The objective of this article is to present a concise summary of the most recent evidence-based guidelines in the management of metastatic brain tumors developed by the American Association of Neurologic Surgeons (AANS), Congress of Neurologic Surgeons (CNS), and the AANS/CNS Joint Section on Tumors in 2010. Target populations include patients with newly diagnosed metastases as well as recurrent or progressive lesions. The roles of radiotherapy, surgical resection, and stereotactic radiosurgery along with combination therapies are reviewed. Other topics include the role of chemotherapy, anticonvulsants, steroids, and investigational therapies.
Metastatic tumors of the brain are defined as secondary lesions that have spread from a primary cancer originating in another system. It is difficult to generate precise data on the incidence of these lesions because they are poorly studied. It is estimated that 1.4 million Americans are diagnosed with cancer every year. Approximately 20% to 40% of these patients with systemic cancer will develop a metastasis to the brain making this disease roughly 4 to 5 times more common than primary brain tumors.
Any attempt to develop strong guidelines based on evidence requires careful definition of the target population, the interventions used, and the measured outcomes. The concept of defining a disease as a metastatic lesion originating from elsewhere implies a wide variation in pathologic presentation and natural course that can depend on several factors. A summary of these variables can be categorized into patient-specific (age, neurologic status, and presence of medical comorbidities), brain lesion-specific (size, location, and number of brain lesions), and tumor-specific (extent and prognosis of the systemic cancer). These 8 variables alone can vary widely from patient to patient, making a rigid algorithm for patient treatment almost impossible to devise given the current state of medical knowledge. Nevertheless, a systematic review of the large number of peer-reviewed publications on this subject can be extremely useful to the practitioners of neurosurgery, radiation oncology, neuro-oncology, and also medical oncology.
The American Association of Neurologic Surgeons (AANS), the Congress of Neurologic Surgeons (CNS), and the AANS/CNS Joint Tumor Section jointly funded an initiative to set up a Management of Brain Metastases Guideline (MBMG) panel to address this issue. The panel included 17 clinical experts from surgical neuro-oncology, radiation oncology, and medical neuro-oncology. A comprehensive electronic literature search from the past 20 years was initiated with articles dating as recently as April 2009. The search yielded 16,966 candidate articles that were subsequently screened for relevance to the particular topic. Screened articles were then reviewed in accordance to the evidence classification adopted by the AANS/CNS ( Table 1 ). Each eligible study was assigned to a class based on study design alone. The levels of recommendations made (see Table 1 ) were based on aspects of study quality as well as design. If there was a consensus by the panel regarding methodological concerns of certain studies, for example, it would warrant a decrease in the level of recommendation.
| Evidence Classification | |
|---|---|
| Class I | Evidence provided by 1 or more well-designed randomized controlled clinical trials, including overview (meta-analyses) of such trials |
| Class II | Evidence provided by well-designed observational studies with concurrent controls (eg, case control and cohort studies) |
| Class III | Evidence provided by expert opinion, case series, case reports, and studies with historical controls |
| Levels of Recommendation | |
| Level 1 | Generally accepted principles for patient management that reflect a high degree of clinical certainty (usually this requires Class I evidence, which directly addresses the clinical questions or overwhelming Class II evidence when circumstances preclude randomized clinical trials) |
| Level 2 | Recommendations for patient management that reflect clinical certainty (usually this requires Class II evidence or a strong consensus of Class III evidence) |
| Level 3 | Other strategies for patient management for which the clinical utility is uncertain (inconclusive or conflicting evidence or opinion) |
The panel organized its review around 8 clinical questions that corresponded to the 8 practice guideline papers that form the major subject of this article. The 8 questions were segregated by target population into 3 categories: 4 questions pertained to patients with newly diagnosed brain metastasis, 1 question pertained to previously treated patients who present with recurrent or progressive metastasis, and 3 questions pertained to all patients with brain metastasis.
It is thought that patients with untreated brain metastasis have a median survival of approximately 1 month with mortality usually related to neurologic compromise. The ultimate goal of treatment is to minimize the effects of these lesions while preserving neurologic function. This goal acknowledges the limitations in attempting to prolong overall survival by altering the course of systemic disease outside the nervous system. There are 3 main treatments that are considered for patients presenting with a newly diagnosed brain metastasis: whole brain radiation therapy, surgical resection, and stereotactic radiosurgery. Each is thought to provide benefit in certain clinical scenarios and is the primary focus of the review.
The role of radiation
Whole-brain radiation therapy (WBRT) has been the standard treatment for all patients with brain metastasis. The rationale behind treatment outside of the tumor bed is the prevention of widely disseminated recurrent metastases throughout the brain. Because the brain can generally tolerate radiation better than other organs, WBRT also has a role in local tumor control. There are certain histopathologic tumor subgroups (small cell lung cancer, leukemia, lymphoma, germ cell tumors, multiple myeloma) that are considered radiosensitive and treated almost exclusively with WBRT. Conversely, other tumor histopathologies, such as melanoma, renal cell carcinoma, and sarcoma, are radioresistant. Between these extremes lay the vast majority of patients with common tumor histopathologies, such as breast cancer and non-small-cell lung cancer. Given the wide variety of presentations based on the variables previously mentioned, a general guideline cannot be applied to everyone. Rather, it is recommended that the guidelines be taken in the context of a multidisciplinary treatment paradigm to choose the optimal course of therapy. A risk to consider when giving WBRT is the development of neurocognitive deficits. These deficits can be subtle and easily missed on many routine medical examinations or basic mental evaluations, such as the Mini-Mental Status Examination. Nevertheless, they can be disturbing to both patients and families.
WBRT Alone versus Combination Surgical Resection and WBRT
Seven studies were reviewed by the MBMG panel to generate a Level 1 recommendation stating that Class I evidence supports the combination of surgical resection plus postoperative WBRT, as compared with WBRT alone, in patients with good performance status (functionally independent and spending less than 50% of the time in bed) and limited extracranial disease. There is insufficient evidence to make a recommendation for patients with poor performance scores, advanced systemic disease, or multiple brain metastases.
Optimal Dosing/Fractionation Schedule for WBRT
A total of 23 studies were reviewed by the MBMG panel to generate a Level 1 recommendation stating that Class I evidence suggests that altered dose/fractionation schedules of WBRT do not result in significant differences in median survival, local control, or neurocognitive outcomes when compared with standard WBRT dose/fractionation. (ie, 30 Gy in 10 fractions or a biologically effective dose [BED] of 39 Gy 10 ). This evidence was generated by performing a meta-analysis of the multiple studies by expressing several different radiation schedules in terms of the BED, which takes into account the total dose of radiation, fraction size, and overall time to deliver the radiation and presume repair of irradiated tissue. The standard dose previously mentioned served as the control dose; none of the trials with low-dose regimens or high-dose regimens relative to the control dose showed a significant difference in overall survival.
WBRT in Different Tumor Histopathologies
The MBMG panel was able to identify only 1 Class III article on this subject and was, therefore, unable to support the choice of any particular dose/fractionation regimen based on histopathology.
The role of surgery
The question of surgical resection arises in patients presenting with brain metastasis. It is the responsibility of the treating neurosurgeon to determine whether it is possible to resect the lesion without causing further neurologic deficit. The brain lesion-specific variables previously mentioned are critically important factors when considering options other than radiation alone. The brain-lesion specific variables of size, number, and location of lesions can be best determined by a gadolinium-enhanced MRI scan or, if unavailable, CT scan with contrast of the brain.
For size , surgical resection can be thought of as a cytoreductive strategy to reduce the overall tumor burden for other therapies. In this scenario, tumors less than 0.5 cm in diameter may be too small to warrant an exclusive surgical intervention; whereas, those greater than 3 cm may not be effectively treated by any modality other than surgery. Size may be a complicating factor if there is sufficient mass effect to compromise neurologic function. An easily accessible tumor in the posterior fossa or temporal lobe, for example, can cause significant neurologic compromise because of the risk of compression to adjacent structures. In these scenarios, there may not be sufficient time for nonsurgical therapies to work.
For number , it is generally thought that resection of more than 1 lesion via multiple craniotomies is inadvisable. One may consider surgery for multiple, large metastatic lesions with mass effect that may be amenable to surgery or multiple lesions that may be accessible through a single craniotomy. Another indication for surgery in the face of multiple metastases is for biopsy for diagnosis in the absence of a known primary source. Approximately 37% to 50% of patients with brain metastases with primary cancers that are solid tumors will present with only 1 lesion. Given this statistic, many patients will be candidates for surgical resection.
Regarding location , the question arises as to whether the lesion is accessible through standard neurosurgical approaches with minimal risk of damage to eloquent structures. Again the extremes of a 1-cm lesion in the superficial cortex of the right frontal lobe (resectable) versus in the midbrain (nonresectable) bound a variety of scenarios that should be evaluated on a case by case basis by the treating neurosurgeon.
Combination Surgical Resection Plus WBRT versus Surgical Resection Alone
The MBMG panel reviewed 4 studies, including 1 randomized control trial (RCT). Based on these studies, a Level 1 recommendation stated that combination surgical resection followed by WBRT represents a superior treatment modality, in terms of improving tumor control at the original site of the metastasis and in the brain overall, when compared with surgical resection alone. These patients may still benefit from aggressive local control even with uncontrolled systemic disease. However, they usually have a Karnofsky Performance Score (KPS) greater than or equal to 70. The outcomes of overall survival and time with KPS greater than or equal to 70 were not significantly different. This finding may be caused by progression of systemic disease.
The role of surgery
The question of surgical resection arises in patients presenting with brain metastasis. It is the responsibility of the treating neurosurgeon to determine whether it is possible to resect the lesion without causing further neurologic deficit. The brain lesion-specific variables previously mentioned are critically important factors when considering options other than radiation alone. The brain-lesion specific variables of size, number, and location of lesions can be best determined by a gadolinium-enhanced MRI scan or, if unavailable, CT scan with contrast of the brain.
For size , surgical resection can be thought of as a cytoreductive strategy to reduce the overall tumor burden for other therapies. In this scenario, tumors less than 0.5 cm in diameter may be too small to warrant an exclusive surgical intervention; whereas, those greater than 3 cm may not be effectively treated by any modality other than surgery. Size may be a complicating factor if there is sufficient mass effect to compromise neurologic function. An easily accessible tumor in the posterior fossa or temporal lobe, for example, can cause significant neurologic compromise because of the risk of compression to adjacent structures. In these scenarios, there may not be sufficient time for nonsurgical therapies to work.
For number , it is generally thought that resection of more than 1 lesion via multiple craniotomies is inadvisable. One may consider surgery for multiple, large metastatic lesions with mass effect that may be amenable to surgery or multiple lesions that may be accessible through a single craniotomy. Another indication for surgery in the face of multiple metastases is for biopsy for diagnosis in the absence of a known primary source. Approximately 37% to 50% of patients with brain metastases with primary cancers that are solid tumors will present with only 1 lesion. Given this statistic, many patients will be candidates for surgical resection.
Regarding location , the question arises as to whether the lesion is accessible through standard neurosurgical approaches with minimal risk of damage to eloquent structures. Again the extremes of a 1-cm lesion in the superficial cortex of the right frontal lobe (resectable) versus in the midbrain (nonresectable) bound a variety of scenarios that should be evaluated on a case by case basis by the treating neurosurgeon.
Combination Surgical Resection Plus WBRT versus Surgical Resection Alone
The MBMG panel reviewed 4 studies, including 1 randomized control trial (RCT). Based on these studies, a Level 1 recommendation stated that combination surgical resection followed by WBRT represents a superior treatment modality, in terms of improving tumor control at the original site of the metastasis and in the brain overall, when compared with surgical resection alone. These patients may still benefit from aggressive local control even with uncontrolled systemic disease. However, they usually have a Karnofsky Performance Score (KPS) greater than or equal to 70. The outcomes of overall survival and time with KPS greater than or equal to 70 were not significantly different. This finding may be caused by progression of systemic disease.
Related posts:
Review of Imaging Techniques in the Diagnosis and Management of Brain Metastases
Radiotherapy for Brain Metastases
Management of Skull Base Metastases
Radiosurgical Management of Brain Metastases
Neurocognitive and Quality of Life Measures in Patients with Metastatic Brain Disease
Investigational Therapies for Brain Metastases
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