Brain Metastases

Nancy U. Lin

Brian M. Alexander

Ian F. Dunn

The management of patients with brain metastases from breast cancer remains a challenging clinical problem. The goals of treatment are to extend life and improve or stabilize patient symptoms while minimizing treatment-related toxicities. Of note, because of their unique location, even relatively small tumors in the central nervous system (CNS) may result in neurological symptoms that negatively impact quality-of-life (QOL). Intracranial involvement with breast cancer can also occur as leptomeningeal involvement, and this is covered in Chapter 78. Because most systemic therapies do not effectively treat brain metastases, progression in the brain can represent a significant mortality risk. Indeed, for a subset of women with advanced breast cancer, control of CNS disease has become a vital component of overall disease control as well as QOL.

INCIDENCE AND RISK FACTORS

Because of incomplete reporting, the true incidence of brain metastases is difficult to determine with certainty. Registry data from the Netherlands and the United States indicate that among patients with primary lung, breast, melanoma, renal, and colorectal cancers presenting at any stage, the combined incidence of brain metastases is between 8.5% and 9.6% (1, 2). Of patients diagnosed with brain metastases, between 13% and 20% will carry a primary diagnosis of breast cancer, making breast cancer the second most common cause of CNS involvement, after lung cancer.

Clinical factors such as disease stage, young age, and African-American ethnicity are associated with an increased risk of developing brain metastases (1). In patients presenting with localized, early-stage breast cancer, overall, less than 5% will ultimately be diagnosed with brain metastases. Among patients with advanced breast cancer not selected by tumor subtype, brain metastases will be diagnosed in approximately 15% (1). These figures likely are an underestimate of the true incidence, given that in autopsy studies from the 1970s and 1980s, up to 30% of patients were found to have CNS involvement at the time of death (3).

Biological risk modifiers include tumor grade, ER status, HER2 status, and BRCA mutation status. In studies of early breast cancer patients prior to the widespread introduction of adjuvant trastuzumab, HER2 has been shown to be a risk factor for CNS relapse (4, 5). Within the HER2-positive subset, hormone receptor status appears to further influence the risk of CNS relapse, such that patients with ER-negative/HER2-positive tumors experience a higher rate of CNS involvement compared to patients with ER-positive/HER2-positive tumors (6). The risk of CNS as first site of relapse does not appear to be diminished by the use of adjuvant trastuzumab, though the absolute risk is low (<5%) (7). However, in the HERA trial, the overall risk of CNS relapse (first plus subsequent sites) was not increased with the use of adjuvant trastuzumab (8). In the advanced setting, multiple groups have reported a 25% to 55% incidence of CNS relapse among patients with HER2-positive breast cancer, which is significantly higher than historical control data of patients unselected by tumor subtype (9, 10 and 11). Among deceased patients in the HERA trial, approximately half had developed brain metastases prior to death (8).

There is also increasing evidence that ER-, PR-, and HER2-negative (i.e., triple-negative) tumors are associated with a high risk of CNS relapse. In a database of 1,434 patients with early-stage breast cancer treated with breast conserving therapy, the 5-year cumulative incidence of brain metastases for patients with triple-negative tumors was 7.4%, compared with 0.1% in patients with Luminal A tumors (5). Among over 15,000 women presenting with Stage I-III breast cancer in the National Comprehensive Cancer Network breast cancer
database, triple-negative subtype was strongly associated with CNS relapse, relative to the hormone receptor-positive/HER2-negative subtype (OR 3.5, 95% CI, 2.1-5.85, p < .001) (12). The median time to brain metastasis diagnosis is also significantly shorter in triple-negative, compared to ER positive/HER2-negative tumors (5, 13). In patients with metastatic triple-negative breast cancer, it has been reported that between 25% and 46% of patients will eventually develop brain metastases (14, 15).

Of interest, deleterious BRCA1 alterations are also associated with a high rate of CNS relapse (16). Whether this is purely attributable to the association between BRCA1 carrier status and triple-negative breast cancer, or whether there is an additional phenotypic difference conferred by nonfunctional BRCA1 is not clear at this time. Of note, in at least one study, BRCA1 mutation carriers were more likely to develop brain metastases, even when compared to noncarriers with triple-negative tumors (17).

METHOD OF SPREAD AND DISTRIBUTION

Parenchymal brain metastases are thought to arise from hematogenous dissemination of tumor cells. Involvement of the cerebrum and cerebellum are common; brainstem involvement remains relatively uncommon. Older studies indicated that approximately half of patients with brain metastases presented with a single lesion. However, with the introduction of magnetic resonance (MR) imaging, a significantly more sensitive technique, current series indicate that only about one-fourth of patients with brain metastases have a confirmed single lesion at initial presentation. The term solitary brain metastasis indicates a single brain lesion in the absence of systemic metastases.

CLINICAL MANIFESTATIONS

Because brain imaging is not generally part of routine clinical care for asymptomatic patients with breast cancer, brain metastases are most commonly diagnosed in the setting of new neurological symptoms. Headaches are present in up to half of patients and are commonly bifrontal. In patients with single metastasis or a dominant lesion, there may be a predominance of the pain on the side of the metastasis. Coexisting nausea or emesis occurs in about half of patients with headaches, and is a predictive factor for the presence of brain metastases. Focal neurologic dysfunction is the presenting symptom in 20% to 40% of patients. Hemiparesis is the most common focal complaint. The distribution of symptoms depends upon the location of the metastases and the presence or absence of surrounding edema. Patients who present with cranial nerve deficits should be thoroughly evaluated for evidence of leptomeningeal or base of skull involvement.

Cognitive dysfunction, including mental status changes, memory problems, or mood or personality changes, is the presenting symptom in one-third of patients. Frequently, neurological examination will elicit additional deficits of which the patient is unaware. However, medications, metabolic abnormalities, and infections are more common causes of encephalopathy in cancer patients than brain metastases, and should be included in the differential diagnosis of altered mental status.

Seizures are the presenting symptom in 10% to 20% of patients with brain metastases, and an additional 10% to 26% will develop seizures at some time during the course of their illness. Supratentorial involvement increases the risk of seizure, whereas seizures are quite uncommon in patients with posterior fossa lesions.

In contrast to melanoma or choriocarcinoma, brain metastases from breast cancer tend not to bleed; therefore, acute cerebral hemorrhage is rarely a presenting symptom.

DIAGNOSTIC EVALUATION

In patients presenting with suspicious neurological signs or symptoms, evaluation with computed tomography (CT) or contrast-enhanced magnetic resonance imaging (MRI) is indicated. Of these approaches, MRI is the more sensitive noninvasive, diagnostic test.

MRI detects more lesions in the posterior fossa, where beam-hardening artifact can make CT difficult to interpret. MRI is also superior in defining the number of CNS lesions, a distinction that may affect clinical recommendations. For example, in a study of 23 patients who underwent both double-dose delayed CT and contrast-enhanced MRI, MRI detected more than 67 definite lesions, compared to only 37 lesions on CT (18).

The differential diagnosis of enhancing mass lesions in a patient with breast cancer includes metastasis, primary brain tumor, abscess, demyelinating disorders, cerebral infarction, hemorrhage, progressive multifocal leukencephalopathy, and posttreatment change (i.e., radiation necrosis, post-surgical change). Radiographic features that may differentiate brain metastases from other CNS lesions include the presence of multiple lesions (which helps to distinguish metastases from primary brain tumors), localization at the junction of the gray and white matter, circumscribed margins, and relatively large amounts of vasogenic edema compared to the size of the lesion. The clinical history can also be helpful in guiding appropriate diagnostic testing. For patients with advanced breast cancer who present with multiple brain lesions, further testing may not be necessary. For patients without evidence of extracranial involvement by breast cancer, consideration should be given to tissue sampling to distinguish between metastatic breast cancer versus metastasis from a non-breast primary, primary brain tumor, or nonmalignant cause. A tissue diagnosis should also be strongly considered for patients presenting with a single brain lesion. In a randomized trial evaluating the role of surgical resection for single brain metastasis, 11% of patients were found to have an alternate diagnosis on pathologic review (19). Finally, the differential diagnosis of duralbased lesions includes meningiomas. Because the incidence of meningioma has been reported to be somewhat higher in breast cancer patients than the general population, and because imaging studies may be inconclusive, tissue diagnosis may be required (20). Thus, in any patient in whom the diagnosis of brain metastases is in doubt based upon the radiographic appearance of the lesion(s), the presence of a single lesion, or the clinical history, obtaining tissue is important to establish the diagnosis conclusively.

Another diagnostic dilemma exists in distinguishing necrosis from tumor progression in patients who have previously received whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS). One approach is to consider supplemental imaging with either positron emission tomography (PET), single photon emission CT (SPECT), functional MRI, or MR spectroscopy (21). With a detection rate of only 61% to 68% compared to contrast-enhanced MRI, ¹⁸F-flurorodeoxyglucose (FDG)-PET does not appear sufficiently sensitive for use as a screening tool for brain metastases (22, 23). However, ¹⁸FDG-PET may be helpful in distinguishing radiation necrosis from tumor progression.
In a study of 32 patients with brain metastases from any solid tumor, ¹⁸FDG-PET with MRI co-registration had a sensitivity of 86% and specificity of 80%, though not all groups have been able to replicate these findings (24). Others have found that a dynamic assessment of ¹⁸FDG uptake with PET offered higher sensitivity and specificity (25). Another potentially useful tool is Tl-201 SPECT. In one study of 72 patients, the sensitivity was reported at 91% for differentiating between radiation necrosis and tumor progression (26). Finally, a variety of newer techniques are under evaluation, including the use of alternative PET tracers (i.e.,¹⁸F-fluorocholine, ¹⁸F-flurorothymidine, or L-[methyl-¹¹C] methionine) and quantification of blood vessel tortuosity (21, 27). In cases in which the imaging studies remain equivocal, management options include following the patient carefully over time versus proceeding to a biopsy for tissue diagnosis. Symptomatic lesions may require steroids and/or an earlier therapeutic intervention such as surgical resection.

PROGNOSIS

Historically, CNS involvement tended to occur late in the course of metastatic breast cancer, and median survival was poor, on the order of 4 to 6 months. More recently, breast cancer-specific prognostic indices have sought to improve upon the Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA), a widely used, but older system which was not tumor-type specific and likely underestimated survival in breast cancer patients (28). The Graded Prognostic Assessment (GPA) examined multiple potential risk factors associated with survival in tumor-specific contexts, and found that, for patients with breast cancer, performance status was the only significant prognostic factor (29). Further refinement of the breast GPA included an analysis of the influence of tumor subtype and showed that age and tumor subtype were also prognostic in the final model, which consisted of four groups, with the most favorable group experiencing a median survival in the range of 2 years (Table 76-1) (30). Based on data from retrospective studies, it is likely that improved systemic tumor control is a major contributing factor to this difference between historical and present outcomes, particularly in patients with HER2-positive breast cancer. Although one must interpret retrospective data cautiously because of potential selection bias in terms of prescribed treatment, multiple groups have observed a substantially longer survival in patients with brain metastases who continue to receive anti-HER2 therapy following their CNS diagnosis, compared to those who received either no systemic therapy or chemotherapy without anti-HER2 therapy (31, 32 and 33). In addition, it appears that death from CNS progression (in the context of controlled extracranial disease) is substantially more common in the setting of HER2-positive disease, compared to triple-negative disease, where systemic therapy is generally less effective (10, 15). Together these data suggest that i) improvements in systemic therapy are allowing some patients to live longer than older historical estimates would predict, ii) continuation of systemic therapy is likely beneficial, particularly in patients with HER2-positive disease, and iii) pursuing more aggressive approaches in the CNS among breast cancer patients with well-controlled systemic disease and/or HER2-positive disease may be reasonable.

MANAGEMENT

The management of patients with brain metastases can be divided into symptomatic and definitive therapy. Symptomatic therapy includes the use of corticosteroids for the treatment of peritumoral edema and anticonvulsants for control of seizures, whereas definitive therapy includes treatments such as surgery, radiotherapy, chemotherapy, targeted therapy, and radiosensitizers directed at eradicating the tumor itself.

TABLE 76-1 Prognosis of Breast Cancer Patients with Brain Metastases According to the Diagnosis-Specific Breast GPA (DS-GPA)

DS-GPA Scoring Criteria
Prognostic factor	0	0.5	1.0	1.5	2.0	Patient Score
KPS	≤50	60	70-80	90-100	n/a	—
Subtype	Basal	n/a	LumA	HER2	LumB	—
Age, years	≥60	<60	n/a	n/a	n/a
Sum total						—
GPA, graded prognostic assessment; n/a, not applicable; KPS, Karnofsky performance status; Basal, ER-/PR-/HER2-negative; LumA, ER/PR positive, HER2-negative; HER2, ER/PR negative, HER2 positive; LumB, ER/PR positive, HER2 positive.
DS-GPA Score	Median Survival Time (Months; 95% CI)
0-1.0	3.4 (3.1, 3.8)
1.5-2.0	7.7 (5.6, 8.7)
2.5-3.0	15.1 (12.9, 15.9)
3.5-4.0	25.3 (23.1, 26.5)
All	13.8 (11.5, 15.9)
DS-GPA, diagnosis specific grade prognostic assessment.
Modified from Sperduto PW, Kased N, Roberge D, et al. Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol 2012;30(4):419-425.

Symptomatic Therapy

Corticosteroids

Corticosteroids are indicated in patients with symptomatic edema, and are thought to exert their effect by reducing capillary permeability, restoring arteriolar tone, and facilitating transport of fluid into the ventricular system. Most patients will improve symptomatically within 24 to 72 hours, although improvement of edema on imaging studies may not be immediately apparent. Patients who present with edema on imaging but who are asymptomatic generally do not require the prophylactic initiation of steroids.

Of the corticosteroids, dexamethasone is the most widely used because of its relatively weak mineralocorticoid activity, which reduces the potential for fluid retention. The usual starting dose is 4 mg every 6 hours, and may be preceded by a 10 mg load, depending on clinical circumstances. Because of potential adverse effects, such as myopathy, hyperglycemia, insomnia, fluid retention, gastritis, and immunosuppression, the dose of corticosteroids should be kept to the minimum effective dose and tapered during or after definitive therapy. Corticosteroid use also increases the risk of Pneumocystis jiroveci. In two case series, the median duration of dexamethasone therapy was only 10 weeks before onset of symptoms, and symptoms commonly appeared during tapering of steroid therapy (34, 35). Therefore, P. jiroveci prophylaxis should be considered for patients for whom the anticipated duration of steroid use exceeds 4 to 5 weeks.

Anticonvulsants

Approximately 10% to 20% of patients with brain metastases present with seizures, and an additional 10% to 26% will develop seizures at some time during the course of their illness. For most patients, confirmation of the diagnosis with electroencephalography is not necessary, and the use of standard anticonvulsants is generally indicated.

To determine whether the routine use of anticonvulsants is indicated in patients without a prior history of seizure, the Quality Standards Subcommittee of the American Academy of Neurology reviewed the results of twelve studies that addressed this question (36). None of the individual studies indicated a significant reduction in seizure incidence between the prophylaxis and nonprophylaxis groups. A meta-analysis of the four randomized trials indicated no difference in seizure incidence (OR 1.09; 95% CI, 0.63-1.89, p = .8), seizure-free survival (OR 1.03; 95% CI, 0.74-1.44, p = .9), or overall survival (0.93; 95% CI, 0.65-1.32, p = .7). Because of the known potential for adverse effects and drug interactions, and the lack of clear benefit, the routine use of anticonvulsants is not recommended in patients without a history of seizures. A possible exception includes patients with lesions in areas of high epileptogenicity (e.g., motor cortex), though a benefit has not been clearly demonstrated in clinical studies.

In the periprocedural setting, a meta-analysis including six controlled trials of patients receiving anticonvulsant drugs in the setting of supratentorial craniotomies has been completed. It showed a non-significant trend (p = .1) for fewer postoperative seizures, though it should be noted that the included trials were generally quite small (37). High-level randomized evidence regarding the use of prophylactic anticonvulsants in the setting of SRS is not available.

Venous Thromboembolic Disease

Venous thromboembolic (VTE) disease occurs in approximately 20% of patients with brain metastases (38). Because of the concern for intracranial hemorrhage (ICH), many clinicians are reluctant to fully anticoagulate patients. However, mechanical approaches, such as the placement of an inferior vena cava (IVC) filter is reported to be associated with complications in two-thirds of patients (39). In addition, VTE recurs in up to 40% of patients with brain metastases treated with an IVC filter alone (40).

Compared to IVC filter placement, anticoagulation is associated with a lower rate of recurrent VTE, and, for most patients with brain metastases, the risk of hemorrhage appears acceptable. In a series of 42 patients treated at Memorial Sloan Kettering Cancer Center in New York who had brain metastases from a variety of solid tumors and who were anticoagulated for VTE, only three patients (7%) experienced ICH, including two patients in the setting of supratherapeutic anticoagulation (40). In a study of 25 patients with either primary or metastatic brain tumors treated with anticoagulation, only one patient experienced an incidentally found, asymptomatic focal intraventricular bleeding event (41). Consequently, the data, though limited, suggests that anticoagulation is preferable to IVC filter placement in most breast cancer patients who develop clinically significant VTE.

DEFINITIVE TREATMENT

The goals of definitive treatment of brain metastases are to relieve and/or stabilize neurological symptoms, to achieve long-term tumor control, and to extend life, while minimizing toxicity. The choice of therapy is influenced by a) the size, number, and location of lesions, b) the presence or absence of neurological symptoms, c) the patient’s life expectancy, including the patient’s performance status and the status of the patient’s extracranial disease, d) prior treatment, e) expected toxicities of treatment, f) availability of systemic treatment options, and g) patient preference. In general, initial management will include some combination of surgical resection, stereotactic radiosurgery (SRS), and/or WBRT. Systemic therapy could be a consideration on a clinical trial, in the context of minimal disease burden in a well-informed patient with close follow-up, or in the context of progressive extracranial disease in which rapid disease control is felt necessary. Given these complex considerations, the optimal care of patients with brain metastases involves close multidisciplinary collaboration in order to avoid overtreatment of patients with a limited life expectancy, as well as potential under-treatment of patients with well-controlled systemic disease and significant CNS-related morbidity.

SURGERY

The role of surgery in patients with brain metastases is to provide relief of symptoms resulting from mass effect of the tumor, to establish a histologic diagnosis, to improve local control, and to provide a potential benefit to survival.

Three prospective, randomized trials have been conducted to evaluate the role of surgery in patients with brain metastases (Table 76-2). The first trial, reported by Patchell and colleagues, randomly assigned 48 patients with a single brain metastasis (6% with a breast primary) to either surgery followed by WBRT versus WBRT alone (19). Patients in the combined-modality arm achieved better local control (20% vs. 52%, p <.02), improved median duration of functional independence (38 weeks vs. 8 weeks; p <.005), and longer overall survival (40 weeks vs. 15 weeks; p <.01), compared to the patients who received WBRT alone. These findings were replicated in a study of 63 patients (19% with breast primaries) led by Noordijk et al., in which patients treated with surgery and WBRT achieved prolonged survival (median 10 months vs. 6 months; p = .04) and functionally independent survival (7.5 months vs. 3.5 months; p = .06) compared to patients treated with WBRT alone (42). Of note, only patients with stable or absent extracranial disease appeared to derive a survival benefit from surgery; patients with progressive extracranial disease experienced a median survival of only 5 months irrespective of the allocated treatment. A third study reported no difference in either survival or functionally independent survival with the addition of surgery to WBRT (43). In contrast to the first two trials, nearly half of patients in this study were enrolled with co-existing extracranial metastases, and approximately 40% of patients had a Karnofsky performance status of 70% or less at study entry. In addition, the presence of a single brain lesion was categorized according CT rather than MRI (which could have missed multiple lesions), and 10 of 43 patients randomly assigned to radiotherapy underwent surgical resection at some point in their disease course, which may have further confounded the results.

TABLE 76-2 Summary of Selected Prospective Randomized Clinical Trials Evaluating Surgical and/or Radiotherapy-Based Approaches for Management of Brain Metastases

Trial	Study Design	Population	N	# With Breast Cancer	Results
Trials evaluating whole brain radiotherapy dose-fractionation schedules^a
Borgelt et al., 1980 (51)
First study	30 Gy/10 fractions vs. 30 Gy/15 fractions vs. 40 Gy/15 fractions vs. 40 Gy/20 fractions	Solid tumors	910	166	More rapid symptom improvement with larger fractions (55% of patients achieved improved symptoms at 2 weeks with 30 Gy/10 fractions compared to 43% for other regimens, p = .06). No difference in OS among arms.
Second study	20 Gy/5 fractions vs. 30 Gy/10 fractions vs. 40 Gy/15 fractions	Solid tumors	902	146	More rapid symptom improvement with larger fractions (64% of patients achieved improved symptoms at 2 weeks with 20 Gy/5 fractions compared to 54% for the other regimens, p = .01). No difference in OS between arms.
Borgelt et al., 1981 (61)
First study	10 Gy/1 fraction vs. protracted course (20, 30, or 40 Gy/10-20 fractions)	Solid tumors	26^b	2	No difference in rate of symptom improvement or OS. Shorter duration of improvement (4 weeks vs. 10 weeks, p = .02) and TTP (median 8 weeks vs. 11.5 weeks, p = .07) with high-dose radiation.
Second study	12 Gy/2 fractions vs. protracted course (20, 30, or 40 Gy/10-20 fractions)	Solid tumors	33^a	1	No statistically significant difference in rate of symptom improvement, duration of improvement, or OS with high-dose radiation.
Murray et al., 1997 (63)	32 Gy/20 fractions over 10 d followed by boost (24.4 Gy/14 fractions over 7 d) vs. 30 Gy/10 fractions	Solid tumors	429	43	No difference in OS with accelerated hyperfractionation (p = .52)
Trials evaluating the role of surgery in addition to WBRT
Patchell et al., 1990 (19)	Surgery followed by WBRT (36 Gy/12 fractions) vs. WBRT alone	Solid tumors, single brain metastasis	48	3	Improved local control, 80% vs. 48% (p < .02), OS (median 40 weeks vs. 15 weeks, p < .01), and functionally independent survival (median 38 weeks vs. 8 weeks, p < .005).
Noordijk et al., 1994 (42)	Surgery followed by WBRT (40 Gy/20 fractions over 10 d) vs. WBRT alone	Solid tumors, single brain metastasis	63	12	Improved OS (median 10 months vs. 6 months, p = .04) and functionally independent survival (7.5 months vs. 3.5 months, p = .06).
Mintz et al., 1996 (43)	Surgery followed by WBRT (30 Gy/10 fractions) vs. WBRT alone	Solid tumors, single brain metastasis	84	10	No difference in OS (median 5.6 months vs. 6.3 months, p = .24) or proportion of functionally independent days (mean 0.32 for both arms, p = .98)
Trials evaluating the role of WBRT in addition to local therapy
Patchell et al., 1998 (53)	Surgery + WBRT (50.4 Gy/28 fractions) vs. surgery alone	Solid tumors, single brain metastasis status post complete surgical resection	95	9	Improved local control (10% vs. 46%, p < .001) and distant control (recurrence in other sites in the brain 14% vs. 37%, p < .01). Decreased death due to neurologic causes (14% vs. 44%, p = .03). No difference in OS (median 48 weeks vs. 43 weeks, p = .39) or functionally independent survival (median 37 weeks vs. 35 weeks, p = .61).
Aoyama et al., 2006 (54)	WBRT (30 Gy/10 fractions) + SRS (with 30% dose reduction) vs. SRS alone	Solid tumors, 1-4 lesions, all ≤3 cm	132	9	Improved local control (89% vs. 73%, p = .002) at one year. Decreased likelihood of recurrence of tumor anywhere in the brain at 1 y (47% vs. 76%, p < .001). No difference in preservation of neurologic function. No difference in primary endpoint of OS (7.5 months vs. 8.0 months, p = .42). No difference in death due to neurologic causes (22.8% vs. 19.3%, p = .64).
Kocher et al., 2011 (52)	WBRT (30 Gy/10 fractions) vs. observation after either SRS or surgery	Solid tumors, 1-3 lesions, stable systemic disease	359 (199 SRS, 160 surgery)	42	WBRT vs. observation (2 years) Surgery group recurrence Local: 27% vs. 59% DR: 23% vs. 42 % SRS group recurrence Local: 19% vs. 31% Distant: 33% vs. 48% No difference in OS (10.7 months vs. 10.9 months), survival with functional independence 9.5 months vs. 10 months). Patients in observation arm reported better QOL (66).
Chang et al., 2009 (70)	WBRT (30 Gy/12 fractions) + SRS vs. SRS alone	Solid tumors, 1-3 lesions	58	8	Study stopped early due to decrease in HVLT-R total recall at 4 months in WBRT arm (primary endpoint). Local (100% vs. 67%) and distant (73% vs. 45%) control at 1-yr improved with WBRT. WBRT arm had more deaths from systemic causes leading to worse OS (5.7 months vs. 15.2 months).
Trials evaluating dose intensification of radiotherapy
Kondziolka et al., 1999 (77)	WBRT (30 Gy/12 fractions) + SRS vs. WBRT alone	Solid tumors, 2-4 lesions, all ≤2.5 cm	27	4	Improved local control (local recurrence rate at one year 8% vs. 100%; median time to local recurrence 36 months vs. 6 months, p = .0005). Longer time to recurrence of tumor anywhere in the brain (34 months vs. 5 months, p = .002). No difference in OS (11 months vs. 7.5 months, p = .22).
Andrews et al., 2004 (65)	WBRT (37.5 Gy/15 fractions) + SRS vs. WBRT alone	Solid tumors, 1-3 lesions, all ≤4 cm	333	34	Improved local control at 1 y (82% vs. 71%), p = .01). Higher likelihood of stable or improved performance status at 6 months (43% vs. 27%, p = .03). No difference in primary end point of OS (6.5 months vs. 5.7 months, p = .14). Survival advantage observed in subgroup of patients with a single brain metastasis (median 6.5 months vs. 4.9 months, p = .04).
Trials evaluating radiosensitizers
Mehta et al., 2003 (113)	WBRT (30 Gy/10 fractions) + motexafin gadolinium vs. WBRT alone	Solid tumors	401	75	No difference in OS (median 5.2 months vs. 4.9 months, p = .48), time to neurologic progression (median 9.5 months vs. 8.3 months, p = .95), or death due to neurologic causes (49% vs. 52%, p = .60).
Suh et al., 2006 (114)	WBRT (30 Gy/10 fractions) + efaproxiral vs. WBRT alone	Solid tumors, RPA class I or II	515	107	No difference in OS (median 5.4 months vs. 4.4 months, p = .16), time to neurological progression, or death due to neurologic causes. In an exploratory subgroup analysis, improved OS (HR for death 0.51, p = .003) and response rate (54% vs. 41%, p = .01) in breast cancer patients. A subsequent trial limited to breast cancer patients was negative (116).
Knisely et al., 2008 (118)	WBRT 37.5 Gy/15 fractions) + thalidomide vs. WBRT alone	Solid tumors, multiple (>3), large (>4 cm) or midbrain metastases	175	31	No difference in OS (median 3.9 months for both arms), or in deaths due to neurologic causes.
^aAll fractions given once daily unless otherwise specified.
^bRepresents number of patients assigned to the high-dose arm. These patients were compared to 143 control patients who received a more protracted course of radiation.
OS, overall survival; TTP, time to progression; WBRT, whole-brain radiotherapy; SRS, stereotactic radiosurgery; HR, hazard ratio.