients. Radiosurgery has been used as an alternative to surgery for acoustic neurnoma. Control rates of > 80% at 20 years have been reported. Among patients with useful hearing prior to radiosurgery, that function is preserved in < 50%. Following radiosurgery, 10% of patients experience facial weakness and 25%, trigeminal neuropathy. The risk of cranial neuropathies is related to the size of the lesion treated.

Chemotherapy

Malignant Gliomas
Chemotherapy has limited benefit in the treatment of patients with malignant gliomas. It does not significantly lengthen median survival in these patients as a whole, but a subgroup seems to have prolonged survival when adjuvant chemotherapy is added to radiotherapy. Prognostic factors, such as age, KPS, and histology, do not predict which patients will benefit from adjuvant chemotherapy.

Several alkylating agents have antiglioma activity, but the nitrosoureas are the standard drugs used for initial treatment. Either carmustine (BCNU) as a single agent or the combination of procarbazine, CCNU, and vincristine (PCV) is usually the regimen of first choice (see Table 1 for doses of these regimens).

Despite initial treatment, virtually all malignant gliomas recur. At relapse, patients may benefit from re-resection, focal radiotherapy techniques (such as radiosurgery), and different chemotherapeutic agents. Temozolomide (Temodar) is an oral alkylating drug that has activity against recurrent glioblastoma and anaplastic astrocytoma (see box ).

In a randomized study comparing temozolomide to procarbazine (Matulane) in patients with recurrent glioblastoma, PFS rates at 6 months were 21% and 8%, respectively, and overall survival rates were 60% vs 44% (P = .019) (Yung A, Levin VA, Albright R, et al: Proc Am Soc Clin Oncol 18:139a [abstract], 1999). In a phase II trial in patients with anaplastic astrocytoma, temozolomide produced a response rate (complete and partial responses) of 35% and a median survival of 13.6 months (Prados M, Yung A, Chang S, et al: Proc Am Soc Clin Oncol 18:139a [abstract], 1999).

There has ben considerable interest in the potential use of antiangiogenic agents in malignant gliomas, but the only antiangiogenic drug tested thus far is thalidomide. As a single agent, it has very limited activity.

Astrocytomas Chemotherapy has no role in the initial treatment of low-grade astrocytomas, and usually, at the time of recurrence, they have progressed to a malignant tumour.

Oligodendroglioma
In contrast, the oligodendroglioma is now recognized as a particularly chemosensitive primary brain tumour. This was first observed with the anaplastic oligodendroglioma but has recently been seen with the more common low-grade oligodendroglioma. Chemosensitivity of anaplastic tumors is associated with loss of chromosomes 1p and 19 q.

Several alkylating agents are active, but the best studied regimen is PCV, which produces response rates of 75% and 90% in malignant and low-grade oligodendrogliomas, respectively. Consequently, chemotherapy is an important therapeutic modality, and radiotherapy may be withheld in the case of low-grade tumors. This approach defers or eliminates the late cognitive toxicity associated with cranial irradiation, particularly in patients with a low-grade tumour, who have relatively prolonged survival. Patients with malignant oligodendrogliomas require both radiotherapy and chemotherapy for initial treatment.

Patients with oligodendrogliomas are treated with standard PCV or an intensified form of the regimen. The intensified regimen is cycled every 6 weeks, whereas the standard regimen is cycled every 8 weeks. It is not clear which regimen has greater efficacy, but the intensive regimen is associated with more myelosuppression.


Brain Metastases

Brain metastases occur in ~ 15% of cancer patients as a result of hematogenous dissemination of systemic cancer. Lung and breast cancers are the most common solid tumors that metastasize to the CNS. Melanoma and testicular and renal carcinoma have the greatest propensity to metastasize to the brain, but their relative rarity explains the low incidence of these neoplasms in large series of patients with brain metastases.

Patients with brain metastases from nonpulmonary primaries have a 70% incidence of lung metastases. Although many physicians presume that all brain metastases are multiple, in fact, half are single and many are potentially amenable to focal therapies.

Signs and Symptoms

Lateralizing signs and symptoms of brain metastases depend on the location of the lesion(s), and are similar to the signs and symptoms of other space-occupying masses. However, a few features unique to brain metastases deserve emphasis.

Seizures
Focal or generalized seizures are the presenting symptom in 15%-20% of patients with brain metastasis. Metastases from melanoma have a 50% incidence of seizures, perhaps due to their hemorrhagic nature.

Lateralizing Signs
More than half of patients with brain metastasis have lateralizing signs, including hemiparesis, aphasia, or visual field deficits. Headaches are also seen in about half of patients but are rarely an isolated finding of metastatic disease.

Altered Mental Status
Approximately 75% of patients with brain metastasis have impairment of consciousness or cognitive function. Some patients with multiple bilateral brain metastases may present with an altered sensorium as the only manifestation of metastatic disease; this can be easily confused with a metabolic encephalopathy.

Screening and Diagnosis
Screening

Screening for brain metastases is performed in only a few clinical situations:

Lung Cancer
Approximately 10% of patients with small-cell lung cancer (SCLC) have brain metastases at diagnosis, and an additional 20%-25% develop such metastases during their illness. Therefore, cranial CT or MRI is performed as part of the evaluation for extent of disease.

Occasionally patients with non-small-cell lung cancer (NSCLC) undergo routine cranial CT or MRI prior to definitive thoracotomy, since the presence of brain metastases may influence the choice of thoracic surgical procedure.

Diagnosis

CT and MRI
The diagnosis of brain metastases is established by CT or MRI. MRI is the superior test and should be performed first in any patient being evaluated for metastatic brain disease. A high-quality, contrast-enhanced MRI scan should be obtained to define the number of metastatic nodules and to look for evidence of leptomeningeal disease. A complete spine MRI with gadolinium should also be considered in patients with spinal or radicular symptoms. In some cases, double doses of contrast may be required to define all lesions.

If MRI is unavailable, CT is adequate to exclude brain metastases in most patients, but it can miss small lesions or tumors located in the posterior fossa. Consequently, major therapeutic decisions, such as surgical resection for a presumed single metastasis, should be based on MRI, not CT.

Radiographic Appearance of Lesions
The radiographic appearance of brain metastases is similar on both CT and MRI. Most brain metastases are enhancing lesions surrounded by edema, which extends into the white matter. Unlike primary brain tumors, metastatic lesions rarely involve the corpus callosum or cross the midline.

The radiographic appearance of brain metastases is nonspecific and may mimic other processes, such as infection. Therefore, the CT or MRI scan must always be interpreted within the context of the clinical picture of the individual patient, particularly since cancer patients are vulnerable to opportunistic CNS infections or may develop second primaries, which can include primary brain tumors.

Pathology

The pathology of metastatic brain lesions recapitulates the pathology of the underlying primary neoplasm. This feature often enables the pathologist to suggest the primary source in patients whose systemic cancer presents as a brain metastasis. However, even after a complete systemic evaluation, the site of the primary tumour remains unknown in 5%-13% of patients with brain metastases.

Staging and Prognosis

Any patient with brain metastasis has disseminated systemic cancer, and staging usually is not employed, unless the patient is being considered for surgical resection and the extent of systemic disease is unknown.

For a large proportion of patients with brain metastasis, median survival is only 4-6 months after whole-brain radiotherapy. However, some patients (ie, those who are < 60 years old, have a single lesion, and have no or limited evidence of systemic disease or an active systemic tumour that is amenable to effective therapy) can achieve prolonged survival, and these individuals warrant a more aggressive therapeutic approach. Furthermore, most of these patients qualify for vigorous local therapy of their brain metastasis, such as surgical resection or, possibly, stereotactic radiosurgery. These approaches can achieve a median survival of 40 weeks or longer.

Treatment

As is the case for primary brain tumors, treatment for brain metastases is both supportive (see section on Supportive Therapy on pages 507 and 508) and definitive. Definitive treatment includes surgery, radiotherapy, and chemotherapy.

Definitive Therapy

Surgery
As with primary brain tumors, the goals of surgery for brain metastases are to reduce mass effect and edema, preserve or restore neurologic function, reduce the likelihood of seizures, maintain CSF pathways, and prolong survival.

Resection followed by whole-brain irradiation significantly prolongs survival over whole-brain irradiation alone in patients with a solitary brain metastasis, and some patients achieve long-term disease-free survival. Although most patients with brain metastases have a life expectancy of < 6 months, the majority of patients who undergo resection of a solitary metastatic lesion followed by radiation will die of systemic rather than intracranial disease. If brain metastases are the presenting sign of systemic cancer and no clear primary source can be identified with routine staging, surgery may also be required to establish a tissue diagnosis and plan further therapy. In addition, surgical removal of a brain metastasis often reverses the neurologic deficits caused by compression of local structures by tumour and reduces intracranial hypertension. Excision of metastases is rarely curative, however, as microscopic cells may be left behind. Nevertheless, the reduced tumour burden becomes more amenable to adjuvant irradiation and/or chemotherapy. Criteria for Surgery
The decision of whether to recommend surgery should be based on the following factors:

Extracranial Oncologic Status
A comprehensive work-up of the patient’s extra-cranial oncologic status is necessary. Extensive critical organ metastases preclude surgery in favor of palliative radiation as the sole therapy. Brain surgery should not be performed in patients with very limited expected survival (3-6 weeks) based on extracranial disease.

Number of metastases In general, only patients harboring a single metastasis are considered for resection. Surgery may also be considered for multiple lesions that can be removed through a single craniotomy, particularly in cases of radioresistant tumors, such as renal cell carcinoma or melanoma. Occasionally, a large tumour will be removed in the presence of multiple smaller nodules if the edema and mass effect of this lesion are causing a substantial neurologic deficit that could be dramatically improved by tumour removal.

Three recent studies concluded that when multiple (up to three distinct locations) metastases are resected, either with or without radiotherapy, survival times are identical to those in patients with surgically resected solitary metastases, and almost twice as long as survival times in patients treated by radiation therapy or radiosurgery alone. These studies suggest that a more aggressive surgical approach may be justified in patients with multiple brain metastases who have stable systemic disease.

Recurrence of Solitary Metastases
Stereotactic and image-guided surgery has greatly simplified resection for multiple metastases, such that concurrent craniotomies can be performed simply with no increase in morbidity. Patients with multiple brain metastases that are totally resected appear to fare as well as patients with solitary metastases.

Up to 20% of solitary metastases may recur in long-term survivors. In these cases, a second operation may be warranted to remove the recurrent lesion, confirm the histologic diagnosis (ie, exclude radionecrosis), and administer interstitial radiotherapy.

A recent randomized prospective trial showed that postoperative whole-brain radiotherapy significantly improved intracranial disease control after resection of a single brain metastasis. However, overall survival was unaffected because patients died of their systemic disease (Patchell RA, Tibbs PA, Regine WF, et al: JAMA 280:1485, 1998).

Radiation Therapy

For symptomatic patients with brain metastases, median survival is about 1 month if untreated and 3-6 months if whole-brain radiation therapy is delivered, with no significant differences among various conventional radiotherapy fractionation schemes (20 Gy in 5 fractions, 30 Gy in 10 fractions, 40 Gy in 20 fractions). A more protracted schedule is used for patients who have limited or no evidence of systemic disease or those who have undergone resection of a single brain metastasis, since these patients have the potential for long-term survival or even cure. The use of hypofractionated regimens is associated with an increased risk of late neurologic toxicity.

Relief of Neurologic Symptoms
The major result of whole-brain radiation therapy is an improvement in neurologic symptoms, such as headache, motor loss, and impaired mentation. The overall response rate ranges from 70% to 90%. Unfortunately, symptomatic relief is not permanent, and symptoms recur with intracranial tumour progression.

Improvement in neurologic function depends on the patient’s neurologic condition at the time of whole-brain radiation therapy. The more serious neurologic symptoms are prior to whole-brain radiation therapy, the less chance there is for significant improvement.

Solitary Lesion
In general, whole-brain radiation therapy is used following resection of a single brain metastasis to reduce the incidence of new CNS lesions and the development of carcinomatous meningitis. Patients treated with surgery and whole-brain radiation therapy, delivered in daily doses of 1.8-2 Gy, have significantly fewer recurrences at the initial metastatic site, prolonged survival, and improved quality of life, as compared with those given whole-brain irradiation alone.

Multiple Lesions
Patients with multiple lesions are generally treated with whole-brain radiation therapy alone. The prognosis for patients treated with whole-brain radiation for brain metastases depends on several factors, the most important of which are KPS, extent of systemic disease, age, neurologic function class, and histology.

Concomitant steroid therapy Since the radiographic and clinical response to whole-brain irradiation takes several weeks, patients with significant mass effect should be treated with steroids during whole-brain radiation therapy. Dexamethasone (16 mg/d) is started prior to therapy, and the dose may be tapered as tolerated during treatment. Occasionally, higher doses are necessary to ameliorate neurologic symptoms. However, most patients can be safely tapered off corticosteroids at the completion of whole-brain radiotherapy.

Radiosurgery

Radiosurgery has been used as a boost to whole-brain radiation therapy for brain metastases or for recurrent lesions. Results obtained by various groups indicate crude local control rates of 73%-98% with radiosurgery over a median follow-up of 5-26 months. Better local control was seen in patients treated with whole-brain radiation therapy in addition to radiosurgery. Median survival from the time of radiosurgery was 6-15 months, with breast cancer patients having the best survival. Most patients exhibited clinical improvement and decreased steroid requirements after radiosurgery for brain metastases, and only 11%-25% of patients eventually died of neurologic causes.

It is unclear whether radiosurgery is equivalent to standard surgical resection. Some retrospective studies suggest that the two techniques produce identical results, but case-control studies demonstrate that surgery is superior to radiosurgery in the treatment of single brain metastases. Several ongoing prospective studies being conducted by the RTOG are comparing the efficacy of radiosurgery vs surgery in addition to whole-brain radiotherapy in the treatment of brain metastases.

Treatment Recommendations

In patients with a single brain metastasis, aggressive local therapy (surgical resection combined with whole-brain radiation therapy) appears to produce superior survival and quality of life, compared with whole-brain radiation therapy alone. However, aggressive therapy should be restricted to patients with controlled or controllable systemic disease.

For asymptomatic or mildly symptomatic patients with a small lesion, radiosurgery appears to be an excellent alternative to surgery. In addition, elderly patients at greater risk for surgical morbidity may be excellent candidates for stereotactic radiosurgery. While radiosurgery is noninvasive, the same selection criteria should be considered as are used for surgical resection.

Chemotherapy

Chemotherapy has a limited role in the treatment of brain metastases and has not proven to be effective as an adjuvant therapy after radiation or surgery. This lack of efficacy is partially due to the blood-brain barrier, although areas of tumour discernible on CT or MRI have an abnormal or more permeable blood-brain barrier. However, the minimal activity of most drugs against the major primary tumors that lead to brain metastases (eg, lung cancer) is likely a more important determinant.

Brain metastases from chemosensitive primary tumors Brain metastases from primary tumors that are chemosensitive, such as SCLC, choriocarcinoma, and breast cancer, may be responsive to systemic therapy. Single drugs or drug combinations should be selected based on their expected activity against the primary tumour.

Suggested Reading

• On Primary Intracranial Tumors


Cairncross G, Keisuke U, Zlatescu MC, et al: Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 90:1473–1479, 1998.

This study demonstrates that chemosensitivity correlates with loss of chromosomes 1p and 19q.


DeAngelis LM, Burger PC, Green SB, et al: Malignant glioma: Who benefits from adjuvant chemotherapy? Ann Neurol 44:691–695, 1998.

Adjuvant BCNU increased long-term survival in patients regardless of prognostic factors, and oligodendroglial pathology did not explain long-term survival.


Friedman H, Petros W, Friedman A, et al: Irinotecan therapy in adults with recurrent or progressive malignant glioma. J Clin Oncol 17:1516–1525, 1999.

Irinotecan (CPT-11, Camptosar) produced a 15% partial response rate in patients with recurrent malignant gliomas.


Karim ABMF, Maat B, Hatlevoll R, et al: A randomized trial on dose-response in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) study 22844. Int J Radiat Oncol Biol Phys 36:549–556, 1996.

This randomized trial compared 45 Gy vs 59.4 Gy delivered after biopsy or resection for adults with low-grade astrocytomas, including oligodendrogliomas and mixed low-grade tumors. Time to recurrence and overall survival were the same for both groups, suggesting that 59.4 Gy is still on the initial slope of the tumour control probability curve. Future studies will require further dose escalation, probably employing hyperfractionation. The study did indicate, however, a positive relationship between the amount of tumour resected and overall survival.


Kondziolka D, Lunsford LD, Flickinger JC, et al: Stereotactic radiosurgery using the Gamma Knife: Indications and results. The Neurologist 3:45–52, 1997.

A review of stereotactic radiosurgery for a variety of brain tumors.


Leighton C, Fisher B, Bauman G, et al: Supratentorial low-grade glioma in adults: An analysis of prognostic factors and timing of radiation. J Clin Oncol 15:1294–1301, 1997.

A very large retrospective review of adult patients treated for low-grade astrocytomas. Similar to the prospective EORTC study conducted by Karim et al, this retrospective study found a positive relationship between the extent of surgical resection and overall survival. The retrospective study was unable to answer the important question of the appropriate timing of postoperative radiotherapy.


Shafman TD, Loeffler JS: Novel radiation technologies for malignant gliomas. Curr Opin Oncol 11:147–151, 1999.

A comprehensive review of the role of radiotherapy in malignant gliomas, including new treatment modalities.


• On Primary Extra-Axial Tumors


Braunstein JB, Vick NA: Meningiomas: The decision not to operate. Neurology 48:1459–1462, 1997.

Some patients do not require resection of a meningioma identified on neurologic imaging because of the tumour’s slow growth.


Goldsmith BJ, Wara WM, Wilson CB, et al: Postoperative irradiation for subtotally resected meningiomas. J Neurosurg 80:195–201, 1994.

The largest series of patients given radiotherapy for incompletely resected meningiomas, with follow-up to 20 years, shows the effectiveness of this modality.


Hakim R, Alexander E III, Loeffler JS, et al: Results of linear accelerator-based radiosurgery for intracranial meningioma. Neurosurgery 42:446–454, 1998.

Discussion of the results of radiosurgery in the treatment of meningiomas, with long-term follow-up.


• On Brain Metastases


Loeffler JS, Barker FG, Chapman PH: Role of radiosurgery in the management of central nervous system metastases. Cancer Chemother Pharmacol 40:11–14, 1999.

Comprehensive review of the results of radiosurgery in the treatment of brain metastases.


Patchell RA, Tibbs PA, Regine WF, et al: Postoperative radiotherapy in the treatment of single metastases to the brain. JAMA 280:1485–1489, 1998.

This randomized, prospective trial of postoperative whole-brain radiotherapy after resection of a single brain metastasis showed that radiotherapy improves control of CNS disease but does not prolong survival.


Wen PY, Loeffler JS: Management of brain metastases. Oncology 13:941-961, 1999.

In-depth review of the diagnosis and management of brain metastases.

Top
Loading...