The role of stereotactic radiosurgery in the management of patients with newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline

The following electronic databases were searched from 1990 to September 2008: MEDLINE^®, Embase^®, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Registry, Cochrane Database of Abstracts of Reviews of Effects. A broad search strategy using a combination of subheadings and text words was employed. The search strategy is documented in the methodology paper for this guideline series by Robinson et al. [30]. Reference lists of included studies were also reviewed.

Two independent reviewers evaluated citations using a priori criteria for relevance and documented decisions in standardized forms. Cases of disagreement were resolved by a third reviewer. The same methodology was used for full text screening of potentially relevant papers. Studies which met the eligibility criteria were data extracted by one reviewer and the extracted information was checked by a second reviewer. The PEDro scale was used to rate the quality of randomized trials [31, 32]. The quality of comparative studies using non-randomized designs was evaluated using eight items selected and modified from existing scales.

Both the quality of the evidence and the strength of the recommendations were graded according to the AANS/CNS criteria. These criteria are provided in the methodology paper to this guideline series.

The AANS/CNS convened a multi-disciplinary panel of clinical experts to develop a series of practice guidelines on the management of brain metastases based on a systematic review of the literature conducted in collaboration with methodologists at the McMaster University Evidence-based Practice Center.

Overall 16,966 publications were screened. Fifty-six publications passed through the title and abstract screening to the full text screening level. Ultimately, 32 publications (31 primary studies and one companion paper) met the eligibility criteria. Figure 1 outlines the flow of the studies through the review process.

Two prospective RCTs (class I evidence) [25, 33] and one retrospective cohort study with historical controls (class III evidence) [34] evaluated WBRT alone vs. WBRT + SRS for the initial management of patients with solid metastatic brain tumors. One prospective cohort study (class II evidence) evaluated WBRT alone vs. WBRT + SRS for the initial management of patients with solid metastatic brain tumors in two arms of a three-arm study that also evaluated SRS alone [35] (Table 1). One retrospective cohort study (class II evidence) evaluated WBRT alone vs. WBRT + SRS as two of the arms in a four arm study that also included SRS alone and surgery alone (Table 1) [36]. In all five of these unique studies, only single-dose SRS was evaluated, and the results cannot be assumed to apply to 2–5 dose SRS [28, 29].

The first RCT is a Radiation Therapy Oncology Group (RTOG) multi-center trial led by Andrews et al., published in 2004 [33]. The trial randomized adults with a Karnofsky performance status (KPS) ≥ 70 with 1–3 solid brain metastases with a maximum diameter of 4 cm for the largest and ≤3 cm for the remainder. Patients were stratified by number of metastases and extent of extra-cranial disease. WBRT and SRS doses were standard. Overall follow-up was a median of 12 months. Patient groups were well matched for sex, age (19–90 years), histology, KPS, and mini-mental status exam (MMSE) score. There were 164 patients in the WBRT + SRS arm (of which 31/164 (19%) did not receive their planned SRS) and 167 patients in the WBRT alone arm (of which 28/167 (17%) received salvage SRS). The primary endpoint was median survival. Secondary endpoints included tumor control at 1 year, KPS and MMSE at 6 months and cause of death (neurologic vs. non-neurologic). This trial can be criticized for a large bilateral crossover rate in an intent-to-treat model, no follow-up neuroimaging review on 43% of patients, and inclusion of tumors >3 cm diameter which are known to be less favorable for SRS but were included in the original RTOG 90-05 trial and were included for that reason (refer to the surgical resection guideline paper by Kalkanis et al. [27]. Nevertheless, this trial demonstrated significantly better survival for patients with single metastatic tumors (p = 0.01), superior local control for patients with 1–3 metastatic brain tumors (p = 0.01), and improved KPS for patients with 1–3 metastatic brain tumors in the WBRT + SRS arm. The last two conclusions were secondary endpoints assessed with post hoc analysis and thus, are not as strong as the single tumor survival conclusion. There was no significant difference between groups in median survival for patients with 2–3 brain tumors, MMSE at 6 months, incidence of neurologic cause of death, or adverse therapeutic events [33]. However, because of the large follow-up loss in this study, no conclusion can be assured.

The second RCT is a single institution study from the University of Pittsburgh led by Kondziolka et al., published in 1999 [25]. The trial randomized adults with a KPS ≥ 70 with 2–4 solid metastatic brain tumors, each ≤2.5 cm in mean diameter. WBRT and SRS doses were standard. Overall follow-up was not reported. Patient groups were well matched for sex, age (33–77 years), histology, number of brain tumors, KPS score, and extent of systemic disease. There were 14 patients in the WBRT arm and 13 in the WBRT + SRS arm. All patients completed the treatment in their intent-to-treat arm. Since the primary endpoint was imaging-defined local control, no patient received salvage SRS until they were censored for analysis. Secondary endpoints included median survival, and time to recurrence/progression at the original tumor sites. The study was stopped at the 60% accrual point due to an overwhelmingly positive tumor control difference at interim analysis. This trial demonstrated significantly better local control rates measured in terms of local failure at 1 year (8 vs. 100%) and median time to recurrence/progression at original site (36 vs. 6 months) for patients in the WBRT + SRS arm. Since the study was stopped at 60% accrual, its statistical power to assess differences in median survival was limited. Despite a large trend of 11 vs. 7.5 months favoring WBRT + SRS, this result did not achieve statistical significance due to the relatively low number of patients. Functional performance outcome, cause of death, and incidence of adverse events were not reported [25].

In the three arm prospective cohort study by Li et al. [35] recruitment was restricted to patients with both small cell- and non-small-cell lung cancer (NSCLC) and single brain metastases ≤4.5 cm diameter in adults with a KPS ≥ 60, two of the three arms were WBRT (n = 19) vs. WBRT + SRS (n = 18). Groups were similar in terms of sex, age, histology, extent of extracranial disease, and KPS score. WBRT doses and SRS doses were standard. The median survival advantage for WBRT + SRS was highly significant (p < 0.0001) as was the advantage for local tumor control (p = 0.004) and median time to progression for the treated tumor (p < 0.00001).

The four arm retrospective cohort study by Wang et al. [36] evaluated adult patients with 1–6 metastases of varying histologies, each <4 cm in diameter, and a KPS of 40–90; two of the four arms were WBRT alone (n = 120) vs. WBRT + SRS (n = 83). Groups were similar in terms of sex and age. Primary histology, KPS score, and extent of systemic disease were not reported by treatment group. The WBRT + SRS had significantly more patients with multiple brain tumors (50/83) than the WBRT alone arm (34/120). WBRT doses and SRS doses were standard. While 1 month local tumor control rates were similar between groups (95.6 vs. 88.3%), median survival significantly favored the WBRT + SRS group (91 vs. 37 weeks).

Sanghavi et al. [34] performed a large retrospective cohort trial (n = 502) of patients with varying histologies with historical controls based on recursive partitioning analysis (RPA) [37] of a database of patients from RTOG trials (n = 1,200) where patients received WBRT alone. Groups were stratified by RPA class. Groups were similar in age, and extent of extracranial disease. The WBRT group had slightly lower KPS scores, while the WBRT + SRS group had a greater percentage of radioresistant histologies (e.g., melanoma). They found statistically significant improvements in survival for patients in all three RPA classes, suggesting a survival benefit for SRS + WBRT even in patients with >1 metastatic brain tumor, the presence of systemic disease, and low KPS score.

One prospective RCT (class I evidence) with a companion paper [38, 39], and nine retrospective cohort studies (class II evidence) [40‐48] evaluated SRS alone vs. WBRT + SRS for the initial management of patients with solid metastatic brain tumors. One prospective cohort study (class II evidence) evaluated SRS alone vs. WBRT + SRS for the initial management of patients with solid metastatic brain tumors in two arms of a three-arm study that also evaluated WBRT alone [35] (Table 1). One retrospective cohort study (class II evidence) evaluated SRS alone vs. WBRT + SRS as two of the arms in a four arm study that also included WBRT alone and surgery alone (Table 1) [36]. In all 12 of these unique studies, only single-dose SRS was evaluated, and the results cannot be assumed to apply to 2–5 dose SRS [28, 29].

The RCT is a multi-institutional study from Japan led by Aoyama et al., published in 2006 [38, 39]. The trial randomized adults with a KPS ≥ 70 with 1–4 solid brain metastases with a maximum diameter of ≤3 cm. Follow-up was 20.7 months for the SRS arm and 30.5 months for the WBRT + SRS arm. Isolated WBRT and SRS alone doses were standard, however, the SRS dose was reduced by 30% in the WBRT + SRS arm relative to the SRS alone arm. Patient groups were similar in terms of sex, age, histology, number of tumors, extent, and stability of extracranial disease, primary tumor status, KPS score, and MMSE score. There were 67 patients in the SRS alone arm (of which 2/67 (3%) did not receive SRS, and 11/67 (16%) received WBRT as a salvage therapy) and 65 in the WBRT + SRS arm (of which 6/65 (9%) did not receive SRS, 2/65 (3%) did not receive WBRT, and 10/65 (15%) received additional salvage SRS). The primary endpoint was median survival. Secondary endpoints included 1 year tumor control rate, 1 year recurrence rate at untreated sites, neurologic cause of death, 1 year KPS score, 1 year MMSE score, and adverse event rate. This trial can be criticized for a large bilateral crossover rate in an intent-to-treat model. Results revealed no significant difference between study groups for median survival (8.0 vs. 7.5 months), 1 year local control rate (72.5 vs. 88.7%), neurologic cause of death, 1 year KPS score, MMSE score, or acute or late neurotoxicity. However, the 1 year chance of recurrence locally (27.5 vs. 11.3%), at a distant site (63.7 vs. 41.5%), or anywhere in the brain (76.4 vs. 46.8%) was significantly greater for the SRS alone arm than the WBRT + SRS arm, as was the chance of requiring additional salvage therapy in the form of either SRS or WBRT (43.3 vs. 15.4%). In a second, secondary endpoint analysis publication from the same study looking at the 70% subset of patients with initial and follow-up MMSE examinations, and then restricting analysis still further to the 62% of patients with pre-treatment MMSE scores of ≥27 or who improved on follow-up to MMSE scores ≥27, the addition of up-front WBRT significantly increased the time to MMSE deterioration, which was often due to distant tumor recurrence [39].

In the three arm prospective cohort study by Li et al. [35] recruitment was restricted to patients with both SCLC and NSCLC, and single brain metastases ≤4.5 cm diameter in adults with a KPS ≥ 60; two of the three arms were SRS (n = 23) vs. WBRT + SRS (n = 18). Groups were similar in terms of sex, age, histology, extent of extracranial disease, and KPS score. WBRT doses and SRS doses were standard. There was no significant difference between the two groups in terms of median survival (9.3 vs. 10.6 months) or in terms of recurrence/progression at the treated site. Distant brain recurrence was not assessed.

Of the 10 retrospective cohort studies addressing this comparison in patients with both single and multiple brain metastases of varying histologies, nine are direct comparisons of SRS alone vs. WBRT + SRS [40‐48] and one is a four arm retrospective cohort study with SRS and WBRT + SRS as two of the four comparison arms [36]. Of these 10 studies, eight show no significant difference in median survival between both treatment options with ranges for median survival of 7–13.9 months and 6.4–14.9 months, respectively [40, 42‐48]. One study of patients with breast cancer brain metastases showed improved median survival of 9 vs. 6 months favoring SRS alone [41], and another studying tumors of varying histology showed improved median survival of 91 vs. 67 weeks favoring WBRT + SRS [36]. Of the 10 studies, only one (which studied only patients who had survived >1 year since treatment) revealed a statistically significant increase in local recurrence rate or reduced time to local recurrence [48]. However, four revealed either increased distant brain or overall brain recurrence rates and/or reduced time to distant brain or overall brain recurrence [40, 42, 44, 45]. On the other hand, the study of patients who had survived >1 year since treatment suggested that while the median time to local recurrence/progression was significantly increased with SRS alone, the median time to distant recurrence was not significantly different between the two arms [48].

No RCTs were identified that met the eligibility criteria for this treatment comparison. One prospective cohort study (class II evidence) evaluated SRS alone vs. WBRT alone for the initial management of patients with solid metastatic brain tumors in two arms of a three-arm study that also evaluated WBRT + SRS [35]. There were two retrospective cohort studies with concomitant control groups (class II evidence) that compared SRS alone vs. WBRT alone (Table 1) [49, 50]. There were two retrospective cohort studies with historical controls (class III evidence) that compared SRS alone vs. WBRT alone (Table 1) [51, 52]. One retrospective cohort study (class II evidence) evaluated SRS alone vs. WBRT alone as two of the arms in a four arm study that also included WBRT + SRS and surgery alone (Table 1) [36]. In all of these unique studies, only single-dose SRS was evaluated, and the results cannot be assumed to apply to 2–5 dose SRS [28, 29].

The three arm prospective cohort study by Li et al. (2000) [35] evaluated adult patients with both SCLC and NSCLC, and single brain metastases ≤4.5 cm diameter in adults with a KPS ≥ 60, two of the three arms were SRS alone (n = 23) vs. WBRT alone (n = 19). Groups were similar in terms of sex, age, histology, extent of extracranial disease, and KPS score. WBRT doses and SRS doses were standard. The SRS alone arm had significantly longer median survival (9.3 vs. 5.7 months), neuroimaging tumor response (complete or partial response 87 vs. 38%, and progression 0 vs. 14%), and median time to progression (6.9 vs. 4.0 months). Distant brain recurrence was not assessed.

In the small retrospective cohort study by Lee et al. [49] recruitment was restricted to patients with 1–12 non-germ cell epithelial ovarian cancer brain metastases; 15 patients were treated with either SRS alone (n = 7) or WBRT alone (n = 8). Groups were poorly analyzed in terms of potentially relevant intergroup differences and SRS and WBRT dosing parameter was not provided. Despite these issues, the authors reported a significantly improved median survival outcome for the SRS arm (29 vs. 6 months for WBRT alone).

In the large retrospective cohort study by Rades et al. [50] 186 patients with 1–3 brain metastases of varying histologies ≤4 cm diameter received either WBRT alone (n = 91) or SRS alone (n = 95). Groups were well matched for sex, age, RPA class, number of metastases, extent of extracranial disease, baseline functional performance, and histology. Median survival was significantly longer for the SRS alone group (13 vs. 7 months for WBRT alone). One-year local and overall brain control rates were likewise significantly better for the SRS alone arm (64 vs. 26% and 49 vs. 23%, respectively). Distant brain control rates were similar for both groups (66% WBRT alone vs. 61% SRS alone). Toxicity rates were similar for both groups.

The four arm retrospective cohort study by Wang et al. [36] evaluated adult patients with one or more brain metastases of varying histologies, each <4 cm in diameter and a KPS > 50. Two of the four arms were SRS alone (n = 130) vs. WBRT alone (n = 120). Groups were similar in terms of sex and age. Primary histology, KPS score, and extent of systemic disease were not reported by treatment group. The SRS treatment group had more patients with multiple brain tumors (50/83) than the WBRT alone arm (34/120). WBRT doses and SRS doses were standard. While 1 month local tumor control rates were similar between groups (93.3 vs. 88.3%), median survival significantly favored the SRS group (67 vs. 37 weeks).

Kocher et al. [52] performed a retrospective cohort trial of SRS (n = 117) compared against 138 WBRT historic control patients treated 1–20 years previously at the same institution for brain metastases patients with multiple histologies and ≤3 tumors. Groups were similar in terms of sex and age and were stratified according to RPA classification which accounted for extent of extra-cranial disease, number of tumors, and functional status [37]. The SRS alone arm had more melanoma patients (27 vs. 6%). WBRT and SRS doses were standard. They reported significantly better results with SRS alone for RPA class I (25.4 vs. 4.7 months) and RPA class II (5.9 vs. 4.1 months). Difference in results for RPA class III (4.2 vs. 2.5 months) did not reach statistical significance.

Datta et al. [51] performed a retrospective cohort trial of SRS ± WBRT (12/53 (22.6%) received WBRT) compared against 67 WBRT historic control patients treated 1–3 years previously at the same institution for brain metastases patients with multiple histologies and <4 tumors each <30 cc in volume. Groups were similar in terms of sex and age, but differed in terms of lung and breast cancer histology (67.9 vs. 83.6%). Number of brain tumors, extent of extracranial disease, and baseline performance status were not reported. WBRT and SRS doses were standard. They reported similar median survival of only 6 months for both groups.

No prospective studies were identified that met the eligibility criteria for this treatment comparison. There were four retrospective cohort studies (class II evidence) that evaluated SRS + WBRT vs. resection + WBRT for the initial management of patients with solid metastatic brain tumors (Table 1) [53‐56]. In all four of these unique studies, only single-dose SRS was evaluated, and the results cannot be assumed to apply to 2–5 dose SRS [28, 29].

Bindal et al. [53] performed a retrospective cohort trial of 62 patients with single brain metastases <3 cm in diameter treated with resection ± WBRT matched for sex, age, histology, KPS, and extent of disease to 31 patients undergoing SRS ± WBRT. WBRT was used in 66% of patients in the first arm and 71% of patients in the second. WBRT and SRS doses were standard. In this study, resection + WBRT achieved significantly longer median survival (16.4 vs. 7.5 months) and median time to recurrence, as well as significantly lower rates of neurologic death (19 vs. 50%) and adverse event rates than SRS + WBRT. This study reported significantly lower median survival rates (only 7.5 months), as well as higher radiation necrosis rates (12.9%), than have ever been reported by other studies evaluating single brain metastases treated with SRS + WBRT. Given the poor compliance with completion of WBRT in both arms, this study warrants retrospective down-grading to a class III evidence level, a study with flawed internal validity.

In contrast, Garell et al., (1999) (1–2 tumors each <3 cm diameter, n = 45), O’Neill et al., (2003) (single tumors <3.5 cm, n = 97), and Schoggl et al., (2000) (single tumors <3 cm diameter, n = 133) each reported retrospective cohort studies of patients with brain metastases with very different results [54‐56]. Median survival was not significantly different but favored SRS + WBRT in two (12.5 vs. 8 months and 12 vs. 9 months, respectively) [54, 56], while 1 year survival was not significantly different but slightly favored resection + WBRT (62 vs. 56%) in the third [55]. Median time to recurrence, incidence of neurologic death, and incidence of acute and long term adverse events were similar in both arms for the Mayo Clinic study [55]. Median time to local recurrence was significantly shorter (3.9 vs. 4.9 months) and the incidence of neurologic death was greater (21.8 vs. 12.5%) in the resection + WBRT arm in the University of Vienna study, while adverse event rates were similar [56]. Cause of death and adverse event rates were not reported for the University of Iowa study [54], median time to recurrence was not reported in either the University of Iowa or the Mayo Clinic Studies [54, 55], and functional performance results were not reported in any of the three [54‐56].

One prospective RCT (class I evidence) [57], and two retrospective cohort studies (class II evidence) evaluated SRS alone vs. resection + WBRT for the initial management of patients with solid metastatic brain tumors (Table 1) [58, 59]. One retrospective cohort study (class II evidence) evaluated SRS alone vs. resection + WBRT or local RT for the initial management of patients with solid metastatic brain tumors (Table 1) [60]. These four unique studies only evaluated single-dose SRS, and the results cannot be assumed to apply to 2–5 dose SRS [28, 29].

Muacevic et al., (2008) performed a multicenter prospective RCT evaluating patients with single metastatic brain tumors, ≤3 cm diameter located in an operable site, treated with either SRS alone (n = 31) or resection + WBRT (n = 33) [57]. Groups were similar in terms of sex, age, histology, extent of systemic disease, and KPS score. WBRT and SRS doses were standard. There was no significant difference in outcome between the two groups in terms of functional performance outcome, rate of neurological death, or median survival (9.5 months surgery + WBRT vs. 10.3 months SRS). However, the study was stopped early at only 25% accrual and was therefore underpowered to detect <15% differences in outcome between groups. The SRS patients did experience an increased number of distant tumor recurrences (25.8 vs. 3%), but these occurrences did not impact overall outcome when subsequent salvage SRS was taken into account. The resection + WBRT group did experience a significantly larger number of grade 1 or 2 early and late complications compared with the SRS group.

Rades et al. [59] performed a retrospective cohort study of SRS alone (n = 94) vs. resection + WBRT (n = 112), for RPA class I or II patients with metastatic brain tumors ≤4 cm in diameter. Groups were similar in terms of sex, age, histology, number of brain tumors, extent of systemic disease, and KPS score. WBRT and SRS doses were standard. Despite a trend favoring SRS alone, there was no significant difference in outcome between groups for 1 year survival (54 vs. 38%). There was no significant difference in outcomes for 1 year local recurrence rate (36 vs. 44%) or incidence of adverse events. Functional performance and neurologic cause of death outcomes were not reported.

Muacevic et al., (1999) performed a retrospective cohort study of SRS alone (n = 56) vs. resection + WBRT (n = 52), for patients with single metastatic brain tumors ≤3.5 cm in diameter and with stable systemic disease [58].Groups were similar in terms of sex, age, extent of systemic disease, and KPS score. The SRS alone group had a slightly higher proportion of patients with melanoma (28.6 vs. 13.5%). WBRT and SRS doses were standard. Despite a trend favoring resection + WBRT, there was no significant difference in outcome between groups for median survival (35 vs. 68 weeks). There was no significant difference in outcomes for 1 year local recurrence rate (17 vs. 25%), median time to recurrence, functional performance score, or incidence of adverse events.

Shinoura et al., (2002) performed a retrospective cohort study of SRS alone (n = 52) vs. resection + either WBRT or local RT (n = 46, WBRT vs. local RT ratios not reported) for patients with one or more metastatic brain tumors <3 cm in diameter [60]. Groups were similar in terms of sex, age and histology, but the SRS alone group had more patients with multiple tumors (77 vs. 37%). Extent of extracranial disease and functional status were not reported. WBRT, local RT, and SRS doses were standard. They reported significantly longer median survival rates (34.4 vs. 8.2 months) as well as longer mean time to recurrence rates (25 vs. 7.2 months) for the resection + RT arm. Cause of death and incidence of adverse events were not reported.

While our study group was interested in evaluating many more treatment comparisons (including the effectiveness of surgery plus SRS vs. resection plus WBRT, the effectiveness of substituting 2–5 dose SRS or fractionated stereotactic radiotherapy (6–9 dose) for single dose SRS, and the effectiveness of substituting local fractionated radiotherapy for WBRT) in various paradigm combinations, none of these comparisons yielded more than one clinical study for analysis, and some none at all. As a result, few conclusions can be drawn at an evidence-based medicine clinical practice parameter guideline level. Those few studies where evidence exists are presented here for completeness and interest sake and will be discussed further below in the section on “Key Issues for Further Investigation”.

No prospective studies were identified that met the eligibility criteria for this treatment comparison. There was one retrospective cohort study (class II evidence) that evaluated resection + WBRT or local RT vs. SRS alone for the initial management of patients with solid metastatic brain tumors (Table 1) [61]. In this study, only single-dose SRS was evaluated, and the results cannot be assumed to apply to 2–5 dose SRS [28, 29].

Serizawa et al. [61] performed a retrospective cohort study of resection + WBRT (n = 34) vs. resection + SRS (n = 62) for NSCLC patients with multiple brain metastases ≤3 cm in diameter in patients estimated to have at least 2 months to live. Groups were similar in terms of sex, age, number of brain tumors, extent of systemic disease, and KPS score. WBRT and SRS doses were standard. The resection + SRS alone group had significantly longer median survival (377 vs. 199 days). Unfortunately this result is difficult to evaluate given that the number of patients in the resection + WBRT arm that had resection of all tumors vs. resection of only some of the 1–10 tumors per patient were not defined. The resection + SRS arm also showed significantly longer neurological survival rates. Local tumor control rates were not reported.

No prospective studies were identified that met the eligibility criteria for this treatment comparison. There was one retrospective cohort study (class II evidence) that evaluated single-dose SRS alone vs. multi-dose SRS + WBRT for the initial management of patients with solid metastatic brain tumors (Table 1) [62].

De Salles et al. [62] performed a retrospective cohort study of SRS alone (n = 19) vs. WBRT + multi-dose SRS (n = 7) in patients with multiple histologies with one or more metastatic brain tumors with volumes ranging from 0.09 to 51.84 cc (average volume 21.2 cc). Groups were similar in terms of sex and age, but the SRS alone arm had more melanoma patients (16 vs. 0%) and had significantly more multiple brain tumor patients (34 tumors in 19 patients vs. seven tumors in seven patients). WBRT and single-dose SRS doses were standard. The multi-dose SRS regimen was 6 Gy per dose given in 2–3 doses over 2–3 days. There was no significant difference in average survival between both arms (8 vs. 7 months); however, this study was underpowered to detect all but a very large difference.

No prospective studies were identified that met the eligibility criteria for this treatment comparison. There was one retrospective cohort study with historical controls (class III evidence) that evaluated multi-dose SRS vs. WBRT for the initial management of patients with solid metastatic brain tumors (Table 1) [63].

Lindvall et al. [63] performed a retrospective cohort study of multi-dose SRS alone vs. WBRT + either single- or multi-dose SRS in patients with 1–3 brain metastases of varying histologies ranging in volume from 0.9 to 41 cc (median volume 5 cc). Groups were similar in terms of sex, extent of systemic disease, and KPS score. The multi-dose SRS arm had younger patients (61.7% ≥ 60 vs. 85.7% ≥ 60), fewer melanoma patients (4.3 vs. 21.4%), fewer RPA class I patients (4.3 vs. 21.4%) and more patients with multiple brain tumors (23.4 vs. 14.2%). The WBRT dose was standard. The multi-dose SRS regimen was 40 Gy in five 8 Gy doses. The single- or multi-dose boost regimen after WBRT was given in 1–3 doses of 6–12 Gy (mean total dose 17 Gy). There was no significant difference in outcomes between groups for median survival (5 vs. 5 months) or local progression (16 vs. 0%). There was a significantly larger distant recurrence rate for the multi-dose SRS alone arm (25 vs. 0%).

No prospective studies were identified that met the eligibility criteria for this treatment comparison. There was one retrospective cohort study (class II evidence) that evaluated fractionated stereotactic radiotherapy (FSR) alone vs. resection plus WBRT or local RT vs. WBRT or local RT alone, for the initial management of patients with solid metastatic brain tumors (Table 1) [64].

Ikushima et al. [64] performed a three arm retrospective cohort study in patients with 1–3 renal cell carcinoma brain metastases each ≤3 cm in diameter in adult patients with an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2, comparing FSR (n = 10) vs. resection + either WBRT or local RT vs. WBRT or local RT alone. Patients were similar in terms of sex, age, and extent of extracranial disease. The FSR alone arm had more patients with single brain tumors, and the WBRT or local RT alone arm had less patients with multiple brain tumors than the resection + either WBRT or local RT arm (90 vs. 70% and 50 vs. 36%, respectively). The WBRT or local RT alone arm had more ECOG performance status two patients than either the resection + either WBRT or local RT, or the FSR alone arm (50 vs. 18 vs. 0%). The WBRT and local RT doses were standard. The FSR regimen was 42 Gy in seven fractions (6 Gy per fraction) over 2.3 weeks. While 1 year tumor control rates where similar for the FSR alone and the resection + either WBRT or local RT arms (89.6 vs. 87.5%), the FSR group had a significantly longer median survival (25.6 months) than either the surgery + either WBRT or local RT (18.7 months), or the WBRT or local RT alone arms (4.3 months).