Overview
In 2010, an estimated 22,020 new cases of primary brain and other nervous system neoplasms were diagnosed in the United States,1 and approximately 13,140 deaths occurred from these tumors. The incidence of primary malignant brain tumors has been increasing over the past 30 years, especially in elderly persons.2 Metastatic disease to the central nervous system (CNS) occurs much more frequently, with an estimated incidence approximately 10 times that of primary brain tumors. Between 20% and 40% of patients with systemic cancer will develop brain metastases.3
NOTE: This manuscript highlights only a portion of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Central Nervous System Cancers. Please refer to www.NCCN.org for the complete NCCN Guidelines.
Principles of Management
Primary and metastatic brain tumors are a heterogeneous group of neoplasms with varied outcomes and management strategies. Primary brain tumors range from pilocytic astrocytomas, which are very uncommon, noninvasive, and surgically curable, to glioblastoma multiforme, the most common intraparenchymal brain tumor in adults, which is highly invasive and virtually incurable. Likewise, patients with metastatic brain disease may have rapidly progressive systemic disease or no systemic cancer at all. These patients may have one or dozens of brain metastases, and may have a malignancy that is either highly responsive or highly resistant to radiation or chemotherapy. Because of this marked heterogeneity, the prognostic features and treatment options for brain tumors must be carefully reviewed on an individual basis and sensitively communicated to each patient.
In addition, CNS tumors are associated with a range of symptoms and complications, such as edema, seizures, endocrinopathy, fatigue, psychiatric disorders, and venous thromboembolism, which can seriously impact quality of life. Involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of these patients. For any subtype of malignant brain lesions, the panel encourages thorough multidisciplinary review of each patient case once the pathology is available. Further discussion of multidisciplinary care and allied services, and guidelines on medical management of various disease complications, can be found in Principles of Brain Tumor Management on pages 378 and 379.
NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers Version
Version 2.2011, 01-31-11 ©2011 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 4; 10.6004/jnccn.2011.0036
NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers Version
Version 2.2011, 01-31-11 ©2011 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 4; 10.6004/jnccn.2011.0036
NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers Version
Version 2.2011, 01-31-11 ©2011 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 4; 10.6004/jnccn.2011.0036
NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers Version
Version 2.2011, 01-31-11 ©2011 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 4; 10.6004/jnccn.2011.0036
NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers Version
Version 2.2011, 01-31-11 ©2011 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 4; 10.6004/jnccn.2011.0036
NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers Version
Version 2.2011, 01-31-11 ©2011 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 4; 10.6004/jnccn.2011.0036
NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers Version
Version 2.2011, 01-31-11 ©2011 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 4; 10.6004/jnccn.2011.0036
NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers Version
Version 2.2011, 01-31-11 ©2011 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 4; 10.6004/jnccn.2011.0036
NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers Version
Version 2.2011, 01-31-11 ©2011 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 4; 10.6004/jnccn.2011.0036
NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers Version
Version 2.2011, 01-31-11 ©2011 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 4; 10.6004/jnccn.2011.0036
NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers Version
Version 2.2011, 01-31-11 ©2011 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 4; 10.6004/jnccn.2011.0036
NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers Version
Version 2.2011, 01-31-11 ©2011 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 4; 10.6004/jnccn.2011.0036
NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers Version
Version 2.2011, 01-31-11 ©2011 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 4; 10.6004/jnccn.2011.0036
Treatment Principles
Several important principles guide surgical and radiation therapy (RT) for adults with brain tumors. Regardless of tumor histology, neurosurgeons generally provide the best outcome for their patients if they remove as much tumor as possible, keep surgical morbidity to a minimum, and ensure an accurate diagnosis. Decisions regarding aggressiveness of surgery for primary brain lesions are complex and depend on the 1) age and performance status (PS) of the patient; 2) proximity to “eloquent” areas of the brain; 3) feasibility of decreasing the mass effect with aggressive surgery; 4) resectability of the tumor (including the number and location of lesions); and 5) time since last surgery in patients with recurrent disease.4
Surgical options include stereotactic biopsy, open biopsy or debulking procedure, subtotal resection, or maximal safe resection. The pathologic diagnosis is critical and often difficult to determine accurately; therefore, as much tissue as possible should be delivered to the pathologist. Review by an experienced neuropathologist is highly recommended. In addition, a postoperative MRI scan, with and without contrast, should be obtained 24 to 72 hours after surgery to document the extent of disease after surgical intervention.
Radiation oncologists use several different treatment approaches in patients with primary brain tumors, including brachytherapy, stereotactic fractionated RT, and stereotactic radiosurgery (SRS). Standard fractionated external-beam RT (EBRT) is the most common approach, whereas hypofractionation is emerging as an option for select patients. RT for patients with primary brain tumors usually involves only the tumor volume and margins, whereas whole-brain RT (WBRT) and SRS are used for brain metastases.
Clinicians are advised to consult Principles of Brain Tumor Imaging and Principles of Brain Tumor Surgery (page 374) for further discussion of these diagnostic and treatment modalities. The dose of radiation administered varies depending on the pathology, as seen in Principles of Brain Tumor Radiation Therapy on page 375. Appropriate chemotherapeutic and biologic regimens for each tumor subtype are listed under Principles of Brain Tumor Systemic Therapy on page 376.
Tumor Types
These NCCN Guidelines focus on management of adult CNS cancers, such as anaplastic gliomas and glioblastoma multiforme, low-grade infiltrative astrocytomas, oligodendrogliomas, ependymomas, brain metastases, leptomeningeal metastases, primary CNS lymphomas (non-AIDS), and metastatic spinal tumors. In 2010 and 2011, specific guidelines on managing meningiomas, primary spinal cord tumors, medulloblastomas, and supratentorial primitive neuroectodermal tumors were also added. These guidelines are updated annually to include new information or treatment philosophies as they become available. However, because this field evolves continually, practitioners should use all of the available information to determine the best clinical options for their patients.
Low-Grade Infiltrative Astrocytomas and Oligodendrogliomas
Information on low-grade infiltrative astrocytomas and oligodendrogliomas can be found in the full NCCN Guidelines for Central Nervous System Cancers, available online at www.NCCN.org.
Anaplastic Gliomas and Glioblastomas
Anaplastic astrocytomas (grade III) and glioblastomas (grade IV astrocytomas) are the most common primary brain tumors in adults, accounting for 7% and 54% of all gliomas, respectively.5 Glioblastoma is the deadliest brain tumor, with only a third of patients surviving for 1 year, and less than 5% living beyond 5 years. The 5-year survival rate for anaplastic astrocytoma is 27%. The most important prognostic factors identified in an analysis of 1578 patients were histologic diagnosis, age, and PS.6
High-grade astrocytomas diffusely infiltrate surrounding tissues and frequently cross the midline to involve the contralateral brain. Patients with these neoplasms often present with symptoms of increased intracranial pressure or seizures, or focal neurologic findings related to the size and location of the tumor and to associated peritumoral edema. These tumors usually do not have associated hemorrhage or calcification, but produce considerable edema and mass effect on image studies and enhance after the administration of intravenous contrast. Tumor cells have been found in the peritumoral edema, which corresponds to the T2-weighted MRI abnormalities. As a result, this volume is frequently used to define radiation treatment portals.
The results of therapy are difficult to assess with CT or MRI scans, because the extent and distribution of contrast enhancement, edema, and mass effect are more a function of blood–brain barrier integrity than of changes in the size of the tumor. Thus, other factors that exacerbate blood–brain barrier dysfunction (e.g., surgery, radiation, tapering of corticosteroids) can mimic tumor progression by increasing contrast enhancement, T2-weighted abnormalities, and mass effect.
Anaplastic oligodendrogliomas are relatively rare. They are characterized by high cellularity, nuclear pleomorphism, frequent mitosis, endothelial proliferation, and necrosis. On histopathologic assessment, these tumors can be confused with glioblastoma multiforme; however, characteristic allelic losses of chromosomes 1p and 19q are present in anaplastic oligodendrogliomas.7 This distinct histologic subtype has a much better prognosis than anaplastic astrocytomas and glioblastomas because of its marked sensitivity to chemotherapy8; half of the patients are alive at 5 years.5
Treatment Overview
Surgery: The goals of surgery are to obtain a diagnosis, alleviate symptoms related to increased intracranial pressure or compression, increase survival, and decrease the need for corticosteroids. A prospective study in 565 patients with malignant gliomas showed that aggressive surgery is a strong prognostic factor compared with biopsy alone (P < .0001).9 Retrospective analyses also suggest that gross total resection lengthens survival and is especially effective in patients with good PS.10–12 Unfortunately, the infiltrative nature of high-grade astrocytomas frequently renders gross total removal difficult. However, total resection is often possible for oligodendrogliomas, because most occur in the frontal lobes and the tumors are frequently well demarcated.
Unfortunately, nearly all glioblastomas recur. When this occurs, reoperation may improve the outcome for selected patients.13 According to an analysis by Park et al.,14 tumor involvement in specific critical brain areas, poor Karnofsky score, and large tumor volume were associated with unfavorable re-resection outcomes.
Radiation Therapy: Fractionated EBRT after surgery is standard adjuvant therapy for patients with high-grade astrocytomas. Use of radiation is based on 2 randomized trials conducted in the 1970s, which showed increased survival. Walker et al.15 compared postoperative supportive care, carmustine (BCNU), radiation, and radiation plus BCNU in 303 patients, and reported median survivals of 14, 18.5, 35, and 34.5 weeks, respectively. Another trial of 118 patients also found a benefit in median survival with RT after surgery compared with no RT (10.8 vs. 5.2 months).16 The typical dose is 60 Gy in 1.8- to 2.0-Gy fractions. Use of abbreviated courses of radiation (total 40–50 Gy) in older patients has been shown to be efficacious.17,18
The Radiation Therapy Oncology Group (RTOG) conducted a randomized trial of conventional radiotherapy to 60 Gy plus BCNU alone or preceded by a radiosurgery boost (to 15–24 Gy) in patients with glioblastoma of 4 cm or less.19 However, the results were disappointing, with no improvement in local control or survival with the SRS boost. Another trial that randomly assigned patients to 50 Gy of EBRT with or without temporary 125I seed implant to 60 Gy also failed to show any survival benefit with a brachytherapy boost.20
Chemotherapy/Systemic Therapy: Traditionally, chemotherapy was believed to be of marginal value in the treatment of patients with newly diagnosed high-grade gliomas, but this perception is beginning to change. Most earlier trials studied nitrosourea-based chemotherapy regimens. In the largest randomized trial of adjuvant chemotherapy in high-grade gliomas21 the Medical Research Council randomized 674 patients to either radiation alone or radiation plus procarbazine, lomustine, and vincristine (PCV). No survival benefit was seen with the addition of PCV, even in patients with anaplastic astrocytomas.
In contrast, 2 meta-analyses that reviewed data from randomized trials of patients with high-grade gliomas both found a modest survival benefit when chemotherapy was added to postoperative radiation.22,23 Specifically, the Glioma Meta-Analysis Trialists Group reviewed 12 studies involving approximately 3000 patients and reported an absolute increase in 1-year survival rate from 40% to 46% and a 2-month increase in median survival when chemotherapy was added to postoperative radiation (hazard ratio [HR], 0.85; 95% CI, 0.78–0.91; P < .0001).22 In an earlier analysis of 16 randomized trials, Fine et al.23 also found a 10% and 9% increase in survival at 1 and 2 years, respectively.
Other routes of drug delivery have been evaluated. Local administration of BCNU using a biodegradable polymer (wafer) placed intraoperatively in the surgical cavity showed a statistically significant improvement in survival for patients with recurrent high-grade gliomas (31 vs. 23 weeks; adjusted HR, 0.67; P = .006).24 As a result, the FDA approved the BCNU wafer for this indication. A phase III placebo-controlled study in 32 patients with malignant glioma showed a statistically significant prolongation of survival when the BCNU polymer was used as initial therapy in combination with RT.25 A larger phase III trial in 240 patients with newly diagnosed malignant glioma also found a statistically significant improvement in median survival, from 11.6 months in the placebo group to 13.9 months in the groups treated with the BCNU wafer.26 This benefit was maintained 2 and 3 years after implantation.27 Based on these studies, the FDA extended the approval of the BCNU polymer wafers for use in malignant gliomas as initial therapy. However, clinicians and patients should be aware that BCNU can potentially interact with other agents, resulting in increased toxicity. For example, whether it is safe to administer temozolomide (see later discussion) to patients treated with BCNU is still a matter of debate. Implantation of the wafer may also preclude future participation in clinical trials involving other adjuvant therapy. Therefore, the panel has considerable disagreement over the value of including the wafer as initial therapy (category 2B).
Temozolomide, an alkylating agent, is becoming a standard addition to postoperative RT for patients with glioblastoma (without carmustine wafer) who are younger and have good PS. In a phase III study assessing temozolomide in 573 patients with glioblastoma aged 70 years or younger with WHO PS of 2 or less, Stupp et al.28 randomized subjects to either daily temozolomide administered concomitantly with postoperative RT followed by 6 cycles of adjuvant temozolomide, or radiotherapy alone. Side effects for temozolomide include hair loss, nausea, vomiting, headaches, fatigue, and anorexia. Because of the risk of lymphocytopenia and subsequent opportunistic infection, prophylaxis against Pneumocystis carinii pneumonia (PCP) is required when the agent is administered with radiotherapy. A later study by Stupp et al.29 showed that the chemoradiation arm resulted in a statistically better median survival (14.6 vs. 12.1 months) and 2-year survival (26.5% vs. 10.4%) than RT. Final analysis confirmed the survival advantage at 5 years (10% vs. 2%). However, the study design does not illuminate which is responsible for the improvement: temozolomide administered with radiation, following radiation, or both. This trial used a dosage of 75 mg/m2 daily of concurrent temozolomide during the course of radiotherapy, then 150 to 200 mg/m2 post-RT on a 5-day schedule every 28 days. Alternate schedules, such as a 21/28 dose-dense or a 50 mg/m2 continuous daily regimen, have been explored in a phase II trial for newly diagnosed glioblastoma.30 A comparison of the dose-dense 21/28 and standard 5/28 schedules have been completed with RTOG 0525. The results of that trial have not been reported.
The panel disagreed about the adjuvant use of temozolomide in patients with an implanted BCNU wafer and those older than 70 years but with good performance (category 2B). For the latter group, some evidence from small studies suggests the usefulness of temozolomide in addition to adjuvant radiation despite old age.31,32 Another approach is to administer temozolomide alone. A retrospective review of patients aged 70 or older with mean Karnofsky score of 70 found no survival difference between those receiving radiation alone and those taking monthly temozolomide only.33 Given the susceptibility of elderly patients to radiation-induced neurotoxicity, especially when the PS is poor, chemotherapy alone seems to be a reasonable option.
Research suggests that MGMT (O-6-methylguanine-DNA methyltransferase) status may determine which patients will benefit from adjuvant temozolomide therapy.34 MGMT is a DNA repair enzyme that may cause resistance to DNA-alkylating drugs. Oligodendrogliomas frequently exhibit MGMT hypermethylation and low expression levels, which may explain its high chemosensitivity.35
In terms of adjuvant treatment for anaplastic astrocytomas, postoperative chemotherapy is an alternative to radiation. In a phase III trial of sequential radiochemotherapy in 318 patients with anaplastic gliomas, Wick et al.36 randomized patients to 1 of 3 arms: RT, PCV, or temozolomide. At progression, patients in arm 1 received PCV or temozolomide, whereas patients in arms 2 and 3 were irradiated. The 3 strategies resulted in comparable time-to-progression and survival. No published data directly compare the benefit of postoperative combined chemoradiation plus temozolomide with that of a nitrosourea in patients with newly diagnosed anaplastic astrocytomas. This study is currently underway through the RTOG (RTOG 9813). Adjuvant chemoradiation within a trial is a recommended option. However, its use outside a clinical trial received strong objection from some panelists (category 3).
Unfortunately, currently available chemotherapy does not provide cures. Patients with malignant gliomas eventually recur or progress. In addition to temozolomide37–39 and the nitrosoureas,24 regimens that are commonly used as second-line or salvage chemotherapy include combination PCV,40 cyclophosphamide,41 and platinum-based regimens.42 Anaplastic gliomas may also be treated by irinotecan43 or etoposide.44
Bevacizumab, an antiangiogenic agent, received accelerated approval in 2009 for recurrent glioblastoma based on 2 phase II studies. AVF 3708g randomized 167 patients to bevacizumab with or without irinotecan; MRI-defined objective response was seen in 28% and 38% of patients, respectively.45 Median survival was around 9 months, similar to that seen in a previous phase II trial.46 A published report of the other pivotal study (NCI 06-C-0064E) recorded a median survival of 31 weeks in 48 heavily pretreated patients.47 Bevacizumab alone or in combination with chemotherapy has also shown activity in anaplastic gliomas.48–53 Although efficacious, bevacizumab is associated with potentially serious adverse events, including hypertension, impaired wound healing, colonic perforation, and thromboembolism.
NCCN Recommendations
Primary Treatment: When a patient presents with a clinical and radiologic picture suggestive of high-grade glioma, neurosurgical input is needed regarding the feasibility of maximal safe tumor resection. Whenever possible, major tumor removal should be performed. However, when CNS lymphoma is suspected, a biopsy should be performed first and management should follow the corresponding pathway if the diagnosis is confirmed. If high-grade glioma is supported by intraoperative frozen section diagnosis, BCNU wafer placement is an option (category 2B). The extent of tumor debulking should be documented with a postoperative MRI scan within 72 hours after surgery, with and without contrast. If major tumor removal is deemed too risky, a stereotactic or open biopsy or subtotal resection should be performed to establish the diagnosis. Multidisciplinary consultation is encouraged once the pathology is available.
Adjuvant Therapy: After surgical intervention, the choice of adjuvant therapy depends on the tumor pathology and PS of the patient. In the case of anaplastic gliomas, patients with a good Karnofsky score (≥ 70) can choose between fractionated EBRT, chemotherapy, or chemoradiation in the context of a clinical trial. Chemoradiation outside of a trial is controversial (category 3). Patients with a poor PS (< 70) can be managed with radiation, chemotherapy, or best supportive care.
If glioblastoma is diagnosed, the options for a patient with poor performance include radiation, chemotherapy, best supportive care, or chemoradiation (category 2B) only if no BCNU wafer was implanted. BCNU-naïve patients with favorable PS should undergo postoperative radiation (category 1); addition of concurrent and adjuvant temozolomide is a category 1 recommendation for younger patients (age < 70 years) but category 2B for older patients. If a BCNU wafer was used, addition of temozolomide is also a category 2B recommendation for patients with good performance.54
Follow-Up and Recurrence: Patients should be followed up closely with serial MRI scans (at 2–6 weeks, then every 2–4 months for 2–3 years, then less frequently) after the completion of RT. Because RT can produce additional blood–brain barrier dysfunction, corticosteroid requirements may actually increase; therefore, scans may appear worse during the first 3 months after completion of RT, even though no actual tumor progression has occurred. Early MRI scans allow for appropriate titration of corticosteroid doses, depending on the extent of mass effect and brain edema. Later scans are used to identify tumor recurrence. Early detection of recurrence is warranted, because local and systemic treatment options are available for patients with recurrent disease. However, MR spectroscopy, MR perfusion, or PET can be considered to rule out radiation-induced necrosis or “pseudoprogression.”55
Management of recurrent tumors depends on the extent of disease and patient condition. For local recurrence, repeat resection, with or without wafer placement in the surgical bed, can be performed if possible. Following re-resection, or if the local recurrence is unresectable, patients with poor performance should undergo best supportive care without further active treatment. If PS is favorable, systemic chemotherapy may be administered (especially for anaplastic oligodendrogliomas); reirradiation is a category 2B option if prior radiation produced a good/durable response. For diffuse or multiple recurring lesions, the options are best supportive care for patients with poor performance; systemic chemotherapy; or surgery to relieve mass effect. All patients should receive best supportive care.
Intracranial Ependymomas
Information on intracranial ependymomas can be found in the full NCCN Guidelines for Central Nervous System Cancers, available online at www.NCCN.org.
Medulloblastoma and Supratentorial Primitive Neuroectodermal Tumors
Cranial primitive neuroectodermal tumors (PNETs) are embryonal neoplasms showing varying degrees of differentiation. They are described by their location as infratentorial (medulloblastomas) and supratentorial. The WHO classification system further divided these tumors into histologic variants.56 CNS PNETs are infrequent in children and very rare in adults, with an overall incidence of 0.26 per 100,000 person-years reported by the Central Brain Tumor Registry of the United States (CBTRUS).57 Overall, PNETs represent only 1.8% of all brain tumors, although they are the most common type among pediatric brain malignancies.
Approximately half of the affected patients will present with elevated intracranial pressure. Headache, ataxia, and nausea are commonly observed symptoms.58 All PNETs of the brain are WHO grade IV because they are invasive and rapidly growing. They also have the tendency to disseminate through the CSF. Larger retrospective case series of adult patients reported 10-year survival rates of 48% to 55%, with frequent recurrence beyond 5 years, commonly in the posterior fossa.59,60
Treatment Overview
Surgery: Evidence in adult patients is meager for this rare disease and no randomized trial data are available, but general consensus is that surgical resection should be the routine initial treatment to establish diagnosis, relieve symptoms, and maximize local control. Complete resection can be achieved in half of the patients58,61,62 and is associated with improved survival.61,63 In addition, surgical placement of a ventriculoperitoneal shunt can be used to treat hydrocephalus.
Radiation Therapy: Adjuvant radiation after surgery is the current standard of care, although most studies are based on the pediatric population. The traditional dose of craniospinal RT is 30 to 36 Gy with a boost to a total of 55 Gy to the primary brain site.61,63 A lower craniospinal dose of 23.4 Gy, combined with chemotherapy, has gained popularity for average-risk patients to lessen side effects while maintaining 55.8 Gy to the posterior fossa,59,64,65 although one randomized trial found an increased relapse risk with dose reduction.66 Recently, SRS demonstrated safety and efficacy in a small series of 12 adult patients with residual or recurrent disease.67
Systemic Therapy: The use of postirradiation chemotherapy to allow radiation dose reduction is becoming increasingly common especially for children,64,65 but optimal use of adjuvant chemotherapy is still unclear for adult patients.58–60,68,69 A phase III study that enrolled more than 400 patients between 3 and 21 years of age to receive postirradiation cisplatin-based chemotherapy regimens recorded an encouraging 86% 5-year survival.70
Several regimens are in use in the recurrence setting, most of which include etoposide.71–73 High-dose chemotherapy in combination with autologous stem cell transplantation is a feasible strategy for patients who have had good response with lower doses.73,74
NCCN Recommendations
Primary Treatment: MRI scan is the gold standard in the assessment and diagnosis of PNET. The typical tumor shows enhancement and heterogeneity. Fourth ventricular floor infiltration is a common finding related to worse prognosis.59,60,69 Multidisciplinary consultation before treatment initiation is advised. Maximal safe resection is recommended wherever possible. Contrast-enhanced brain MRI should be performed within 24 to 72 hours after surgery, but spinal MRI should be delayed by 2 to 3 weeks. Because of the propensity of PNET to CSF seeding, CSF sampling through lumbar puncture after spine imaging is also necessary for staging. Medulloblastoma should be staged according to the modified Chang system using information from both imaging and surgery.75,76
Adjuvant Therapy: Patients should be stratified according to recurrence risk for planning of adjuvant therapy (reviewed by Brandes et al.77). The panel agrees that patients with large cell or anaplastic medulloblastoma, supratentorial PNET, disease dissemination, unresectable tumors, or residual tumors larger than 1.5 cm2 postsurgery are at heightened risk. These patients should undergo irradiation of the neuraxis followed by chemotherapy. For patients at average risk, craniospinal radiation alone or concurrent chemoradiation followed by chemotherapy are both viable options.
Recurrence and Progression: No robust data support an optimal follow-up schedule. General guidelines include brain MRI every 3 months and biannual spinal MRI for the first 2 years, biannual brain MRI and annual spinal MRI for the next 3 years, then yearly brain scans. If recurrent disease is detected on these scans, CSF sampling is also required. Bone scans, CT scans, and bone marrow biopsies should be conducted as indicated.
Maximal safe resection should be attempted on recurrent brain tumors. High-dose chemotherapy with autologous stem cell rescue is also feasible for patients showing no evidence of disease after resection or conventional reinduction chemotherapy. On disease progression, options include chemotherapy alone, radiation alone (including SRS), and chemoradiation. Patients with metastases should be managed with chemotherapy or best supportive care, such as palliative radiation.
Primary CNS Lymphomas
Information on primary CNS lymphomas can be found in the full NCCN Guidelines for Central Nervous System Cancers, available online at www.NCCN.org.
Primary Spinal Cord Tumors
Spinal tumors are classified according to their anatomic location as extradural, intradural–extramedullary, and intradural–intramedullary. Extradural tumors are primarily caused by metastatic disease and are discussed in Metastatic Spinal Tumors (page 391). This section focuses on intradural primary spinal tumors.
Primary spinal cord tumors are a histologically diverse set of disease that represents 2% to 4% of all primary CNS tumors. The overall incidence is 0.74 per 100,000 person-years with a 10-year survival rate of 64%.78 Extramedullary lesions, most commonly benign meningiomas, account for 70% to 80% of spinal cord tumors.79 Astrocytomas (more prevalent in children) and ependymomas (more prevalent in adults) are the most common intramedullary tumors. Clinicians are advised to refer to the corresponding sections in these NCCN Guidelines for further details regarding these subtypes because intracranial and spinal lesions are biologically similar.
Individuals with type I neurofibromatosis, type II neurofibromatosis, and von Hippel-Lindau syndrome are predisposed to form spinal astrocytomas, spinal peripheral nerve sheath tumors, spinal ependymomas, and intramedullary hemangioblastomas, respectively.
Because 70% of primary spinal cord tumors are low-grade and slow-growing,78 it is common for patients to experience pain for months to years before diagnosis. Pain that worsens at night is a classic symptom of intramedullary lesions. Progressive motor weakness occurs in half of the patients, and patients may experience sensory loss with late autonomic dysfunction (incontinence).
Treatment Overview
Observation: Many asymptomatic primary tumors of the spinal cord, especially grade I meningiomas and peripheral nerve sheath tumors, follow an indolent course and can be followed up with observation without immediate intervention.
Surgery: Surgery is preferred for symptomatic tumors. For lesions that are radiographically well defined, such as ependymoma, WHO grade I astrocytoma, hemangioblastoma, schwannoma, and WHO grade I meningioma, potentially curative maximal safe resection is the goal. En bloc total resection yielded excellent local control rates greater than 90%.80–83
Gross total resection is seldom feasible with grade II or higher astrocytomas, because these tumors are infiltrative and poorly circumscribed. In a study of 202 patients with intramedullary tumors, more than 80% of grade I astrocytomas were completely resected, whereas total resection was achieved in only 12% of grade II tumors.84 Nevertheless, Benes et al.85 conducted a review of 38 studies on spinal astrocytomas and concluded that maximal safe resection should be attempted whenever possible based on reports of survival benefit.
Radiation Therapy: RT is not recommended as primary therapy because of limited response, unknown histology without surgery, and low radiation tolerance of the spinal cord. RT is also not advisable after gross total resection, because tumors that can be excised completely have a low local recurrence rate. A large retrospective analysis involving more than 1700 patients with primary spinal gliomas found an association between RT and worse cause-specific and overall survival, although these results may reflect a bias because patients who received radiation may have had more adverse risk factors.86 The role of adjuvant RT after incomplete excision or biopsy is controversial.85,87,88 However, EBRT is considered a viable option at disease progression or recurrence. SRS has also shown safety and efficacy in several series.89–91
Systemic Therapy: Unfortunately, evidence on efficacious chemotherapeutic agents for primary spinal cord tumors is too scant for specific recommendations. The panel agrees that salvage chemotherapy should be an option when surgery and radiation fail, but no consensus exists on the best regimen. Chemotherapy is best given in the setting of a clinical trial.
NCCN Recommendations
MRI is the gold standard for diagnosing spinal cord lesions. Asymptomatic patients may be observed (especially for suspected low-grade lesions) or resected, whereas all symptomatic patients should undergo some form of surgery. The surgical plan and outcome are influenced by whether a clear surgical plane is available.92 Whenever possible, maximal safe resection should be attempted. In most cases, postoperative adjuvant radiation is not recommended. However, if symptoms persist after incomplete resection or biopsy, radiation should be administered.
All patients should be followed up with sequential MRI scans. At progression or recurrence, re-resection is the first choice. If this is not feasible, conventional external-bean RT or SRS is the next option. Chemotherapy is reserved for when both surgery and radiation are contraindicated.
Meningiomas
Meningiomas are extra-axial CNS tumors arising from the arachnoid cap cells in the meninges. They are most often discovered in mid to late adult life, and have a female predominance. The annual incidence for men and women reported by CBTRUS are 1.8 and 3.4 per 100,000 people, respectively.57 In a review of 319 cases using the WHO grading scale, 92% of meningiomas are grade I (benign), 6% are grade II (atypical), and 2% are grade III (malignant).93 Small tumors are often asymptomatic, incidental findings.94 Seizure is a common presenting symptom occurring in 27% of patients.95
Imaging
Brain imaging with contrast-enhanced CT or MRI is the most common method of diagnosing, monitoring, and evaluating response to treatment (review by Campbell et al.96). The CT scan best reveals the chronic effects of slowly growing mass lesions on bone remodeling. Calcification in the tumor (seen in 25%) and hyperostosis of surrounding skull are features of an intracranial meningioma that can be easily identified on a noncontrast CT scan. Nonetheless, MRI reveals several imaging characteristics highly suggestive of meningioma and has been used to operationally define pathology in recent stereotactic radiotherapy articles. These MR findings include a tumor that is dural-based and isointense with gray matter and shows prominent and homogeneous enhancement (> 95%), frequent CSF/vascular clefts, and often an enhancing dural tail (60%). However, approximately 10% to 15% of meningiomas have an atypical MRI appearance mimicking metastases or malignant gliomas. In particular, secretory meningiomas may have a significant amount of peritumoral edema. Cerebral angiography is occasionally performed, often for surgical planning, because meningiomas are vascular tumors prone to intraoperative bleeding. In some instances, preoperative embolization is helpful for operative hemostasis management. Angiographic findings consistent with a meningioma include a dual vascular supply with dural arteries supplying the central tumor and pial arteries supplying the tumor periphery. A “sunburst effect” may be seen because of enlarged and multiple dural arteries, and a prolonged vascular stain or so-called “blushing” can be seen, which results from intratumoral venous stasis and expanded intratumoral blood volume.
Meningiomas are also known to have high somatostatin receptor density, allowing for the use of octreotide brain scintigraphy to help delineate extent of disease and pathologically define an extra-axial lesion.97–99 Octreotide imaging with radiolabeled indium or, more recently, gallium may be particularly useful in distinguishing residual tumor from postoperative scarring in subtotally resected/recurrent tumors.
Treatment Overview
Observation: Studies examining the growth rate of incidental meningiomas in otherwise asymptomatic patients suggest that many asymptomatic meningiomas may be followed up safely with serial brain imaging until either the tumor enlarges significantly or becomes symptomatic.100,101 These studies confirm the tenet that many meningiomas grow very slowly and that a decision not to operate is justified in selected asymptomatic patients. Because the growth rate is unpredictable in any individual, repeat brain imaging is mandatory to monitor an incidental asymptomatic meningioma.
Surgery: The treatment of meningiomas is dependent on patient-related (e.g., age, PS, medical comorbidities) and treatment-related factors (e.g., reasons for symptoms, resectability, goals of surgery). Most patients diagnosed with surgically accessible symptomatic meningioma undergo surgical resection to relieve neurologic symptoms. Complete surgical resection may be curative and is therefore the preferred treatment. Both the tumor grade and the extent of resection impact the rate of recurrence. In a cohort of 581 patients, the 10-year progression-free survival rate was 75% after gross total resection, but dropped to 39% for patients undergoing subtotal resection.102 Short-term recurrences reported for grade I, II, and III meningiomas were 1% to 16%, 20% to 41%, and 56% to 63%, respectively.103–105 The Simpson classification scheme that evaluates meningioma surgery based on extent of resection of the tumor and its dural attachment (grades I–V in decreasing degree of completeness) correlates with local recurrence rates.106 First proposed in 1957, it is still being widely used by surgeons.
Radiation Therapy: Safe gross total resection is sometimes not feasible because of tumor location. In this case, subtotal resection followed by adjuvant EBRT has been shown to be associated with similar comparable long-term survival rates as gross total resection (86% vs. 88%, respectively), compared with only 51% after incomplete resection alone.107 Of 92 patients with grade I tumors, Soyuer et al.108 found that radiation after subtotal resection reduced progression compared with incomplete resection alone, but has no effect on overall survival.
Because high-grade meningiomas have a significant probability of recurrence even after gross total resection,109 postoperative high-dose EBRT (> 54 Gy) has become the accepted standard of care for these tumors to improve local control.110 A review of 74 patients showed that adjuvant RT improves survival in patients with grade III meningioma and in those with grade II disease with brain invasion.111 The role of RT after gross total resection in benign cases remains controversial.
Technical advances have enabled stereotactic administration of radiotherapy by linear accelerator (LINAC), Leksell Gamma Knife, or Cyberknife radiosurgery. The use of stereotactic RT (either single fraction or fractionated) in the management of meningiomas continues to evolve. Advocates have suggested this therapy in lieu of EBRT for small (< 35 mm) recurrent or partially resected tumors. In addition, it has been used as primary therapy in surgically inaccessible tumors (i.e., base of skull meningiomas) or in patients deemed poor surgical candidates because of advanced age or medical comorbidities.
A study of approximately 200 patients compared surgery with SRS as primary treatment for small meningiomas.112 The SRS arm had similar 7-year progression-free survival rates as gross total resection, and superior survival over incomplete resection. In another study, Kondziolka et al.113 followed a cohort of 972 patients with meningiomas managed with SRS over 18 years. Half of the patients underwent previous surgery. SRS provided excellent tumor control (93%) in patients with grade I tumors. For grade II and III meningiomas, tumor control was 50% and 17%, respectively. These results suggest that stereotactic radiation is effective as primary and salvage treatment for meningiomas smaller than 3.5 cm.
Systemic Therapy: Notwithstanding limited data, hydroxyurea has been modestly successful in patients with recurrent meningiomas.114 Targeted therapies that have shown partial efficacy in refractory meningiomas are somatostatin analogues115 and alpha interferon.116
NCCN Recommendations
Initial Treatment: Meningiomas are typically diagnosed with CT or MRI imaging. Biopsy or octreotide scan may be considered for confirmation. For treatment planning, multidisciplinary panel consultation is encouraged. Patients are stratified by the presence or absence of symptoms and the tumor size. Most asymptomatic patients with small tumors (< 30 mm) are best managed with observation. If neurologic impairment is imminent, surgery (if accessible) or RT (EBRT or SRS) is feasible. Asymptomatic tumors 30 mm or larger should be surgically resected or observed. Symptomatic disease requires active treatment with surgery whenever possible. Nonsurgical candidates should undergo radiation.
Regardless of tumor size and symptom status, all patients with surgically resected grade III meningioma (even after gross total resection) should receive adjuvant radiation to enhance local control. After subtotal resection, radiation should be considered for small, asymptomatic grade II tumors and for large grade I and II tumors. SRS may be used in lieu of conventional radiation as adjuvant or primary therapy in asymptomatic cases.
Follow-Up and Recurrence: In the absence of data, panelists have varying opinions on the best surveillance scheme, and patients should be followed up based on individual clinical conditions. Generally, malignant or recurrent meningiomas are followed up more closely than grades I and II tumors. A typical schedule for low-grade tumors is MRI every 3 months in year 1, then every 6 to 12 months for another 5 years. Less frequent imaging is required beyond 5 to 10 years.
After recurrence is detected, the lesion should be resected whenever possible and then the patient should undergo radiation. Nonsurgical candidates should undergo radiation. Chemotherapy is reserved for patients with an unresectable recurrence refractory to radiotherapy.
Brain Metastases
Metastases to the brain are the most common intracranial tumors in adults and occur 10 times more frequently than primary brain tumors. More recent population-based data report that 8% to 10% of people with cancer develop symptomatic metastatic tumors in the brain.117,118 A much higher incidence on autopsy has been reported. Because of advances in diagnosis and treatment, most patients improve with treatment and do not die of these metastatic lesions. Primary lung cancers are the most common source, accounting for half of intracranial metastases, although melanoma has been documented to have the highest predilection to spread to the brain. Diagnosis of CNS involvement is becoming more common in patients with breast cancer as therapy for metastatic disease is improving.119
Almost 80% brain metastases occur in the cerebral hemispheres, an additional 15% occur in the cerebellum, and 5% occur in the brainstem.120 These lesions typically follow a pattern of hematogenous spread to the gray–white junction where the relatively narrow caliber of the blood vessels tends to trap tumor emboli. Most cases have multiple brain metastases evident on MRI scans. The presenting signs and symptoms of metastatic brain lesions are similar to those of other mass lesions in the brain, such as headache, seizures, and neurologic impairment.
Treatment Overview
Surgery: Advances in surgical technique have rendered upfront resection followed by WBRT, the standard of care for solitary brain metastases. A retrospective analysis of 13,685 patients admitted for resection of metastatic brain lesions showed a decline in in-hospital mortality from 4.6% in 1988 through 1990 to 2.3% in 1997 through 2000.121 High-volume hospitals and surgeons produced superior outcomes.
Patchell et al.122 randomized 95 patients with single intracranial metastases to complete resection alone or surgery plus adjuvant WBRT, and found post-operative radiation was associated with dramatic reduction in tumor recurrence (18% vs. 70%; P < .001) and likelihood of neurologic deaths (14% vs. 44%; P = .003). No difference was seen in the secondary end point of overall survival. Surgery plus WBRT versus WBRT alone is discussed later.
For multiple lesions, the role of surgery is more restricted to obtaining biopsy samples or relieving mass effect. However, evidence from retrospective series suggested survival benefits from tumor resection for selected patients with good prognosis who had up to 3 metastatic sites.123,124
Stereotactic Radiosurgery: The advent of SRS offered a minimally invasive option as opposed to surgery. Patients undergoing SRS avoid the risk of surgery-related morbidity. Late side effects, such as edema and radiation necrosis, are uncommon.125 SRS is mostly successful for small, deep tumors.
In a randomized Japanese study of 132 patients with 1 to 4 metastatic brain tumors smaller than 3 cm, addition of WBRT to SRS did not prolong median survival compared with SRS alone (7.5 vs. 8.0 months, respectively).126 However, 1-year brain recurrence rate was lower in the WBRT plus SRS arm (47% vs. 76%; P < .001). This likely served to decrease the need for salvage therapy in this group (10 of 65 patients) compared with patients receiving no upfront WBRT (29 of 67 patients).
Retrospective comparative studies showed that SRS plus WBRT resulted in equivalent if not better survival compared with surgery and WBRT.127–129 SRS also conferred a significant improvement in local control, especially for patients with radiosensitive tumors or solitary brain lesions. Muacevic et al.130 compared SRS alone with resection plus WBRT in a randomized controlled trial. The study was stopped prematurely because of poor accrual. In the final analysis based on 64 patients with solitary brain metastases, radiosurgery alone was less invasive and resulted in equivalent survival and local control, but was associated with a higher rate of distant relapse.
Small patient series have shown local control rates greater than 70% with SRS in the recurrence setting for patients with good PS and stable disease who have received prior WBRT.131–135
WBRT: Historically, WBRT was the mainstay of treatment for metastatic lesions in the brain. It continues to play multiple roles in the modern era, as primary intervention where surgery or SRS are not feasible, as adjunctive therapy to prevent recurrence, and as treatment for recurrent disease.
Three randomized trials investigated the effectiveness of WBRT with or without surgery in patients with single brain metastases. In a study of 48 patients, Patchell et al.136 showed that surgery followed by WBRT lengthened overall survival (40 vs. 15 weeks in WBRT arm; P < .01) and functional dependence (38 vs. 8 weeks; P < .005), and decreased recurrence (20% vs. 52%; P < .02) compared with radiation alone. Similarly, Vecht et al.137 showed that combined treatment led to longer survival and functional independence in another randomized study (n = 63). The greatest difference was observed in patients with stable disease; median survival was 12 versus 7 months and functional independence was 9 versus 4 months. A third study of 84 patients found no difference in survival between the strategies; however, patients with extensive systemic disease and lower performance levels were included, which likely resulted in poorer outcomes in the surgical arm.138
The impact of SRS in addition to WBRT was evaluated in 2 randomized controlled studies. A multi-institutional trial by RTOG (RTOG 9508) randomly assigned 333 patients with 1 to 3 brain metastases to WBRT plus SRS or radiation only.139 Despite the inclusion of larger tumors (3–4 cm) that are not favorable to SRS, the authors found a significant survival benefit in the combined arm (6.5 vs. 4.9 months; P = .04) when a single lesion was involved; this was not observed in patients with multiple lesions. A much smaller trial of 27 patients with 2 to 4 lesions found no significant difference in survival, although SRS did extend time to local failure (36 vs. 6 months; P = .0005).140
Based on these results, WBRT in conjunction with surgery or SRS leads to better clinical outcomes than WBRT alone for patients with good performance and solitary metastatic intracranial lesions. However, many patients are not candidates for resection because of the inaccessibility of the tumor, extensive systemic disease, or other factors. WBRT is the main choice of primary therapy for this patient group.
No randomized data are available in the recurrent setting, but case series reported 31% to 70% of symptom-relieving response to irradiation.141–143
Systemic Therapy: Systemic therapy is rarely used as primary therapy for brain metastases. In randomized studies, addition of carboplatin or temozolomide to WBRT did not improve overall survival compared with radiation alone,144,145 although there have been reports of increase in progression-free survival or radiologic response with temozolomide.145,146 Many tumors that metastasize to the brain are not very chemosensitive or have been already heavily pretreated with potentially effective agents. Poor penetration through the blood–brain barrier is an additional concern. Therefore, chemotherapy is usually considered a last line of therapy for recurrent disease when other options have been exhausted (surgery, SRS, radiation). The choice of agent depends on the histology of the primary tumor.
Among various agents, temozolomide may be useful in some patients with previously untreated brain metastases from metastatic melanoma.147 Temozolomide, given on a prolonged schedule, plus thalidomide was tested in a phase II study of patients with brain metastases, but the high toxicity and lack of response rendered the regimen inappropriate.148
In a study of high-dose methotrexate in patients mostly diagnosed with breast cancer, 56% experienced disease control.149 Other agents shown to have activity in breast cancer include platinum plus etoposide,150,151 and capecitabine.152
A phase I/II study of topotecan plus WBRT showed a 72% response rate in 75 patients with brain metastases.153 Unfortunately, a follow-up phase III trial was closed early because of slow accrual.154
NCCN Recommendations
Workup: Patients who present with a single mass or multiple lesions on MRI or CT imaging suggestive of metastatic cancer to the brain and do not have a known primary require a careful systemic workup with chest radiograph or CT, abdominal or pelvic CT, or other tests as indicated. FDG-PET can be considered if more than one brain lesion is present and no primary has been found. If no tumor is readily accessible for biopsy, a stereotactic or open biopsy resection is indicated to establish a diagnosis. Among patients with a known history of cancer, if concerns exist about the diagnosis of CNS lesions, a stereotactic or open biopsy resection or subtotal resection is also needed. Because brain metastases are often managed with multiple modalities, the panel encourages multidisciplinary consultation before treatment for optimal planning.
Treatment for Limited (1–3) Metastatic Lesions: For patients with limited systemic disease or who have reasonable options for systemic treatment, aggressive management should be strongly considered. For surgical candidates, a high level of evidence supports category 1 recommendations for surgical resection plus postoperative WBRT, and for SRS plus WBRT if only one brain lesion is involved. SRS alone or after resection are also reasonable options. Macroscopic total removal is the objective of surgery. The choice between open resection and SRS depends on multiple factors, such as tumor size and location. The best outcome for SRS is achieved for small, deep lesions at institutions with experienced staff. If the tumor is unresectable, WBRT or radiosurgery can be used.
Patients with progressive extracranial disease whose survival is less than 3 months should be treated with WBRT alone, but surgery may be considered for symptom relief. The panel did not reach a consensus on the value of chemotherapy (category 2B), but it may be considered in select patients using regimens specific to the primary cancer.
Patients should be followed up with MRI every 3 months for 1 year and then as clinically indicated. Recurrence on radiograph can be confounded by treatment effects. Tumor tissue sampling should be strongly considered if there is a high index of suspicion of recurrence. When recurrent disease is detected, prior therapy clearly influences the choice of further therapies. Patients with recurrent CNS disease should be assessed for local versus systemic disease, because therapy will differ. For local recurrences, patients previously treated with surgery have the option of undergoing surgery, SRS, WBRT, or chemotherapy. However, patients who previously received WBRT or SRS should not undergo WBRT at recurrence. SRS should be reconsidered in patients who had previous SRS with a durable response for greater than 6 months if imaging supports active tumor and not necrosis. The algorithm for distant brain recurrences branches depending on whether patients have either 1 to 3 lesions or more than 3 lesions. In both cases, patients may undergo WBRT or consider local/systemic chemotherapy, but patients with 1 to 3 recurrent tumors have the additional options of surgery or SRS.
WBRT should be used (30–45 Gy, given in 1.8- to 3.0-Gy fractions depending on the patient's PS) if it was not used for initial therapy. Local or systemic chemotherapy may be considered for select patients if the multiple lesions cannot be controlled by a combination of surgery and radiosurgery.155
If systemic CNS disease progression occurs in the setting of limited systemic treatment options, WBRT should be administered in patients who were not previously irradiated. For patients who received prior WBRT, reirradiation is an option only if they had a positive response to the first course of RT treatment. Best supportive care is also an option for either case.
Treatment for Multiple (> 3) Metastatic Lesions: All patients diagnosed with more than 3 metastatic lesions should be treated with WBRT as primary therapy. The standard regimens for WBRT are 30 Gy in 10 fractions or 37.5 Gy in 15 fractions, but no significant impact on survival was reported with variations in fractionation and dosing according to a meta-analysis of 9 randomized trials.156 For patients with poor neurologic performance, a more rapid course of RT can be considered (20 Gy, delivered in 5 fractions). SRS may be considered in select patients (e.g., with 4 small lesions). Palliative neurosurgery should be considered if a lesion is causing a life-threatening mass effect, hemorrhage, or hydrocephalus.
After WBRT, patients should have a repeat contrast-enhanced MRI scan every 3 months for 1 year. If a recurrence is found, the algorithm branches depending on whether patients have systemic disease progression with limited systemic treatment options, or stable systemic disease or reasonable systemic treatment options. For patients with systemic disease progression, options include best supportive care or reirradiation. For patients with stable systemic disease, options include surgery, reirradiation, or chemotherapy.
Leptomeningeal Metastases
Information on leptomeningeal metastases can be found in the full NCCN Guidelines for Central Nervous System Cancers, available online at www.NCCN.org.
Metastatic Spinal Tumors
Bone metastases are a growing problem among cancer patients because of increasing life expectancy, with the spine being the most frequently affected site. In a report of 832 patients who died of malignancies, vertebral involvement was found in 36% on autopsy.157 Spinal metastases primarily arise from breast, lung, prostate, and renal cancers.158,159 Extradural lesions account for approximately 95% of spinal tumors, mostly in the thoracic region.
Some patients are found to have vertebral involvement as an asymptomatic, incidental finding. However, for most affected patients, pain is the primary presenting symptom preceding neurologic dysfunction. Three types of pain have been classically defined: local, mechanical, and radicular. Local pain from tumor growth is often described as a constant, deep, aching that improves with steroid medications. Mechanical back pain varies with movement and position and is attributed to structural spinal instability. Although seldom responsive to steroids, mechanical pain can be alleviated with surgical stabilization. Radicular pain is a sharp or stabbing sensation that occurs when nerve roots are compressed by the tumor. Patients may experience any or a combination of these types of pain.
Spinal cord compression is the most debilitating complication of spine metastases. It affects 5% to 10% of all patients with cancer, with more than 20,000 cases diagnosed each year in the United States.160 Most patients initially complain of progressive radicular pain,161 which is followed by neurologic symptoms such as motor weakness and sensory loss, and may even include autonomic bladder dysfunction. If left untreated, neurologic deficits rapidly progress to paralysis. Unfortunately, a study of 319 patients with cord compression showed significant delay in reporting of initial pain (3 months) and in diagnosis (2 months), which can lead to irreversible spinal cord damage.162 Therefore, clinicians must watch for early suspicious signs and use MRI of the spine for prompt diagnosis. Once diagnosed, spinal cord compression is considered a medical emergency; intervention should be implemented immediately to prevent further neurologic decline.
Treatment Overview
Dissemination to the spinal column is largely incurable. Therefore, the goals of treatment are palliation and improvement of quality of life through preservation of neurologic function, pain relief, and stabilization of mechanical structure. One exception is slow-growing cancers (mainly renal cell carcinoma) with solitary spinal metastasis, for which surgery may achieve cure.163
The type and aggressiveness of the primary tumor often dictates the choice of treatment, because different cancers have varying sensitivities to systemic therapy and radiation. In addition, characteristics such as PS and comorbidities will determine whether patients can tolerate surgery and, if so, which technique should be used.
Surgery: The general consensus is that a patient should have a life expectancy of at least 3 months to be a surgical candidate. Paraplegia for more than 24 hours is an exclusion criterion because of the low chances of improvement when prolonged neurologic deficits exist before surgery.164 Patients with hematologic malignancies should also be excluded, because they are best managed with radiotherapy or chemotherapy. Because estimation of life expectancy can be difficult, several groups have developed prognostic scoring systems to help predict surgical outcomes.165–168
Posterior laminectomy has been widely used in the past but is now obsolete because of frequent complications and lack of benefit. Modern surgical techniques enable surgeons to achieve 360° decompression of the spinal cord, and stabilization can be performed concomitantly if required. The development of a plethora of spinal implants composed of high-quality materials, such as titanium, greatly improve reconstruction outcome. The surgical approach, either anterior, posterior, or combined/circumferential, is primarily determined by disease anatomy.169,170
Sundaresan et al.163 reported favorable results using various surgical approaches in 80 patients with solitary spine metastases, with most patients experiencing improvement in both pain and mobility. Overall survival reached 30 months, with 18% surviving 5 years or more. The best outcomes were observed in patients with kidney and breast cancers.
Surgery followed by adjuvant EBRT has emerged as a highly effective approach in relieving spinal cord compression and restoring function, especially for patients with solid tumors. A meta-analysis involving 24 surgery cohort studies and 4 radiation studies found that patients are twice as likely to regain ambulatory function after surgery than after radiation alone.171 However, data also showed significant surgery-related mortality (6.3%) and morbidity (23%). In another review of literature from 1964 to 2005, anterior decompression with stabilization plus radiation was associated with superior outcomes over radiation alone or laminectomy, achieving a 75% mean improvement in neurologic function, although a high surgical mortality rate (mean, 10%) was also reported.172
To date, only one relevant randomized trial has been reported.173 Approximately 100 patients with metastatic spinal compression were randomized to surgery plus postoperative RT or RT alone. Compared with the radiation group, significantly more patients in the surgery group regained walking ability (84% vs. 57%; P = .001) and for a longer time (median, 122 days vs. 13 days; P = .003). The impressive results were obtained with strict eligibility criteria; the study excluded patients with radiosensitive tumors, neurologic deficits for 24 hours, multiple spinal tumors, lesions only compressing spinal roots, and prior RT to the vertebrae. Although studies have shown high efficacy of surgery, the formidable complications related to surgery cannot be overlooked. Using the National Inpatient Sample all-payor database, Patil et al.174 reviewed data of more than 26,000 patients who had undergone surgery for spinal metastases. The in-hospital mortality and complication rates were 5.6% and 22%, respectively. The most common complications were pulmonary (6.7%) and hemorrhages or hematomas (5.9%). Clearly, careful individual patient selection based on life expectancy and overall health is warranted.
Radiation: Traditionally, EBRT has been the main form of treatment for spinal metastases. In the modern surgery era, radiation alone is often not sufficient to achieve decompression or stabilization (see earlier discussion) but is routinely used as adjuvant therapy after surgery because wide negative margins are difficult to obtain. Given the potential impact of RT on wound healing, most studies suggested an interval of 1 to 3 weeks between resection and subsequent radiation.175
Marazano et al.176 reported an excellent response to RT alone for spinal compression after randomizing 300 patients to a short-course (8 Gy × 2 days) or split-course (5 Gy × 3; 3 Gy × 5) schedule. After RT, 35% of nonambulatory patients regained walking ability, and pain relief was recorded in 57% of patients, with a median survival of 4 months. Efficacy of RT is highly dependent on the histology: 70% of nonambulatory patients with breast cancer recovered mobility compared with only 20% of those with hepatocellular carcinoma. In general, solid tumors are considered either moderately radiosensitive (e.g., breast and prostate cancers) or radioresistant (e.g., melanoma, osteosarcomas, and cancers of the thyroid, colon, and kidney).177 However, hematologic malignancies such as lymphomas and multiple myelomas are highly responsive to RT. Hence, radiation alone is routinely used as therapy for these cancers, even in the presence of cord compression.
In the absence of compression, fracture, or instability, EBRT is effective in achieving local control as primary treatment. A mean 77% local control rate from 7 retrospective studies involving 885 patients was found in a systematic review by Gerszten et al.177 Radiation is also a mainstay of palliative treatment for patients with poor PS, significant comorbidities, or limited life expectancy (< 3–4 months). The meta-analysis by Klimo et al.171 involving 543 patients treated with radiation revealed pain control rates of 54% to 83%. Unlike surgery, radiation has no immediate significant treatment-related complications and very few local recurrences. However, it increases surgical complications because it impairs wound healing.
The advent of SRS allowed precise high-dose targeting in 1 or 2 fractions while minimizing exposure of the surrounding cord. This is especially important in pre-irradiated patients. The largest prospective study involved a cohort of nearly 400 patients with 500 spinal metastases, 70% of whom had previous conventional irradiation.178 At a median follow-up of 21 months, radiosurgery resulted in long-term pain improvement and tumor control in 85% and 90% of cases, respectively. Other single-institution reports also suggest that SRS is safe and offers more durable response than conventional therapy.177 However, robust randomized trials with long-term outcomes are still lacking.
Vertebral Augmentation: Percutaneous vertebroplasty and kyphoplasty involve injection of cement (polymethyl methacrylate) into the vertebral body. Vertebroplasty is a direct injection, whereas kyphoplasty involves inserting a balloon that provides a cavity for the injection. These vertebral augmentation procedures immediately reinforce and stabilize the column, thereby relieving pain and preventing further fractures.179 They are suitable in poor surgical candidates with painful fractures, but are relatively contraindicated in the case of spinal cord compression because they do not produce decompression. Symptomatic complications occur in up to 8% of patients (mostly with vertebroplasty), including embolization of the cement and local metastasis along the needle tract.
Systemic Therapy: Corticosteroids remain a routine initial prescription for patients presenting with cord compression, with several theoretical benefits, including anti-inflammation, reduction in edema, short-term neurologic function improvement, and enhanced blood flow. However, the preference between high-dose (96 mg daily) and low-dose (10–16 mg daily) is still unclear.180–182
Chemotherapy has a limited role in metastatic spinal tumors, except for chemosensitive tumors such as lymphoma, myeloma, and germ cell tumor. Agents efficacious for the primary tumor are used.
NCCN Recommendations
Workup: Initial workup depends on the presence or absence of symptoms. Patients with an incidental, asymptomatic metastatic lesion confirmed with systemic imaging can be observed with MRI. However, biopsy and further treatment of an incidental lesion are indicated if treatment of the patient is altered as a result of treatment of the incidental lesion. In the absence of symptoms, obtaining a spinal MRI for every incidental metastatic lesion seen on surveillance bone scans is not mandatory. The alternate category involves severe or new back pain. Increasing intensity, duration, and changes in the character of pain should trigger an evaluation with an MRI study, even in patients with preexisting degenerative spine conditions. Immediate spinal MRI is warranted when neurologic symptoms occur, including weakness, paresthesias, and bladder or bowel incontinence. Contrast can be used to highlight and further evaluate any focal abnormality. The MRI can be used to image the entire spine or a focal area of interest. If the patient is unable to have an MRI, then a CT myelogram is recommended.
A normal neurologic examination implies that no spinal radiculopathy or myelopathy correlates with the patient's symptoms. In this case, other causes should be considered (e.g., leptomeningeal disease). An abnormal neurologic examination includes motor abnormalities, sphincter abnormalities, or sensory deficits attributable to a dysfunction of nerve roots and/or the spinal cord. Therefore, detection of radiculopathy, myelopathy, or cauda equina syndrome is indicative of an abnormal examination. However, reflex asymmetry and/or presence of pathologic reflexes, and sensory deficits of a stocking/glove distribution are excluded.
Treatment: Once metastatic vertebral involvement is diagnosed, treatment is based on whether the patient is experiencing spinal cord compression, fracture, or spinal instability. In the presence of multiple metastatic spinal tumors, the one causing the patient's main symptoms is addressed first. Additional tumors can be treated at a later point according to the algorithm.
Radiographic spinal cord compression implies deformation of the spinal cord because of epidural tumor, retropulsed bone fragment, or both. Epidural tumors may occupy part of the spinal canal with or without partial obliteration of CSF around the spinal cord. Those cases are excluded because no cord deformation is present. For tumors occurring below L1, any canal compression of 50% or more should be considered equally as important as spinal cord compression. Patients with radiographic cord compression should start on dexamethasone (10–100 mg) to alleviate symptoms. Decompressive surgery (concomitant stabilization if indicated) and adjuvant radiation is the preferred treatment in the presence of spinal instability and no surgical contraindication. Primary EBRT alone is appropriate for patients with radiosensitive cancers (hematologic malignancies) and without evidence of spinal instability. Many fractionation schemes are available (20–37.5 Gy in 5–15 fractions over 1–3 weeks); the most common is a total of 30 Gy in 3-Gy daily fractions for 10 days.183,184 Primary chemotherapy is also an option for chemoresponsive tumors in the absence of clinical myelopathy.
Metastases to the spine without cord compression include the presence of tumor in the vertebral body, pedicles, lamina, transverse, or spinous process. It can also include epidural disease without cord deformation. Patients in this category should be assessed for fractures and spinal instability. Because the criteria for spinal destabilization secondary to tumor remain unclear, consultation with a surgeon is recommended. Spinal instability is grossly defined as the presence of significant kyphosis or subluxation (deformity) or of significantly retropulsed bone fragment. Not every pathologic fracture implies unstable structure. The degree of kyphosis or subluxation compatible with instability depends on the location of the tumor in the spine. The cross-sectional area of the vertebral body unaffected by the tumor and the patient's bone mineral density are additional factors affecting stability. In addition, vertebral body involvement is more important than dorsal element involvement with regard to stability. Circumferential disease and junctional and contiguous tumor location should be taken into account when assessing spinal stability. If fracture or instability is detected, patient should undergo surgical stabilization or minimally invasive vertebral augmentation to relieve pain. These procedures should be followed by adjuvant radiation to obtain local control.
If no fracture or instability is found, EBRT is the preferred treatment. Alternatives are chemotherapy for responsive tumors, or surgery plus adjuvant RT in select cases. Surgery or SRS should be considered in patients experiencing intractable pain or rapid neurologic decline during RT. Neurologic deterioration is apparent when the patient's neurologic examination is becoming worse on a daily basis and the patient's ambulatory status is threatened. Intractable pain means either that pain is not controlled with oral analgesics or that the patient cannot tolerate the medication because of side effects.
Progression and Recurrence: Follow-up involves MRI or CT imaging within 1 to 3 months posttreatment, then every 3 to 6 months as indicated. When progression or recurrence is detected on imaging scans, the management strategy is based on previous treatment. Patients who underwent prior RT or surgery plus adjuvant RT may consider surgery or reirradiation to the recurred area. Patients previously treated by chemotherapy can consider salvage radiotherapy.
Individual Disclosures for the NCCN Central Nervous System Cancers Panel
NCCN Clinical Practice Guidelines in Oncology for Central Nervous System Cancers
NCCN Categories of Evidence and Consensus
Category 1: The recommendation is based on high-level evidence (e.g., randomized controlled trials) and there is uniform NCCN consensus.
Category 2A: The recommendation is based on lower-level evidence and there is uniform NCCN consensus.
Category 2B: The recommendation is based on lower-level evidence and there is nonuniform NCCN consensus (but no major disagreement).
Category 3: The recommendation is based on any level of evidence but reflects major disagreement.
All recommendations are category 2A unless otherwise noted.
The full NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Central Nervous System Cancers are not printed in this issue of JNCCN, but can be accessed online at www.NCCN.org.
Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Please Note
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines™ is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representation or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their applications or use in any way.
© National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.
Disclosures for the NCCN Guidelines Panel for Central Nervous System Cancers
At the beginning of each NCCN Guidelines panel meeting, panel members disclosed any financial support they have received from industry. Through 2008, this information was published in an aggregate statement in JNCCN and online. Furthering NCCN's commitment to public transparency, this disclosure process has now been expanded by listing all potential conflicts of interest respective to each individual expert panel member.
Individual disclosures for the NCCN Guidelines for Central Nervous System Cancers panel members can be found on page 400. (The most recent version of these guidelines and accompanying disclosures, including levels of compensation, are available on the NCCN Web site at www.NCCN.org.)
These guidelines are also available on the Internet. For the latest update, please visit www.NCCN.org.
References
- 2.↑
Maher EA, McKee AC. Neoplasms of the central nervous system. In: Skarin AT, Canellos GP, eds. Atlas of diagnostic oncology, 3rd edition. London, United Kingdom: Elsevier Science Ltd; 2003.
- 4.↑
Sawaya R, Hammoud M, Schoppa D et al.. Neurosurgical outcomes in a modern series of 400 craniotomies for treatment of parenchymal tumors. Neurosurgery 1998;42:1044–1055.
- 5.↑
Central Brain Tumor Registry of the United States. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2004–2006. 2010. Available at: http://www.cbtrus.org/reports/reports.html. Accessed September 29, 2010.
- 6.↑
Curran WJ Jr, Scott CB, Horton J et al.. Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 1993;85:704–710.
- 7.↑
Cairncross JG, Ueki K, Zlatescu MC et al.. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 1998;90:1473–1479.
- 8.↑
Cairncross G, Berkey B, Shaw E et al.. Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group trial 9402. J Clin Oncol 2006;24:2707–2714.
- 9.↑
Laws ER, Parney IF, Huang W et al.. Survival following surgery and prognostic factors for recently diagnosed malignant glioma: data from the Glioma Outcomes Project. J Neurosurg 2003;99:467–473.
- 10.↑
Simpson JR, Horton J, Scott C et al.. Influence of location and extent of surgical resection on survival of patients with glioblastoma multiforme: results of three consecutive Radiation Therapy Oncology Group (RTOG) clinical trials. Int J Radiat Oncol Biol Phys 1993;26:239–244.
- 11.
Wood JR, Green SB, Shapiro WR. The prognostic importance of tumor size in malignant gliomas: a computed tomographic scan study by the Brain Tumor Cooperative Group. J Clin Oncol 1988;6:338–343.
- 12.↑
Lacroix M, Abi-Said D, Fourney DR et al.. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 2001;95:190–198.
- 13.↑
Barker FG II, Chang SM, Gutin PH et al.. Survival and functional status after resection of recurrent glioblastoma multiforme. Neurosurgery 1998;42:709–720.
- 14.↑
Park JK, Hodges T, Arko L et al.. Scale to predict survival after surgery for recurrent glioblastoma multiforme. J Clin Oncol 2010;28:3838–3843.
- 15.↑
Walker MD, Alexander E Jr, Hunt WE et al.. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg 1978;49:333–343.
- 16.↑
Kristiansen K, Hagen S, Kollevold T et al.. Combined modality therapy of operated astrocytomas grade III and IV. Confirmation of the value of postoperative irradiation and lack of potentiation of bleomycin on survival time: a prospective multicenter trial of the Scandinavian Glioblastoma Study Group. Cancer 1981;47:649–652.
- 17.↑
Keime-Guibert F, Chinot O, Taillandier L et al.. Radiotherapy for glioblastoma in the elderly. N Engl J Med 2007;356:1527–1535.
- 18.↑
Roa W, Brasher PM, Bauman G et al.. Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol 2004;22:1583–1588.
- 19.↑
Souhami L, Seiferheld W, Brachman D et al.. Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol. Int J Radiat Oncol Biol Phys 2004;60:853–860.
- 20.↑
Laperriere NJ, Leung PM, McKenzie S et al.. Randomized study of brachytherapy in the initial management of patients with malignant astrocytoma. Int J Radiat Oncol Biol Phys 1998;41:1005–1011.
- 21.↑
Medical Research Council Brain Tumor Working Party. Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: a Medical Research Council trial. J Clin Oncol 2001;19:509–518.
- 22.↑
Stewart LA. Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 2002;359:1011–1018.
- 23.↑
Fine HA, Dear KB, Loeffler JS et al.. Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 1993;71:2585–2597.
- 24.↑
Brem H, Piantadosi S, Burger PC et al.. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet 1995;345:1008–1012.
- 25.↑
Valtonen S, Timonen U, Toivanen P et al.. Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study. Neurosurgery 1997;41:44–48; discussion 48–49.
- 26.↑
Westphal M, Hilt DC, Bortey E et al.. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol 2003;5:79–88.
- 27.↑
Westphal M, Ram Z, Riddle V et al.. Gliadel wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial. Acta Neurochir (Wien) 2006;148:269–275; discussion 275.
- 28.↑
Stupp R, Mason WP, van den Bent MJ et al.. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987–996.
- 29.↑
Stupp R, Hegi ME, Mason WP et al.. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10:459–466.
- 30.↑
Clarke JL, Iwamoto FM, Sul J et al.. Randomized phase II trial of chemoradiotherapy followed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma. J Clin Oncol 2009;27:3861–3867.
- 31.↑
Brandes AA, Vastola F, Basso U et al.. A prospective study on glioblastoma in the elderly. Cancer 2003;97:657–662.
- 32.↑
Minniti G, De Sanctis V, Muni R et al.. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma in elderly patients. J Neurooncol 2008;88:97–103.
- 33.↑
Glantz M, Chamberlain M, Liu Q et al.. Temozolomide as an alternative to irradiation for elderly patients with newly diagnosed malignant gliomas. Cancer 2003;97:2262–2266.
- 34.↑
Hegi ME, Diserens AC, Gorlia T et al.. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352:997–1003.
- 35.↑
Mollemann M, Wolter M, Felsberg J et al.. Frequent promoter hypermethylation and low expression of the MGMT gene in oligodendroglial tumors. Int J Cancer 2005;113:379–385.
- 36.↑
Wick W, Hartmann C, Engel C et al.. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol 2009;27:5874–5880.
- 37.↑
Perry JR, Rizek P, Cashman R et al.. Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule: the ``rescue'' approach. Cancer 2008;113:2152–2157.
- 38.
Perry JR, Belanger K, Mason WP et al.. Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol 2010;28:2051–2057.
- 39.↑
Yung WK, Prados MD, Yaya-Tur R et al.. Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group. J Clin Oncol 1999;17:2762–2771.
- 40.↑
Triebels VH, Taphoorn MJ, Brandes AA et al.. Salvage PCV chemotherapy for temozolomide-resistant oligodendrogliomas. Neurology 2004;63:904–906.
- 41.↑
Chamberlain MC, Tsao-Wei DD. Salvage chemotherapy with cyclophosphamide for recurrent, temozolomide-refractory glioblastoma multiforme. Cancer 2004;100:1213–1220.
- 42.↑
Brandes AA, Basso U, Vastola F et al.. Carboplatin and teniposide as third-line chemotherapy in patients with recurrent oligodendroglioma or oligoastrocytoma: a phase II study. Ann Oncol 2003;14:1727–1731.
- 43.↑
Chamberlain MC, Wei-Tsao DD, Blumenthal DT, Glantz MJ. Salvage chemotherapy with CPT-11 for recurrent temozolomide-refractory anaplastic astrocytoma. Cancer 2008;112:2038–2045.
- 44.↑
Fulton D, Urtasun R, Forsyth P. Phase II study of prolonged oral therapy with etoposide (VP16) for patients with recurrent malignant glioma. J Neurooncol 1996;27:149–155.
- 45.↑
Friedman HS, Prados MD, Wen PY et al.. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009;27:4733–4740.
- 46.↑
Vredenburgh JJ, Desjardins A, Herndon JE II et al.. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 2007;25:4722–4729.
- 47.↑
Kreisl TN, Kim L, Moore K et al.. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 2009;27:740–745.
- 48.↑
Chamberlain MC, Johnston S. Bevacizumab for recurrent alkylator-refractory anaplastic oligodendroglioma. Cancer 2009;115:1734–1743.
- 49.
Chamberlain MC, Johnston S. Salvage chemotherapy with bevacizumab for recurrent alkylator-refractory anaplastic astrocytoma. J Neurooncol 2009;91:359–367.
- 50.
Norden AD, Young GS, Setayesh K et al.. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 2008;70:779–787.
- 51.
Soffietti R, Ruda R, Trevisan E et al.. Phase II study of bevacizumab and nitrosourea in patients with recurrent malignant glioma: a multicenter Italian study [abstract]. J Clin Oncol 2009;27(Suppl 15S):Abstract 2012.
- 52.
Taillibert S, Vincent LA, Granger B et al.. Bevacizumab and irinotecan for recurrent oligodendroglial tumors. Neurology 2009;72:1601–1606.
- 53.↑
Vredenburgh JJ, Desjardins A, Herndon JE II et al.. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 2007;13:1253–1259.
- 54.↑
McGirt MJ, Than KD, Weingart JD et al.. Gliadel (BCNU) wafer plus concomitant temozolomide therapy after primary resection of glioblastoma multiforme. J Neurosurg 2009;110:583–588.
- 55.↑
Tsien C, Galban CJ, Chenevert TL et al.. Parametric response map as an imaging biomarker to distinguish progression from pseudoprogression in high-grade glioma. J Clin Oncol 2010;28:2293–2299.
- 56.↑
Louis DN, Ohgaki H, Wiestler OD et al.. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007;114:97–109.
- 57.↑
Surawicz TS, McCarthy BJ, Kupelian V et al.. Descriptive epidemiology of primary brain and CNS tumors: results from the Central Brain Tumor Registry of the United States, 1990–1994. Neuro Oncol 1999;1:14–25.
- 58.↑
Kunschner LJ, Kuttesch J, Hess K, Yung WK. Survival and recurrence factors in adult medulloblastoma: the M.D. Anderson Cancer Center experience from 1978 to 1998. Neuro Oncol 2001;3:167–173.
- 59.↑
Padovani L, Sunyach MP, Perol D et al.. Common strategy for adult and pediatric medulloblastoma: a multicenter series of 253 adults. Int J Radiat Oncol Biol Phys 2007;68:433–440.
- 60.↑
Carrie C, Lasset C, Alapetite C et al.. Multivariate analysis of prognostic factors in adult patients with medulloblastoma. Retrospective study of 156 patients. Cancer 1994;74:2352–2360.
- 61.↑
Chan AW, Tarbell NJ, Black PM et al.. Adult medulloblastoma: prognostic factors and patterns of relapse. Neurosurgery 2000;47:623–631.
- 62.↑
Frost PJ, Laperriere NJ, Wong CS et al.. Medulloblastoma in adults. Int J Radiat Oncol Biol Phys 1995;32:951–957.
- 63.↑
Chargari C, Feuvret L, Levy A et al.. Reappraisal of clinical outcome in adult medulloblastomas with emphasis on patterns of relapse. Br J Neurosurg 2010;24:460–467.
- 64.↑
Douglas JG, Barker JL, Ellenbogen RG, Geyer JR. Concurrent chemotherapy and reduced-dose cranial spinal irradiation followed by conformal posterior fossa tumor bed boost for average-risk medulloblastoma: efficacy and patterns of failure. Int J Radiat Oncol Biol Phys 2004;58:1161–1164.
- 65.↑
Merchant TE, Kun LE, Krasin MJ et al.. Multi-institution prospective trial of reduced-dose craniospinal irradiation (23.4 Gy) followed by conformal posterior fossa (36 Gy) and primary site irradiation (55.8 Gy) and dose-intensive chemotherapy for average-risk medulloblastoma. Int J Radiat Oncol Biol Phys 2008;70:782–787.
- 66.↑
Deutsch M, Thomas PR, Krischer J et al.. Results of a prospective randomized trial comparing standard dose neuraxis irradiation (3,600 cGy/20) with reduced neuraxis irradiation (2,340 cGy/13) in patients with low-stage medulloblastoma. A Combined Children's Cancer Group-Pediatric Oncology Group Study. Pediatr Neurosurg 1996;24:167–176.
- 67.↑
Germanwala AV, Mai JC, Tomycz ND et al.. Boost Gamma Knife surgery during multimodality management of adult medulloblastoma. J Neurosurg 2008;108:204–209.
- 68.↑
Riffaud L, Saikali S, Leray E et al.. Survival and prognostic factors in a series of adults with medulloblastomas. J Neurosurg 2009;111:478–487.
- 69.↑
Herrlinger U, Steinbrecher A, Rieger J et al.. Adult medulloblastoma: prognostic factors and response to therapy at diagnosis and at relapse. J Neurol 2005;252:291–299.
- 70.↑
Packer RJ, Gajjar A, Vezina G et al.. Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 2006;24:4202–4208.
- 71.↑
Ashley DM, Meier L, Kerby T et al.. Response of recurrent medulloblastoma to low-dose oral etoposide. J Clin Oncol 1996;14:1922–1927.
- 72.
Chamberlain MC, Kormanik PA. Chronic oral VP-16 for recurrent medulloblastoma. Pediatr Neurol 1997;17:230–234.
- 73.↑
Dunkel IJ, Gardner SL, Garvin JH Jr et al.. High-dose carboplatin, thiotepa, and etoposide with autologous stem cell rescue for patients with previously irradiated recurrent medulloblastoma. Neuro Oncol 2010;12:297–303.
- 74.↑
Gill P, Litzow M, Buckner J et al.. High-dose chemotherapy with autologous stem cell transplantation in adults with recurrent embryonal tumors of the central nervous system. Cancer 2008;112:1805–1811.
- 75.↑
Cohen ME, Duffner P, eds. Brain tumors in children, 2nd edition. New York, NY: McGraw-Hill; 1994.
- 76.↑
Chang CH, Housepian EM, Herbert C Jr. An operative staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastomas. Radiology 1969;93:1351–1359.
- 77.↑
Brandes AA, Franceschi E, Tosoni A et al.. Adult neuroectodermal tumors of posterior fossa (medulloblastoma) and of supratentorial sites (stPNET). Crit Rev Oncol Hematol 2009;71:165–179.
- 78.↑
Schellinger KA, Propp JM, Villano JL, McCarthy BJ. Descriptive epidemiology of primary spinal cord tumors. J Neurooncol 2008;87:173–179.
- 79.↑
Grimm S, Chamberlain MC. Adult primary spinal cord tumors. Expert Rev Neurother 2009;9:1487–1495.
- 80.↑
Gezen F, Kahraman S, Canakci Z, Beduk A. Review of 36 cases of spinal cord meningioma. Spine (Phila Pa 1976) 2000;25:727–731.
- 81.
Solero CL, Fornari M, Giombini S et al.. Spinal meningiomas: review of 174 operated cases. Neurosurgery 1989;25:153–160.
- 82.
Volpp PB, Han K, Kagan AR, Tome M. Outcomes in treatment for intradural spinal cord ependymomas. Int J Radiat Oncol Biol Phys 2007;69:1199–1204.
- 83.↑
Yang S, Yang X, Hong G. Surgical treatment of one hundred seventy-four intramedullary spinal cord tumors. Spine (Phila Pa 1976) 2009;34:2705–2710.
- 84.↑
Raco A, Esposito V, Lenzi J et al.. Long-term follow-up of intramedullary spinal cord tumors: a series of 202 cases. Neurosurgery 2005;56:972–981.
- 85.↑
Benes V III, Barsa P, Benes V Jr, Suchomel P. Prognostic factors in intramedullary astrocytomas: a literature review. Eur Spine J 2009;18:1397–1422.
- 86.↑
Milano MT, Johnson MD, Sul J et al.. Primary spinal cord glioma: a Surveillance, Epidemiology, and End Results database study. J Neurooncol 2010;98:83–92.
- 87.↑
Sgouros S, Malluci CL, Jackowski A. Spinal ependymomas—the value of postoperative radiotherapy for residual disease control. Br J Neurosurg 1996;10:559–566.
- 88.↑
Lee TT, Gromelski EB, Green BA. Surgical treatment of spinal ependymoma and post-operative radiotherapy. Acta Neurochir (Wien) 1998;140:309–313.
- 89.↑
Ryu SI, Kim DH, Chang SD. Stereotactic radiosurgery for hemangiomas and ependymomas of the spinal cord. Neurosurg Focus 2003;15:E10.
- 90.
Gerszten PC, Burton SA, Ozhasoglu C et al.. Radiosurgery for benign intradural spinal tumors. Neurosurgery 2008;62:887–895.
- 91.↑
Dodd RL, Ryu MR, Kamnerdsupaphon P et al.. CyberKnife radiosurgery for benign intradural extramedullary spinal tumors. Neurosurgery 2006;58:674–685.
- 92.↑
Garces-Ambrossi GL, McGirt MJ, Mehta VA et al.. Factors associated with progression-free survival and long-term neurological outcome after resection of intramedullary spinal cord tumors: analysis of 101 consecutive cases. J Neurosurg Spine 2009;11:591–599.
- 93.↑
Mahmood A, Caccamo DV, Tomecek FJ, Malik GM. Atypical and malignant meningiomas: a clinicopathological review. Neurosurgery 1993;33:955–963.
- 94.↑
Vernooij MW, Ikram MA, Tanghe HL et al.. Incidental findings on brain MRI in the general population. N Engl J Med 2007;357:1821–1828.
- 95.↑
Lieu AS, Howng SL. Intracranial meningiomas and epilepsy: incidence, prognosis and influencing factors. Epilepsy Res 2000;38:45–52.
- 96.↑
Campbell BA, Jhamb A, Maguire JA et al.. Meningiomas in 2009: controversies and future challenges. Am J Clin Oncol 2009;32:73–85.
- 97.↑
Nathoo N, Ugokwe K, Chang AS et al.. The role of 111indium-octreotide brain scintigraphy in the diagnosis of cranial, dural-based meningiomas. J Neurooncol 2007;81:167–174.
- 98.
Nyuyki F, Plotkin M, Graf R et al.. Potential impact of (68)Ga-DOTATOC PET/CT on stereotactic radiotherapy planning of meningiomas. Eur J Nucl Med Mol Imaging 2010;37:310–318.
- 99.↑
Gehler B, Paulsen F, Oksuz MO et al.. [68Ga]-DOTATOC-PET/CT for meningioma IMRT treatment planning. Radiat Oncol 2009;4:56.
- 100.↑
Nakamura M, Roser F, Michel J et al.. The natural history of incidental meningiomas. Neurosurgery 2003;53:62–70.
- 101.↑
Olivero WC, Lister JR, Elwood PW. The natural history and growth rate of asymptomatic meningiomas: a review of 60 patients. J Neurosurg 1995;83:222–224.
- 102.↑
Stafford SL, Perry A, Suman VJ et al.. Primarily resected meningiomas: outcome and prognostic factors in 581 Mayo Clinic patients, 1978 through 1988. Mayo Clin Proc 1998;73:936–942.
- 103.↑
Mahmood A, Qureshi NH, Malik GM. Intracranial meningiomas: analysis of recurrence after surgical treatment. Acta Neurochir (Wien) 1994;126:53–58.
- 104.
Mathiesen T, Lindquist C, Kihlstrom L, Karlsson B. Recurrence of cranial base meningiomas. Neurosurgery 1996;39:2–7; discussion 8–9.
- 105.↑
Perry A, Stafford SL, Scheithauer BW et al.. Meningioma grading: an analysis of histologic parameters. Am J Surg Pathol 1997;21:1455–1465.
- 106.↑
Simpson D. The recurrence of intracranial meningiomas after surgical treatment. J Neurol Neurosurg Psychiatry 1957;20:22–39.
- 107.↑
Condra KS, Buatti JM, Mendenhall WM et al.. Benign meningiomas: primary treatment selection affects survival. Int J Radiat Oncol Biol Phys 1997;39:427–436.
- 108.↑
Soyuer S, Chang EL, Selek U et al.. Radiotherapy after surgery for benign cerebral meningioma. Radiother Oncol 2004;71:85–90.
- 109.↑
Aghi MK, Carter BS, Cosgrove GR et al.. Long-term recurrence rates of atypical meningiomas after gross total resection with or without postoperative adjuvant radiation. Neurosurgery 2009;64:56–60; discussion 60.
- 110.↑
Hug EB, Devries A, Thornton AF et al.. Management of atypical and malignant meningiomas: role of high-dose, 3D-conformal radiation therapy. J Neurooncol 2000;48:151–160.
- 111.↑
Yang SY, Park CK, Park SH et al.. Atypical and anaplastic meningiomas: prognostic implications of clinicopathological features. J Neurol Neurosurg Psychiatry 2008;79:574–580.
- 112.↑
Pollock BE, Stafford SL, Utter A et al.. Stereotactic radiosurgery provides equivalent tumor control to Simpson grade 1 resection for patients with small- to medium-size meningiomas. Int J Radiat Oncol Biol Phys 2003;55:1000–1005.
- 113.↑
Kondziolka D, Mathieu D, Lunsford LD et al.. Radiosurgery as definitive management of intracranial meningiomas. Neurosurgery 2008;62:53–58; discussion 58–60.
- 114.↑
Newton HB, Scott SR, Volpi C. Hydroxyurea chemotherapy for meningiomas: enlarged cohort with extended follow-up. Br J Neurosurg 2004;18:495–499.
- 115.↑
Chamberlain MC, Glantz MJ, Fadul CE. Recurrent meningioma: salvage therapy with long-acting somatostatin analogue. Neurology 2007;69:969–973.
- 116.↑
Chamberlain MC, Glantz MJ. Interferon-alpha for recurrent World Health Organization grade 1 intracranial meningiomas. Cancer 2008;113:2146–2151.
- 117.↑
Barnholtz-Sloan JS, Sloan AE, Davis FG et al.. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol 2004;22:2865–2872.
- 118.↑
Schouten LJ, Rutten J, Huveneers HA, Twijnstra A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer 2002;94:2698–2705.
- 120.↑
Eichler AF, Loeffler JS. Multidisciplinary management of brain metastases. Oncologist 2007;12:884–898.
- 121.↑
Barker FG II. Craniotomy for the resection of metastatic brain tumors in the U.S., 1988-2000: decreasing mortality and the effect of provider caseload. Cancer 2004;100:999–1007.
- 122.↑
Patchell RA, Tibbs PA, Regine WF et al.. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA 1998;280:1485–1489.
- 123.↑
Paek SH, Audu PB, Sperling MR et al.. Reevaluation of surgery for the treatment of brain metastases: review of 208 patients with single or multiple brain metastases treated at one institution with modern neurosurgical techniques. Neurosurgery 2005;56:1021–1034.
- 124.↑
Stark AM, Tscheslog H, Buhl R et al.. Surgical treatment for brain metastases: prognostic factors and survival in 177 patients. Neurosurg Rev 2005;28:115–119.
- 125.↑
Suh JH. Stereotactic radiosurgery for the management of brain metastases. N Engl J Med 2010;362:1119–1127.
- 126.↑
Aoyama H, Shirato H, Tago M et al.. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 2006;295:2483–2491.
- 127.↑
O'Neill BP, Iturria NJ, Link MJ et al.. A comparison of surgical resection and stereotactic radiosurgery in the treatment of solitary brain metastases. Int J Radiat Oncol Biol Phys 2003;55:1169–1176.
- 128.
Rades D, Kueter JD, Veninga T et al.. Whole brain radiotherapy plus stereotactic radiosurgery (WBRT+SRS) versus surgery plus whole brain radiotherapy (OP+WBRT) for 1-3 brain metastases: results of a matched pair analysis. Eur J Cancer 2009;45:400–404.
- 129.↑
Schoggl A, Kitz K, Reddy M et al.. Defining the role of stereotactic radiosurgery versus microsurgery in the treatment of single brain metastases. Acta Neurochir (Wien) 2000;142:621–626.
- 130.↑
Muacevic A, Wowra B, Siefert A et al.. Microsurgery plus whole brain irradiation versus Gamma Knife surgery alone for treatment of single metastases to the brain: a randomized controlled multicentre phase III trial. J Neurooncol 2008;87:299–307.
- 131.↑
Akyurek S, Chang EL, Mahajan A et al.. Stereotactic radiosurgical treatment of cerebral metastases arising from breast cancer. Am J Clin Oncol 2007;30:310–314.
- 132.
Loeffler JS, Kooy HM, Wen PY et al.. The treatment of recurrent brain metastases with stereotactic radiosurgery. J Clin Oncol 1990;8:576–582.
- 133.
Noel G, Medioni J, Valery CA et al.. Three irradiation treatment options including radiosurgery for brain metastases from primary lung cancer. Lung Cancer 2003;41:333–343.
- 134.
Noel G, Proudhom MA, Valery CA et al.. Radiosurgery for re-irradiation of brain metastasis: results in 54 patients. Radiother Oncol 2001;60:61–67.
- 135.↑
Sheehan J, Kondziolka D, Flickinger J, Lunsford LD. Radiosurgery for patients with recurrent small cell lung carcinoma metastatic to the brain: outcomes and prognostic factors. J Neurosurg 2005;102 (suppl):247–254.
- 136.↑
Patchell RA, Tibbs PA, Walsh JW et al.. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990;322:494–500.
- 137.↑
Vecht CJ, Haaxma-Reiche H, Noordijk EM et al.. Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol 1993;33:583–590.
- 138.↑
Mintz AH, Kestle J, Rathbone MP et al.. A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis. Cancer 1996;78:1470–1476.
- 139.↑
Andrews DW, Scott CB, Sperduto PW et al.. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 2004;363:1665–1672.
- 140.↑
Kondziolka D, Patel A, Lunsford LD et al.. Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 1999;45:427–434.
- 141.↑
Cooper JS, Steinfeld AD, Lerch IA. Cerebral metastases: value of reirradiation in selected patients. Radiology 1990;174:883–885.
- 142.
Sadikov E, Bezjak A, Yi QL et al.. Value of whole brain re-irradiation for brain metastases—single centre experience. Clin Oncol (R Coll Radiol) 2007;19:532–538.
- 143.↑
Wong WW, Schild SE, Sawyer TE, Shaw EG. Analysis of outcome in patients reirradiated for brain metastases. Int J Radiat Oncol Biol Phys 1996;34:585–590.
- 144.↑
Guerrieri M, Wong K, Ryan G et al.. A randomised phase III study of palliative radiation with concomitant carboplatin for brain metastases from non-small cell carcinoma of the lung. Lung Cancer 2004;46:107–111.
- 145.↑
Verger E, Gil M, Yaya R et al.. Temozolomide and concomitant whole brain radiotherapy in patients with brain metastases: a phase II randomized trial. Int J Radiat Oncol Biol Phys 2005;61:185–191.
- 146.↑
Antonadou D, Paraskevaidis M, Sarris G et al.. Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. J Clin Oncol 2002;20:3644–3650.
- 147.↑
Agarwala SS, Kirkwood JM, Gore M et al.. Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. J Clin Oncol 2004;22:2101–2107.
- 148.↑
Krown SE, Niedzwiecki D, Hwu WJ et al.. Phase II study of temozolomide and thalidomide in patients with metastatic melanoma in the brain: high rate of thromboembolic events (CALGB 500102). Cancer 2006;107:1883–1890.
- 149.↑
Lassman AB, Abrey LE, Shah GD et al.. Systemic high-dose intravenous methotrexate for central nervous system metastases. J Neurooncol 2006;78:255–260.
- 150.↑
Cocconi G, Lottici R, Bisagni G et al.. Combination therapy with platinum and etoposide of brain metastases from breast carcinoma. Cancer Invest 1990;8:327–334.
- 151.↑
Franciosi V, Cocconi G, Michiara M et al.. Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma: a prospective study. Cancer 1999;85:1599–1605.
- 152.↑
Rivera E, Meyers C, Groves M et al.. Phase I study of capecitabine in combination with temozolomide in the treatment of patients with brain metastases from breast carcinoma. Cancer 2006;107:1348–1354.
- 153.↑
Hedde JP, Neuhaus T, Schuller H et al.. A phase I/II trial of topotecan and radiation therapy for brain metastases in patients with solid tumors. Int J Radiat Oncol Biol Phys 2007;68:839–844.
- 154.↑
Neuhaus T, Ko Y, Muller RP et al.. A phase III trial of topotecan and whole brain radiation therapy for patients with CNS-metastases due to lung cancer. Br J Cancer 2009;100:291–297.
- 155.↑
Lang FF, Chang EL, Abi-Said D. Metastatic brain tumors. In: Winn H, ed. Youman's Neurological Surgery, 5th edition. Philadelphia, PA: Saunders; 2004:1077–1097.
- 156.↑
Tsao MN, Lloyd N, Wong R et al.. Whole brain radiotherapy for the treatment of multiple brain metastases. Cochrane Database Syst Rev 2006;3:CD003869.
- 157.↑
Wong DA, Fornasier VL, MacNab I. Spinal metastases: the obvious, the occult, and the impostors. Spine (Phila Pa 1976) 1990;15:1–4.
- 158.↑
Ibrahim A, Crockard A, Antonietti P et al.. Does spinal surgery improve the quality of life for those with extradural (spinal) osseous metastases? An international multicenter prospective observational study of 223 patients. Invited submission from the Joint Section Meeting on Disorders of the Spine and Peripheral Nerves, March 2007. J Neurosurg Spine 2008;8:271–278.
- 160.↑
Schmidt MH, Klimo P Jr, Vrionis FD. Metastatic spinal cord compression. J Natl Compr Canc Netw 2005;3:711–719.
- 161.↑
Helweg-Larsen S, Sorensen PS. Symptoms and signs in metastatic spinal cord compression: a study of progression from first symptom until diagnosis in 153 patients. Eur J Cancer 1994;30A:396–398.
- 162.↑
Levack P, Graham J, Collie D et al.. Don't wait for a sensory level—listen to the symptoms: a prospective audit of the delays in diagnosis of malignant cord compression. Clin Oncol (R Coll Radiol) 2002;14:472–480.
- 163.↑
Sundaresan N, Rothman A, Manhart K, Kelliher K. Surgery for solitary metastases of the spine: rationale and results of treatment. Spine (Phila Pa 1976) 2002;27:1802–1806.
- 164.↑
North RB, LaRocca VR, Schwartz J et al.. Surgical management of spinal metastases: analysis of prognostic factors during a 10-year experience. J Neurosurg Spine 2005;2:564–573.
- 165.↑
Tomita K, Kawahara N, Kobayashi T et al.. Surgical strategy for spinal metastases. Spine (Phila Pa 1976) 2001;26:298–306.
- 166.
Tokuhashi Y, Matsuzaki H, Oda H et al.. A revised scoring system for preoperative evaluation of metastatic spine tumor prognosis. Spine (Phila Pa 1976) 2005;30:2186–2191.
- 167.
van der Linden YM, Dijkstra SP, Vonk EJ et al.. Prediction of survival in patients with metastases in the spinal column: results based on a randomized trial of radiotherapy. Cancer 2005;103:320–328.
- 168.↑
Bartels RH, Feuth T, van der Maazen R et al.. Development of a model with which to predict the life expectancy of patients with spinal epidural metastasis. Cancer 2007;110:2042–2049.
- 169.↑
Choi D, Crockard A, Bunger C et al.. Review of metastatic spine tumour classification and indications for surgery: the consensus statement of the Global Spine Tumour Study Group. Eur Spine J 2010;19:215–222.
- 170.↑
Eleraky M, Papanastassiou I, Vrionis FD. Management of metastatic spine disease. Curr Opin Support Palliat Care 2010;4:182–188.
- 171.↑
Klimo P Jr, Thompson CJ, Kestle JR, Schmidt MH. A meta-analysis of surgery versus conventional radiotherapy for the treatment of metastatic spinal epidural disease. Neuro Oncol 2005;7:64–76.
- 172.↑
Witham TF, Khavkin YA, Gallia GL et al.. Surgery insight: current management of epidural spinal cord compression from metastatic spine disease. Nat Clin Pract Neurol 2006;2:87–94; quiz 116.
- 173.↑
Patchell RA, Tibbs PA, Regine WF et al.. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet 2005;366:643–648.
- 174.↑
Patil CG, Lad SP, Santarelli J, Boakye M. National inpatient complications and outcomes after surgery for spinal metastasis from 1993-2002. Cancer 2007;110:625–630.
- 175.↑
Itshayek E, Yamada J, Bilsky M et al.. Timing of surgery and radiotherapy in the management of metastatic spine disease: a systematic review. Int J Oncol 2010;36:533–544.
- 176.↑
Maranzano E, Bellavita R, Rossi R et al.. Short-course versus split-course radiotherapy in metastatic spinal cord compression: results of a phase III, randomized, multicenter trial. J Clin Oncol 2005;23:3358–3365.
- 177.↑
Gerszten PC, Mendel E, Yamada Y. Radiotherapy and radiosurgery for metastatic spine disease: what are the options, indications, and outcomes? Spine (Phila Pa 1976) 2009;34:S78–92.
- 178.↑
Gerszten PC, Burton SA, Ozhasoglu C, Welch WC. Radiosurgery for spinal metastases: clinical experience in 500 cases from a single institution. Spine (Phila Pa 1976) 2007;32:193–199.
- 179.↑
Mendel E, Bourekas E, Gerszten P, Golan JD. Percutaneous techniques in the treatment of spine tumors: what are the diagnostic and therapeutic indications and outcomes? Spine (Phila Pa 1976) 2009;34:S93–100.
- 180.↑
Sorensen S, Helweg-Larsen S, Mouridsen H, Hansen HH. Effect of high-dose dexamethasone in carcinomatous metastatic spinal cord compression treated with radiotherapy: a randomised trial. Eur J Cancer 1994;30A:22–27.
- 181.
Vecht CJ, Haaxma-Reiche H, van Putten WL et al.. Initial bolus of conventional versus high-dose dexamethasone in metastatic spinal cord compression. Neurology 1989;39:1255–1257.
- 182.↑
Heimdal K, Hirschberg H, Slettebo H et al.. High incidence of serious side effects of high-dose dexamethasone treatment in patients with epidural spinal cord compression. J Neurooncol 1992;12:141–144.
- 183.↑
Kwok Y, Regine WF, Patchell RA. Radiation therapy alone for spinal cord compression: time to improve upon a relatively ineffective status quo. J Clin Oncol 2005;23:3308–3310.
- 184.↑
Rades D, Stalpers LJA, Veninga T et al.. Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression. J Clin Oncol 2005;23:3366–3375.
