Differential Diagnosis

Several neurological conditions may mimic brain metastases both clinically and radiographically. A primary brain tumor must be a consideration, especially in patients with a single brain mass. This is a particularly important consideration in patients with breast cancer and a dural-based tumor (Schoenberg et al., 1975). Abscess, demyelination, progressive multifocal leukoencephalopathy, cerebrovascular disease, and the effects of radiation or chemotherapy also simulate brain metastases. Although the clinical syndrome and the neuroimaging studies usually provide a diagnosis, brain biopsy is sometimes required.

Neuroimaging

Neuroimaging advances since the early 1970s have made the diagnosis of brain metastases relatively easy in almost all cases. Complete coverage of this topic is elsewhere in this section; discussion here is limited to recent comparisons of various imaging modalities. Noncontrasted MRI is as sensitive as contrast-enhanced CT for detection of brain metastases. Use of gadolinium-containing contrast agents dramatically improves the sensitivity of MRI, making it markedly superior to contrast-enhanced CT scanning. Triple-dose administration of contrast further improves the sensitivity of MRI. Although the two dosages are equivalent for detecting metastases larger than 1 cm in diameter, triple-dose studies demonstrate three times as many metastases smaller than 0.5 cm in diameter (Yuh et al., 1995). Delayed imaging after standard dose contrast is intermediate in sensitivity between single- and triple-dose gadolinium.

The differentiation of patients with one brain metastasis from those with multiple metastases has important therapeutic implications. In the pre-MRI era, approximately half of all patients had a single brain metastasis. Currently, 70% to 75% of patients with brain metastases have multiple metastases when studied with MRI. Lung cancer and melanoma are somewhat more likely to produce multiple cerebral metastases, whereas renal cell, breast, and colon cancer tend to produce single metastases. A distinction exists between single and solitary brain metastases. A solitary brain metastasis occurs in a patient with a single brain lesion and no systemic metastases, whereas single brain metastasis implies nothing about the extent of cancer elsewhere in the body.

Management

Supportive Care

Although other chapters address corticosteroids and antiepileptic drug (AED) usage, a few comments pertinent to their rational use in brain metastases are appropriate. Corticosteroids improve symptoms associated with brain metastases in two-thirds of patients. Their use improves median survival in otherwise untreated patients from 1 to 2 months. One randomized controlled trial examined different doses in patients with brain metastases. These patients all had a Karnofsky Performance Score (KPS) less than or equal to 80 (Table 52F.1). All patients received standardized whole-brain radiotherapy (WBRT) after receiving dexamethasone for 1 week. In the first part of the trial, with patients randomized to receive either 8 or 16 mg daily in divided doses, the two groups did equally well, with slightly less toxicity related to steroids in the lower-dose group. Other patients were then randomized to either 4 or 16 mg daily. The lower-dose group did slightly less well at 7 days (although the difference was not significant) and better at 28 days, with significantly less toxicity than the high-dose group. The authors concluded that unless patients were in danger of herniation, 2 mg twice daily was an appropriate starting dose (Vecht et al., 1994).

Table 52F.1 Karnofsky Performance Status

KPS 100	Normal; no complaints, no evidence of disease
KPS 90	Able to carry on normal activity; minor signs or symptoms of disease
KPS 80	Normal activity with effort; some signs or symptoms of disease
KPS 70	Cares for self; unable to carry on normal activity or do active work
KPS 60	Requires occasional assistance but is able to care for most personal needs
KPS 50	Requires considerable assistance and frequent medical care
KPS 40	Disabled; requires special care and assistance
KPS 30	Severely disabled; hospitalization is indicated, although death not imminent
KPS 20	Very sick; hospitalization necessary, active support treatment necessary
KPS 10	Moribund; fatal processes progressing rapidly
KPS 0	Dead

Approximately 10% to 20% of patients with brain metastases present with seizures and require treatment with standard anticonvulsants. The use of prophylactic anticonvulsants in patients who have not had seizures is controversial. Fewer than 20% of these patients experience seizures later in the course of their illness, and this risk does not appear to be reduced with prophylactic anticonvulsants. Consequently, the American Academy of Neurology has issued a practice parameter recommending against the prophylactic use of anticonvulsants in patients with brain metastases who have not had a seizure (Glantz et al., 2000). Potential exceptions to this guideline include patients with metastases from melanoma (which may be more epileptogenic because of multiplicity or hemorrhage), tumors in motor cortex, or concomitant parenchymal and leptomeningeal brain metastases. Although the efficacy is similar among the available anticonvulsants, differences in pharmacokinetic profile may influence which agent is used. Anticonvulsants metabolized by the P450 system interact with corticosteroids and many common antineoplastic therapies such as irinotecan and erlotinib. Consequently, the effectiveness of a given dosage of dexamethasone may be decreased, and tumor exposure to an antineoplastic agent may be reduced. Examples of enzyme-inducing anticonvulsants include phenytoin and carbamazepine. Alternatively, non–enzyme inducing agents such as levetiracetam and pregabalin do not interact with other medications administered concurrently.

Radiation Therapy

The goals of radiation therapy (RT) are to alleviate neurological deficits due to tumor and to shrink the tumors and prolong survival. In terms of meeting the first goal, approximately three-fourths of patients undergoing RT experience symptom palliation, and two-thirds maintain this improvement (Cairncross et al., 1980). With respect to tumor shrinkage, this depends on the size and radiosensitivity of the metastasis. With standard doses of WBRT, 37% of patients with SCLC, 35% with breast cancer, 25% with squamous cell cancer, and 14% with non-breast adenocarcinomas achieve a complete response (CR) (Nieder et al., 1997). Tumors with a pretreatment volume of less than 0.5 mL had a 100% CR rate, whereas tumors with a pretreatment volume larger than 10 mL had little likelihood of disappearing in the same study. These results highlight the unfortunate fact that CR of brain metastasis to WBRT is the exception, not the rule.

The Radiation Therapy Oncology Group (RTOG) has conducted a series of clinical trials exploring and comparing the results of different dose-fractionation schemes. Schedules ranging from 5 fractions of 500 cGy to 20 fractions of 250 cGy have resulted in similar outcomes. With all of the schedules, the median survival with WBRT is approximately 4 months, and the 1-year survival is 15%. Approximately 40% of patients succumb to their intracranial disease; the remainder die from progression of extracranial tumor.

The large RTOG database has permitted the application of statistical techniques such as recursive partitioning analysis (RPA) to separate patients with brain metastases treated with WBRT into different prognostic classes based on clinical features at presentation. Patients with brain metastases can be divided into three classes. Class 1 consists of patients with a KPS greater than or equal to 70 (see Table 52F.1), age younger than 65 years, primary site of tumor resected or controlled with treatment, and no extracranial sites of metastatic tumor. Such patients have a median survival of 7.1 months. Class 3 is composed of all patients whose KPS is less than 70; the median survival in this group is only 2.3 months. Class 2 contains all patients who do not fall into classes 1 and 3; class 2 patients have a median survival of 4.2 months (Gaspar et al., 1997). Subsequent studies have validated these results (Gaspar et al., 2000). The limited number of patients with KPS less than 70 in the RTOG dataset precluded further analysis of this population. Yet it is recognized that other factors may predict outcome. Lutterbach et al. performed a single institutional analysis that not only validated the original RPA classification but also broke down RPA class 3 patients with KPS below 70 into three groups based on age (<65 versus ≥ 65), primary tumor status, and number of lesions (single versus multiple). Survival differences among the groups were statistically significant and did not overlap with class 2 (Lutterbach et al., 2002). Sperduto et al. reanalyzed the RTOG database that included patients from a study completed after the initial RPA review. In addition to age, performance status, and the presence of extracranial metastases, they identified the number of cerebral lesions to be predictive of survival. Four distinct groups were defined whose survival was statistically different (11, 6.9, 3.8, and 2.6 months) (Sperduto et al., 2008).

Radiation sensitizers with selective tumor uptake offer the theoretical promise of increasing the efficacy of WBRT. A recent randomized clinical trial of motexafin gadolinium administered prior to each radiation treatment did not find any prolongation of survival or time to intracranial tumor progression. However, patients with brain metastases from NSCLC had significantly prolonged time to tumor progression with this agent. A confirmatory study of patients with NSCLC failed to show a statistically significant benefit in outcome, although statistical factors and differences in treatment among the participating institutions may have negatively influenced the results. The future of motexafin gadolinium remains uncertain (Mehta et al., 2009). RSR-13, an allosteric modifier of hemoglobin that allows more oxygen to be released to hypoxic tissue and may thereby sensitize brain metastases to radiation, has shown promising results in phase II studies. A phase III trial of WBRT plus supplemental oxygen with or without RSR-13 failed to demonstrate improvement in overall or progression-free survival in patients with brain metastases (Suh et al., 2006). However, among the subgroup with breast cancer, the addition of RSR-13 reduced death rate and improved quality-adjusted survival (Scott et al., 2007). Caution must be used in interpreting the results, as they were derived from subgroup analysis and confirmation is required.

Radiation Toxicity

With standard fractionation schemes, WBRT is tolerated well. Patients should expect temporary alopecia and fatigue. Headache and nausea occasionally occur but are generally alleviated with corticosteroids and antiemetics. In poor-prognosis patients, the acute side effects of WBRT must be considered, however, as they may have a significant impact on the quality of the remaining short predicted lifespan (Komosinska et al., 2010).

Long-term survivors of brain metastases are at risk of suffering late complications of WBRT. Of WBRT recipients for brain metastases, as many as 10% to 30% develop cognitive impairment by 1 year if radiation doses per fraction exceed 300 cGy (Behin and Delattre, 2002). Symptoms commonly include poor short-term memory, abulia, gait unsteadiness, and urinary urgency. MRI frequently reveals extensive symmetrical periventricular white matter changes termed radiation leukoencephalopathy, ventriculomegaly, and sometimes cortical atrophy. The clinical picture may resemble normal-pressure hydrocephalus, but a positive durable response to ventriculoperitoneal shunt is uncommon (DeAngelis et al., 1989). Because the risk of this complication is greater with larger fraction sizes, many radiation oncologists treat patients with good prognosis with 20 fractions of 200 cGy or similar regimens.

The exact incidence of neurocognitive impairment from WBRT is unknown. Neurocognitive decline in the setting of cancer is multifactorial, and establishing attribution is difficult. Progressive central nervous system (CNS) disease, concurrent use of chemotherapy and other pharmacological agents (anticonvulsants, etc.), depression/anxiety, and neurological impairment, among other factors, may contribute. It is now recognized that patients with cancer have cognitive impairment prior to any treatment or intervention. To date, many studies have relied on Mini-Mental Status assessment, which is not optimal. Comprehensive neurocognitive assessments that evaluate multiple cognitive domains provide more meaningful data but require expertise and are more expensive and labor intensive. Neurocognitive endpoints are increasingly being recognized as critical determinants of outcomes and are being used as primary measures of effectiveness in modern cerebral metastases studies. In contrast, overall survival is often used as a primary endpoint despite the fact that the majority of patients die of concurrent systemic disease.

Prophylactic Cranial Irradiation

Brain metastases are extremely common in SCLC, being present in 10% of patients at diagnosis, increasing to 20% during therapy, and 35% at time of autopsy (Jeyapalan and Henson, 2002). At 2 years post diagnosis, the cumulative risk of brain metastasis is 47% for patients with limited disease and 69% for those with extensive disease. Presumably the brain is a pharmacological sanctuary for microscopic tumor against systemic chemotherapy, which does not penetrate the intact blood-brain barrier. This has led to numerous trials designed to test whether prophylactic cranial irradiation (PCI) would decrease the incidence of brain relapse and improve survival in patients who achieved systemic CR. A consistent finding was that PCI significantly decreased the risk of cerebral metastases. An often-cited metaanalysis of these studies indicated that PCI reduced the risk of subsequent brain metastasis (59% versus 33% at 3 years) and modestly increased 3-year survival from 15.3% to 20.7% (P = .01) (Auperin et al., 1999). There was also a suggestion of a dose response, although this was not confirmed in a recent randomized study in which patients were randomized to 25 or 36 Gy (Le Pechoux et al., 2009). The role of PCI in patients with incomplete response to treatment or with extensive small-cell lung cancer remains unclear. The poor prognosis of these patients (median survival of 9 months) brings into question the utility of PCI. Slotman et al. randomized patients with extensive small-cell lung cancer that responded to treatment to observation or PCI. Patients treated with PCI had a cumulative risk of symptomatic brain metastases of 14.6% compared to 40.4% among observation patients. Patients treated with PCI also had a significantly longer overall survival (Slotman et al., 2007). Controversy still remains over whether the benefits of PCI outweigh its toxicities, particularly leukoencephalopathy. Two large prospective randomized trials of PCI did not document increased neuropsychological deficits among PCI recipients. Others argue that the small numbers of long-term survivors in these trials precluded accurate assessment of the risk of leukoencephalopathy, and that because PCI benefited only about a fourth of its recipients, it should not be considered standard therapy.

Surgery

In determining whether or not surgery is appropriate, the patient’s performance status and extent of extracranial disease are the most important considerations. For several decades, neurosurgeons resected single brain metastases in selected patients and argued that surgery produced better results than radiotherapy alone, particularly noting improvement in the percentage of long-term survivors. In 1990, a randomized controlled trial verified the neurosurgeons’ contention. In this study, eligible patients had a single surgically accessible metastasis identified by contrast CT or MRI scan. Patients with highly radiosensitive primary tumors were excluded. Enrolled patients were randomized to biopsy followed by WBRT (36 Gy in 12 fractions) versus resection and WBRT. Patients who underwent surgical resection of the metastasis followed by RT developed fewer local recurrences (20% versus 52%) and significantly improved survival (40 weeks versus 15 weeks) compared to those patients who received only a biopsy and RT. Patients who underwent surgical resection also had improved performance status and a reduced risk of dying as a result of neurological causes. Multivariate analysis showed that surgery and longer time between diagnosis of the primary tumor and the development of brain metastases were associated with increased survival, whereas disseminated disease and increasing age were associated with decreased survival (Patchell et al., 1990). Thus in patients with surgically accessible single brain metastases and absent or controlled systemic cancer, surgical resection became the standard of care.

The role of WBRT following resection of a single metastasis is uncertain. In one trial, patients with a single metastasis on gadolinium MRI scan who underwent complete resection were randomized to receive either 50.4 Gy in 28 fractions or no radiation (Patchell et al., 1998). The recurrence rate either locally or distantly in the brain was significantly reduced in the radiation group (18%) compared to the observation group (70%). However, overall survival did not differ significantly between the two groups. Radiation substantially reduced the death rate resulting from neurological causes; however, patients in the observation group who did not die of neurological causes appeared to live longer than similar patients in the radiotherapy group. There was no difference in how long patients maintained functional independence. In the absence of survival benefit to postoperative WBRT, its use must be decided on an individual case basis. For some patients and physicians, the reduction in recurrent brain metastasis and neurological death will outweigh the potential side effects of radiotherapy. Alternatively, focal radiation to the surgical bed may reduce the risk of local recurrence. Several retrospective studies examining the role of postoperative radiosurgery to the surgical bed found that focused radiation is efficacious in controlling local tumor growth and maintaining long-term quality of life (Jagannathan et al., 2009).

Stereotactic Radiosurgery

Like conventional surgery, stereotactic radiosurgery (SRS) has emerged as a means of enhancing long-term local control of brain metastases. SRS is a technique of external irradiation that uses multiple convergent beams to deliver a high single dose of radiation to a radiographically well-circumscribed treatment volume. SRS is generally administered either with a Gamma Knife apparatus or a modified linear accelerator. With either technique, the use of a stereotactic head frame and the radiation delivery system allow for great precision, with a rapid drop-off in radiation dose within millimeters of the target lesion, sparing normal brain the potentially deleterious consequences of high-dose radiation.

Numerous single-institution experiences with radiosurgery for single or oligometastatic brain lesions have been published. In a review summarizing published series comprising more than 2000 patients treated over 8 years in the 1990s, Loeffler found that SRS achieved permanent local control in more than 80% of patients, with complications in fewer than 10% (mainly radiation necrosis). Outcome appeared independent of the number of metastases treated (Loeffler et al., 1999). Median survival following SRS is approximately 9 to 10 months, very similar to surgical series. Radiosurgical treatment is also effective for metastases that have recurred following fractionated radiotherapy.

One consistent and remarkable finding across numerous SRS series is that metastases from highly radio-resistant tumors like melanoma and renal cell carcinoma, which respond very poorly to fractionated radiotherapy, respond virtually as well to SRS as tumors far more sensitive to conventional radiation. However, intracranial failure rates of highly radioresistant tumors without WBRT were 25.8% and 48.3% at 3 and 6 months, respectively, according to a recent phase II trial conducted by the Eastern Cooperative Oncology Group. Therefore, delaying adjuvant WBRT may be appropriate for some subgroups of patients with radioresistant tumors, but routine avoidance of WBRT should be approached judiciously (Manon et al., 2005).

SRS offers the potential of treating lesions in locations generally considered surgically inaccessible. Metastases in eloquent cortex, basal ganglia, thalamus, and even the brainstem can be treated with relatively low risk. A technical limitation of SRS, compared to conventional surgery, is the inability to treat metastases greater than 3.5 cm in median diameter. Another advantage of surgery is its ability to alleviate mass effect quickly. Approximately 7% of metastases treated with SRS transiently increase in diameter on scan, reflecting a radiation reaction.

According to an evidence-based review by the American Society for Therapeutic Radiation and Oncology (ASTRO), in selected patients with small (<4 cm) brain metastases (up to three in number and four in one randomized trial), radiosurgery boost with WBRT improves local brain control compared to WBRT alone. Similarly, in patients with a single brain metastasis, radiosurgery boost to WBRT improves survival. In selected patients treated with radiosurgery alone for newly diagnosed brain metastases, overall survival is not altered. However, omission of up-front WBRT was associated with markedly poorer local and distant brain control (Mehta et al., 2005).

Because the results for SRS appear similar to those from surgery, one might ask whether SRS has been proven to improve the patient’s outcome, as has surgery when administered with fractionated radiation. An RTOG clinical trial has affirmed this hypothesis by randomizing patients with one to three brain metastases to WBRT with or without radiosurgery. Patients with a single brain metastasis had a significant survival benefit as well as improved performance status from the addition of radiosurgery, as did patients younger than 50 and those in RPA class 1 (Andrews, 2004).

The relative effectiveness of radiosurgery versus surgery in patients with brain metastases has never been ascertained. A retrospective review from the Mayo Clinic compared the efficacy of neurosurgery versus radiosurgery in local tumor control and patient survival in patients with solitary brain metastases. There was no significant difference in patient survival (P = 0.15) between the 74 neurosurgery patients and the 23 radiosurgery patients. The 1-year survival rates for the neurosurgery and radiosurgery groups were 62% and 56%, respectively. There was a significant (P = 0.020) difference in local tumor control, but none of the radiosurgery group had local recurrence compared with 19 (58%) in the neurosurgery group (O’Neill et al., 2003). Although surgeons occasionally remove two or even three brain metastases, surgery is generally restricted to single lesions, whereas multiple lesions generally present no problems for radiosurgery. Radiosurgery appears more cost-effective than surgery, although surgery alleviates symptoms of mass effect much more rapidly and reliably than SRS. Phase III trials comparing these two modalities have been proposed, but no major multicenter study has yet been undertaken.

The role of WBRT following radiosurgery for brain metastases is also uncertain. Two retrospective cohort studies have examined this issue. Pirzkall et al. (1998) compared outcomes in 158 patients treated with radiosurgery alone versus 78 receiving radiosurgery plus fractionated WBRT. All patients had three or fewer brain metastases. The overall median survival was 5.5 months, with no difference between treatment groups. However, median survival in patients without extracranial tumor was increased in patients getting both forms of radiation (15.4 versus 8.3 months, P = .08). A trend existed for superior local control in patients getting combined therapy. A similar smaller study also found no difference in median survival (11 months) or 1-year progression-free survival. Brain relapse was significantly more common in patients receiving radiosurgery alone; however, most patients who did relapse could still be salvaged. In a prospective randomized Japanese study of 132 patients comparing SRS alone with SRS plus WBRT there was increased risk of tumor recurrence both locally (30% versus 14%) and distantly in the brain (52% versus 18%) in those who did not receive up-front WBRT. However, increased risk of intracranial failure was not associated with decreased survival, increased risk of neurological death, or worse neurocognitive performance (Aoyama et al., 2006). Similarly, Chang et al. randomized patients with three or less cerebral metastases to radiosurgery with or without WBRT. The primary endpoint in this study, however, was neurocognitive outcome at 4 months as assessed by Hopkins Learning Verbal Test-Revised. The study was halted by the data-monitoring committee after only 58 patients were enrolled according to the early stopping rules because outcomes were inferior in the combined group (Chang et al., 2009). A more recent study by the European Organization of Research and Treatment of Cancer of 359 patients with one to three brain metastases randomized to adjuvant WBRT or observation after radiosurgery or surgical resection evaluated duration of functional independence (primary endpoint), which did not differ between the two groups. Overall survival and global quality of life were also similar between two groups. The incidence of and time to intracranial progression, however, was significantly greater in the observation group, as was rate of neurological death. Neurocognitive endpoints were not included in this study. Thus, the issue of WBRT remains unresolved, although it is clear that cognitive and quality-of-life endpoints, rather than survival, may be the determinant of whether or not to add WBRT for patients receiving SRS in oligometastatic brain disease. An ongoing U.S. trial will further compare WBRT plus SRS with SRS alone and explore neurocognitive endpoints.

The role of WBRT in patients with oligometastases (four or less lesions) treated with radiosurgery is perhaps one of the greatest debates in neuro-oncology. At the center of the uncertainty is what has a more deleterious effect on neurological status and cognition, CNS disease progression or treatment toxicity. It is recognized that the risk of CNS disease progression is greater among patients treated with focal therapeutics alone. Brain tumor burden has been associated with cognitive impairment. Aoyama et al. (2007) noted that at baseline prior to treatment, MMSE scores correlated with the extent of brain edema and total volume of brain metastases. Among patients treated with WBRT, lesion volume was the only predictor of global neurocognitive impairment prior to therapy (Meyers et al., 2004). Therefore, by extension, progressive disease and the associated increase in tumor volume may lead cognitive and neurological deterioration. In the randomized study reported by Aoyama et al., patients receiving radiosurgery alone experienced a higher rate of neurological decline than those treated with whole-brain radiation. The difference was attributed to a higher rate of brain tumor recurrence (Aoyama et al., 2007). Similarly, in an analysis of patients enrolled in RTOG 91-04, all of whom were treated with WBRT, clinically significant decline in MMSE was noted only among those with uncontrolled brain metastases (Regine et al., 2001). In a retrospective review of patients with cerebral metastases treated with SRS alone, Regine et al. (2002) noted that tumor recurrence was associated with neurological symptoms and deficits in 71% and 59% of patients, respectively; 17% of patients were too impaired to undergo salvage therapy. Consequently, the prevention of progressive brain disease may preserve a patient’s neurological status. Alternatively, with vigilant radiographic surveillance, progressive disease may be captured in a presymptomatic state, allowing patients to be salvaged prior to neurological decline. In a prospective study of patients with up to three brain metastases treated with SRS followed by vigilant observation, only 37% of recurrences were symptomatic. In the remaining patients, recurrence was diagnosed radiographically before symptom onset. Ninety-one percent of patients received salvage treatment, and 58% of symptomatic patients improved neurologically (Luterbach et al., 2003). In addition, deferring WBRT preserves this therapeutic as a future salvage option. A significant limitation of the data is the lack of long-term assessments. While tumor progression may impact cognitive status in the short term (Aoyama et al., 2007; Regine et al., 2001), survivors may experience the chronic adverse effects of treatment. Despite initially being stable, MMSE among patients treated with WBRT was noted to decline after 2 years (Aoyama et al., 2007). Although this exceeds survival in the majority of patients, it may become more of an issue as therapeutics improve in the future.