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. 2013 Mar 4;2(2):181–193. doi: 10.2217/cns.13.4

Role of stereotactic radiosurgery in patients with more than four brain metastases

Vikram Jairam 1,1,*, Veronica LS Chiang 2,2,3,3, James B Yu 1,1,2,2,4,4, Jonathan PS Knisely 5,5
PMCID: PMC3835313  NIHMSID: NIHMS456584  PMID: 24273642

SUMMARY

For patients presenting with brain metastases, two methods of radiation treatment currently exist: stereotactic radiosurgery (SRS) and whole-brain radiation therapy (WBRT). SRS is a minimally invasive to noninvasive technique that delivers a high dose of ionizing radiation to a precisely defined focal target volume, whereas WBRT involves multiple smaller doses of radiation delivered to the whole brain. Evidence exists from randomized controlled trials for SRS in the treatment of patients with one to four brain metastases. Patients with more than four brain metastases generally receive WBRT, which can effectively treat undetected metastases and protect against intracranial relapse. However, WBRT has been associated with an increased potential for toxic neurocognitive side effects, including memory loss and early dementia, and does not provide 100% protection against relapse. For this reason, physicians at many medical centers are opting to use SRS as first-line treatment for patients with more than four brain metastases, despite evidence showing an increased rate of intracranial relapse compared with WBRT. In light of the evolving use of SRS, this review will examine the available reports on institutional trials and outcomes for patients with more than four brain metastases treated with SRS alone as first-line therapy.

Practice Points.

  • Approximately 170,000–200,000 cancer patients have brain metastases diagnosed annually in the USA, and for these patients, whole-brain radiation therapy (WBRT), stereotactic radiosurgery (SRS) or both therapies may be employed.

  • WBRT delivers between 5 and 25 low doses of ionizing radiation to the whole brain, while SRS delivers high-dose radiation only to the visible brain metastases.

  • WBRT has more significant neurocognitive side effects than SRS.

  • Class I evidence supports the use of SRS in the treatment of patients with one to four brain metastases. WBRT is often used without SRS for patients with more than four brain metastases, although the greater possibility of neurocognitive side effects from WBRT has led to an increasing use of SRS without WBRT for patients with more than four metastases.

  • Phase III trials evaluating WBRT + SRS in patients with one to four brain metastases documented survival benefits to adding SRS to WBRT for patients with single metastases, and an improved performance status at 6 months in SRS recipients.

  • Phase III trials evaluating SRS + WBRT in patients with one to four brain metastases documented no survival advantage to the addition of WBRT to SRS, although intracranial relapse rates were higher in patients not receiving WBRT.

  • Current protocols indicate SRS alone is sufficient as an initial treatment for patients with one to four brain metastases; this strategy defers or avoids the acute and delayed side effects of WBRT and reserves WBRT as a potential salvage regimen to be used in the future for appropriate patients.

  • The use of SRS alone for patients with more than four brain metastases is controversial. It has been documented to be safe, and can be repeated without evident harm. No Phase III trials evaluating SRS alone versus WBRT for patients with more than four brain metastases inform opinions.

  • Overall survival is poorly linked to the number of brain metastases. Retrospective analyses on patients treated with initial, definitive SRS for more than four brain metastases consistently show that age, primary tumor control, tumor histology and patient performance status are the best predictors of overall survival, and not the number of brain metastases.

  • In the future, randomized controlled trials comparing SRS alone to WBRT for more than four brain metastases must be performed to truly assess the costs and benefits of these divergent management approaches.

Brain metastases occur in approximately 20–40% of all cancer patients, with an annual incidence of 170,000–200,000 cases [1,2]. Management of brain metastases has improved significantly in the past 10–20 years due to improvements in the fields of neurosurgery and radiation oncology, as well as diagnostic imaging and medical oncology. Current treatment approaches include whole-brain radiation therapy (WBRT), neurosurgical resection and stereotactic radiosurgery (SRS). Systemic cytotoxic chemotherapy and immune-modulating therapy are applicable for certain histologies of brain metastases [3,4]. SRS is a minimally invasive or noninvasive focal technique that uses multiple convergent beams of high-energy photons to deliver high radiation doses to a distinct target volume, while sparing normal surrounding tissues. Radiosurgery can be used to target metastases located in almost any region of the brain, and is better tolerated than surgery in deep-brain structures and eloquent cortical areas [5,6]. In addition to its noninvasiveness, SRS can also treat multiple metastases in the brain simultaneously in a single session, thereby minimizing any interruption of systemic therapy. Disadvantages of SRS treatment can include its increasing toxicity from treatment when treating metastases greater than 3 cm in diameter, delays in the relief from tumor mass effect compared with immediate surgical debulking, as well as a possible induction of a delayed leukoencephalopathic process that tends to resemble regrowing tumors on imaging [7,8]. Furthermore, SRS alone without WBRT treatment has been shown to result in greater rates of intracranial failure. SRS is also more labor-intensive and expensive than standard WBRT.

Clinical research has led to protocols favoring SRS treatment for patients with one to four brain metastases and WBRT for those with five or more metastases. However, WBRT is associated with a host of acute and chronic toxicities that have caused investigators to re-examine the indications and limits of SRS treatment. Patients who undergo WBRT acutely experience hair loss, scalp irritation, nausea, fatigue and worsened neurological function [7], but more concerning are the dementia-like neurocognitive changes that can be seen subacutely and chronically. One of the earliest studies in the area of WBRT and neurocognition was carried out by DeAngelis et al. [9]. This retrospective study examined long-term (>12 months) survivors of WBRT and found that 11% of patients developed clinical dementia. However, the current relevance of this study is questionable since the patients who did develop dementia received higher daily doses of radiation (>5.0 Gy) compared with those who did not develop dementia (<3.0 Gy). A more recent meta-analysis of studies assessing neurocognitive function after WBRT showed that cognitive decline primarily occurs 4 months after treatment [10]. Murine experiments suggest that the basis for this neurocognitive decline is the destruction of neuronal progenitor cells in the subgranular zone in the dentate gyrus of the hippocampus [11]. The initial report of a Phase III study (RTOG 0614) has indicated that the administration of memantine, postulated to lessen radiation injury to the hippocampus, both during and after WBRT can slow memory decline at 6 months after WBRT [101]. Memantine recipients also had improved delayed cognitive function.

In a related vein, a clinical study of hippocampal dosimetry in patients receiving partial-brain radiotherapy identified that a relative hippocampal sparing is associated with less severe impairment on some neurocognitive tests [12]. For this reason, the Radiation Therapy Oncology Group (RTOG) carried out a Phase II trial (RTOG 0933) evaluating neurocognitive performance 4 months after hippocampal-sparing WBRT [102]. The results of this study are still pending.

To avoid the late effects of WBRT, which may only be imperfectly ameliorated with concomitant memantine administration or clever WBRT radiation delivery techniques, many institutions have begun the use of SRS for multiple brain metastases. This paper will review some of the institutional and randomized trials carried out using SRS alone for patients with more than four brain metastases.

Current guidelines indicate SRS for one to four brain metastases

Multiple randomized controlled trials have been carried out using SRS for patients with one to four brain metastases. Early trials were initially carried out to determine whether SRS had any benefit for patients with limited numbers of brain metastases. The first reported trial examined the effect of WBRT compared with WBRT and SRS for patients with two to four brain metastases [13]. A total of 27 patients were enrolled in this study, with 13 receiving WBRT and SRS, and 14 receiving WBRT alone. The trial was closed early because statistically significant differences in intracranial tumor control were observed. Compared with WBRT alone, patients receiving WBRT and SRS had a significantly lower local failure rate after 1 year (8 vs 100%; p = 0.002) and a longer median time to local failure (36 vs 6 months; p = 0.0005). There was also a longer median overall survival in the WBRT and SRS group compared with WBRT alone (11 vs 7.5 months; p = 0.22). The authors also found no evidence of neurologic or systemic morbidity related to the use of SRS.

A multi-institutional trial (RTOG 9508) explored the role of consolidative SRS for patients with one to three brain metastases [14]. A total of 333 patients were enrolled and randomized to WBRT and SRS (167 patients) and WBRT alone (164 patients). No significant difference in median overall survival was found between the two groups (6.5 months for WBRT and SRS vs 5.7 months for WBRT alone; p = 0.14). A preplanned subset analysis, however, showed a survival advantage in the WBRT and SRS group for patients with a single brain metastasis (6.5 vs 4.9 months; p = 0.0393). Patients in the WBRT and SRS groups also had higher Karnofsky performance status (KPS) scores at 6month follow-up than those with WBRT alone (43 vs 27%; p = 0.03). However, there are two main criticisms of this trial. First, there was a lack of follow-up neuroimaging for 43% of the patients. Second, there was a large bilateral crossover rate, as 19% of the patients in the WBRT and SRS group did not receive SRS, and 17% of patients in the WBRT group received salvage SRS. Despite these limitations, these two trials demonstrated a clear benefit of WBRT and SRS in the treatment of patients with one to three metastases.

The successful use of SRS as an adjunct to WBRT led investigators to wonder whether SRS could be used alone in the treatment of patients with limited metastases, with the goal of deferring the use of WBRT, given its potential for deleterious neurocognitive effects. The first randomized trial was a multi-institutional trial carried out in Japan, comparing SRS alone to WBRT and SRS [15,16]. This study examined 132 patients (67 SRS vs 65 WBRT and SRS) with one to four brain metastases using overall survival as the primary end point. Compared with the SRS and WBRT group, the median survival time was not statistically significantly higher in the SRS alone group (7.5 vs 8 months; p = 0.42). The 1-year overall brain metastasis recurrence rate was greater in the SRS alone group (76.4 vs 46.8%; p < 0.001) as was the 1year intracranial recurrence rate of new, distant metastases (63.7 vs 41.5%; p = 0.003). Furthermore, using the Mini-Mental State Examination, the authors showed a greater average time until neurocognitive decline in the WBRT and SRS group compared with SRS alone (16.5 vs 7.6 months; p = 0.05). Mini-Mental State Examination recovery, however, was noted for patients who had SRS alone and underwent salvage SRS or WBRT treatment of new, symptomatic brain metastases, so that there was no statistical difference in neurocognitive preservation after 1 year. Mini-Mental State Examination recovery was not seen in patients who had WBRT and SRS treatment, and protracted glucocorticoid therapy was frequently needed for these patients. These findings suggest that the neurocognitive decline in those receiving initial SRS alone was due to intracranial disease recurrence that could be reversed by salvage therapy as opposed to upfront WBRT and SRS, which provides better intracranial control of brain metastases at the expense of often-irreversible neurocognitive decline in some individuals.

Another recently published single-institution Phase III study by Chang et al. was conducted at the MD Anderson Cancer Center to evaluate neurocognitive outcomes for patients with one to three brain metastases randomized to either SRS alone or SRS and WBRT [17]. A total of 58 patients (30 SRS alone vs 28 SRS and WBRT) were accrued before the trial was stopped prematurely because of stopping rules relating to the primary end point of cognitive decline. Interim analyses showed that patients in the SRS and WBRT group were statistically significantly more likely to show cognitive decline and memory deficits using the Hopkins Learning Test-Revised compared with patients treated with SRS alone (52 vs 24%, respectively). Consistent with all prior studies, freedom from CNS recurrence at 1 year was again higher in the SRS + WBRT group compared with SRS alone (73 vs 27%; p = 0.0003). The median and 1year survival was higher for the SRS alone group than for patients in the SRS and WBRT group (15.2 vs 5.7 months, and 63 vs 21%, respectively; p = 0.003). The causes for this survival difference are not clear and may relate to an increased use of both systemic therapy and salvage neurosurgery for regrowing brain metastases that Chang et al. noted were provided to the patients treated with SRS alone. Based on their results, the authors of this study recommended the use of SRS alone along with close clinical monitoring and subsequent salvage therapy to preserve long-term memory and cognitive abilities in patients with newly diagnosed brain metastases, without any specific indication that this recommendation should be limited to patients with three or fewer brain metastases.

Studies of neurocognitive function after brain metastasis treatment have been criticized in the past for failing to correlate any documented declines with measurable quality of life changes. The European Organization for Research and Treatment of Cancer (EORTC) conducted a randomized controlled trial (EORTC 2295226001) to evaluate whether adjuvant WBRT increases functional independence and quality of life in patients previously treated for brain metastases with SRS or surgical resection [18]. Three hundred and fifty nine patients with one to three brain metastases were recruited, of which 199 underwent SRS and 160 underwent surgery. In the SRS group, 100 were allocated to observation and 99 allocated to WBRT. In the surgery group, 79 were allocated to postoperative observation and 81 were allocated to postoperative adjuvant WBRT. The median time to decline in functional independence to a WHO performance status >2 was not significantly different between patients who received WBRT versus those without WBRT (9.5 vs 10.0 months; p = 0.71). At 2 years, 22.3% of the patients in the observation group and 22.6% in the WBRT group were alive and functionally independent, with WHO performance status scores <2. Similarly, amongst patients with a WHO performance status <2, survival was nearly identical at every time point until 60 months in both the observation and WBRT groups. WBRT also reduced the 2year relapse rate at both the initial sites (surgery: 59 to 27%; p < 0.001; SRS: 31 to 19%; p = 0.04) and at new sites (surgery: 42 to 23%; p = 0.008; SRS: 48 to 33%; p = 0.023). The authors concluded that adjuvant WBRT reduces intracranial relapses but does not improve the duration of functional independence or survival.

In summary, the above clinical trials support the use of SRS in the treatment of patients with one to four brain metastases. The addition of WBRT to SRS certainly improves local and distant control of brain metastases in these patients, but it is unclear whether this leads to a durably improved neurocognitive function, thereby failing to justify the need for WBRT for limited metastases. In fact, these studies suggest that the omission of WBRT may be justified to preserve neurocognition, despite the worsened intracranial tumor control and increased rate of intracranial tumor recurrence, because of the possibility of using salvage treatments such as repeat SRS or WBRT for new brain metastases in those patients who may eventually require additional treatment. Therefore, the use of SRS alone in patients with one to four brain metastases, followed by frequent serial surveillance as well as potential salvage therapies, has been deemed a reasonable clinical strategy.

These seminal studies have provided clues, but the relative contributions of WBRT and SRS to overall survival and neurocognition need further confirmation. A National Cancer Institute-supported Phase III clinical trial (NCT00377156), designed to evaluate the role of SRS alone versus SRS and WBRT in patients with one to three brain metastases has nearly completed accrual [103]. This trial is evaluating survival as well as performing detailed neurocognitive testing to try to elucidate the relative roles of WBRT and of new brain metastasis growth on the quality of life, functional independence and neurocognitive performance of patients with one to three brain metastases.

SRS for more than four metastases

In patients presenting with more than four brain metastases, current evidence for the efficacy of SRS-only treatment is sparse and limited to retrospective data, summarized in Table 1. No randomized controlled trials can currently inform opinions about this option. However, more medical centers are opting to use SRS for patients with more than four metastases, due to technological advancements that make SRS easier to deliver in sites that are already SRS capable and the ongoing concerns of the neurocognitive effects of WBRT.

Table 1. . Summary of studies evaluating stereotactic radiosurgery in patients with more than four metastases.

Study (year) Patients (n) Metastases (n) Median survival (weeks) Major finding Ref.
Serizawa et al. (2000) 96 1–10 SRS: 377
WBRT: 199		 SRS group had a greater mean survival time, higher freedom from neurologic death and higher qualitative survival [19]
Park et al. (2009) 33 2–20 SRS: 32
WBRT: 24		 Median and overall survival were greater in the SRS than the WBRT group [20]
Hunter et al. (2012) 64 ≥5 SRS: 30 SRS can effectively treat five or more metastases at a time [21]
Chang et al. (2010) 323 Group 1: 1–5
Group 2: 6–10
Group 3: 11–15
Group 4: >15		 Group 1: 40
Group 2: 40
Group 3: 52
Group 4: 32
(not significant)		 SRS is a recommended treatment option for all groups for both improved survival and local control [22]
Raldow et al. (2012) 103 Group 1: 5–9
Group 2: 10+		 Group 1: 7.6
Group 2: 8.3
(not significant)		 KPS score was the only variable significantly affecting overall survival [23]
Serizawa et al. (2010) 778 Group A: 1
Group B: 2
Group C: 3–4
Group D: 5–6
Group E: 7–10		 Group A: 44.73
Group B: 35.9
Group C: 35.9
Group D: 30.7
Group E: 32.2
(not significant)		 SRS without WBRT provides excellent survival in patients with one to ten brain metastases [24]
Suzuki et al. (2000) 24 10–47 SRS: 11 SRS achieves acceptable tumor control, low morbidity and good quality of life [25]
Kim et al. (2008) 26 10–37 SRS: 34 SRS can treat patients with ten or more metastases [26]
Grandhi et al. (2012) 61 10–28 SRS: 16 SRS safely and effectively treats patients with ten or more metastases with good local control [27]
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KPS: Karnofsky performance status; SRS: Stereotactic radiosurgery; WBRT: Whole-brain radiation therapy.

One early retrospective study performed by Serizawa et al. studied the survival of 96 patients with non-small-cell lung cancer who had presented with one to ten brain metastases, based upon whether they had received Gamma-knife® SRS (62 patients) or WBRT (34 patients) [19]. These patients were treated between 1990 and 1999. Salvage SRS was used, when needed, for the SRS group, and not WBRT. Compared with the WBRT group, the SRS group had a greater mean survival time (377 vs 199 days; p = 0.0158), a higher freedom from neurological death (p = 0.0237) and a longer survival (737 vs 270 days; p = 0.0007).

A second early retrospective study carried out by Park et al. examined patients with 2–20 brain metastases who were treated using Gamma-knife SRS (14 patients) versus WBRT (19 patients). The 6-month and 1year overall survival rates were 64.3 and 47.7% in the SRS group, compared with 42.1 and 10.5% in the WBRT group, respectively [20]. The median survival time was 32 weeks in the SRS group and 24 weeks in the WBRT group. The overall survival time was also longer in the SRS group (p = 0.04).

Hunter et al. recently reported the results from a retrospective review of a cohort of 64 patients with more than four brain metastases treated with SRS in a single session [21]. They found median overall survival after treatment was 7.5 months. A KPS score ≥80 significantly affected overall survival (4.8 months for KPS ≤70 vs 8.8 months for KPS ≥80; p = 0.0097), but the number of brain metastases and primary site histology did not affect overall survival. On multivariate Cox modeling, KPS score and prior WBRT treatment significantly predicted for overall survival.

Chang et al. carried out a retrospective study examining whether SRS was effective in treating patients with multiple metastases by looking at patient survival and progression-free survival time [22]. Patients were divided into four groups based on the number of brain metastases: group 1, one to five (215 patients); group 2, six to ten (58 patients); group 3, 11–15 (17 patients); and group 4, >15 (33 patients). Overall median survival after SRS was 10 months. No significant differences in survival rates were found among the different groups (group 1, 10 months; group 2, 10 months; group 3, 13 months; and group 4, 8 months). However, group 4 had a greater probability of developing new brain metastases (p = 0.014). The authors report that 14 patients in group 4 had undergone WBRT prior to SRS, but no assertion was made about the use of WBRT in the other cohorts. The use of prior WBRT did not affect survival in group 4. Despite the greater likelihood of new intracranial metastases in group 4, the authors recommended SRS as a treatment option for all groups for both improved survival and local control.

Raldow et al. conducted a retrospective analysis evaluating the effect of SRS for 103 patients with more than four brain metastases who underwent treatment between October 2000 and September 2010 [23]. Patients may have undergone prior SRS for one to four brain metastases, but not WBRT. Intracranial progression-free survival and overall survival from the date of SRS for more than four brain metastases were the primary end points. Median survival was 8.3 months for all patients, and 7.6 and 8.3 months for patients with five to nine and ten or more brain metastases, respectively. A trend towards a higher hazard for intracranial failure was identified in patients with ten or more versus five to nine metastases. KPS was the only variable significantly affecting overall survival, suggesting that SRS for carefully selected patients, regardless of number of brain metastases, is a reasonable course of treatment.

Serizawa et al. reported on 778 patients who presented with one to ten brain metastases and received Gamma-knife SRS without prophylactic WBRT in a prospective multi-institutional study [24]. Patients were grouped according to number of metastases: one (group A, 280 patients); two (group B, 135 patients); three to four (group C, 148 patients); five to six (group D, 93 patients); and seven to ten (group E, 122 patients). Four survival outcomes were measured, including overall, neurological, qualitative and intracranial progression-free survival. Multivariate analysis revealed that active systemic disease, initial KPS <70 and male gender were poor prognostic factors for overall survival. No significant difference was found in overall survival between the various groups (0.83 years for one metastasis, 0.69 years for two metastases, 0.69 years for three to four metastases, 0.59 years for five to six metastases and 0.62 years for seven to ten metastases), although significant differences were found in new lesion emergence between groups A and B and between groups B and C. The authors concluded that SRS without WBRT provides excellent survival in patients with one to ten brain metastases.

Looking specifically at studies of patients with ten or more metastases treated with SRS only, highly variable median survival rates of 4–34 months have been reported [25–27]. Suzuki et al. demonstrated that even with multiple intracranial metastases, treatment with SRS alone resulted in an improved KPS [25]. Analyses to identify favorable prognostic factors of overall survival identified synchronous onset in non-small-cell lung cancer, high KPS (>80) score, primary disease control, non-melanomatous primary tumor and a lower RTOG recursive partitioning analysis (RPA) class [26,27]. However, in one study, 62.3% of patients had undergone prior treatment for brain metastases with WBRT, and it is unclear what proportion of the reported median overall survival was attributable to this potential confounding factor [27].

A ready and relevant criticism of these studies is that there is an inherent selection bias. SRS is generally indicated for patients with controlled systemic disease and referrals to SRS centers may be intrinsically biased. In addition, poorer-performing patients may either be treated with WBRT or supportive care alone, which could contribute to a higher median overall survival for patients referred for and treated with SRS. Bearing these limitations in mind, however, the authors of all these studies conclude that SRS alone may effectively treat five or more brain metastases in well-chosen patients with some of the characteristics discussed above.

One issue that needs to be addressed should SRS become a mainstay of treatment for patients with more than four metastases is the cumulative whole-brain dose delivered. Yamamoto et al. reported on 80 patients with ten or more brain metastases [28]. The median lesion number was 17 (range: 10–43). They found that the median cumulative dose to the whole brain was 4.71 Gy (range: 2.16–8.51), which they concluded did not exceed the threshold for normal brain necrosis. Yang et al. reported an in silico study that identified 25 brain metastases as a possible theoretical maximum number of metastases that could be treated with radiosurgery in a single session, keeping the maximum point doses for each metastasis <40 Gy and the dose to 50% of the brain <5.0 Gy [29]. More studies are required to validate these data and to explore the neurocognitive effects of these single-fraction doses on the whole brain.

Number of metastases & overall survival

Previously Yamamoto et al. reported a large series showing that the number of metastases did have a significant impact on overall survival [30]. In their study they analyzed 456 patients with brain metastases treated with SRS between 1991 and 2004. The mean and median numbers of tumors treated were six and two, respectively (range: 1–55). Mean and median survival times were 12.7 and 7 months, respectively, after SRS. Median survival periods after SRS were 7.4, 4.0, 7.4, 3.4, 4.9 and 4.6 months for one to four (267 patients), five to nine (61 patients), ten to 14 (25 patients), 15–19 (14 patients), 20–29 (20 patients) and 30 or more metastases (nine patients), respectively (p = 0.0002). Furthermore, on univariate analysis, the number of metastases was found to be a strong predictive factor for survival (p = 0.0013). However, one major limitation of the study is that there were significantly fewer patients with large numbers of brain metastases. More recently, however, a number of retrospective studies of patients treated with SRS for many metastases (in clinical settings where SRS was used as consolidative or salvage radiosurgery after WBRT or as a definitive intervention) have been published, suggesting that the number of brain metastases does not predict overall survival. A summary of these studies is provided in Table 2.

Table 2. . Summary of studies examining prognostic factors in overall survival for stereotactic radiosurgery-treated patients.

Study (year) Patients (n) Metastases (n) Median survival (weeks) Most important predictors of overall survival Ref.
Raldow et al. (2012) 103 Group 1: 5–9
Group 2: ≥10		 Group 1: 7.6
Group 2: 8.3
(not significant)		 KPS score was the only variable significantly affecting overall survival [23]
Yamamoto et al. (2009) 456 Group 1: 1–4
Group 2: 5–9
Group 3: 10–14
Group 4: 15–19
Group 5: 20–29
Group 6: ≥30		 Group 1: 29.6
Group 2: 16
Group 3: 29.6
Group 4: 13.6
Group 5: 19.6
Group 6: 18.4		 Age, number of lesions, minimum lesion volume, mean volume, maximum volume and cumulative tumor volume, lesion dose and maximum dose [30]
Yamamoto et al. (2012) 1676 Group 1: 1–4
Group 2: 5–9
Group 3: 10–14
Group 4: 15–19
Group 5: 20–24
Group 6: 25–29
Group 7: 30–39
Group 8: ≥40		 Group 1: 33.2
Group 2: 21.2
Group 3: 27.6
Group 4: 20.8
Group 5: 23.2
Group 6: 12
Group 7: 21.2
Group 8: 17.2		 Statistically significant survival difference between patients with a single metastasis and those with more metastases. Number of metastases, if greater than one, did not affect survival [31]
Nam et al. (2005) 130 Group A: 1–3
Group B: ≥4		 Group A: 48
Group B: 26
(significant)		 RPA class [32]
Bhatnagar et al. (2006) 205 4–18 32 weeks RPA class and treatment volume [33]
Karlsson et al. (2009) 1855 ≥2+ 8.6 Primary tumor control and patient age [35]
Serizawa et al. (2008) 2390 1 to ≥25 Chiba (Japan): 30.8
Mito (Japan): 28		 Active extracranial disease, male gender and low initial KPS [36]
Yamamoto et al. (2012) 3753 ≥1 7.3 KPS, tumor numbers, primary tumor status and extracranial metastases [37]
Serizawa et al. (2010) 1508 1–10 1 metastasis: 52
2–4 metastases: 35
5–10 metastases: 32		 Male gender, RPA class, primary site and number of tumors (single vs multiple metastases). Equivalent survival for patients with two to four and five to ten metastases managed with initial definitive SRS [38]
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KPS: Karnofsky performance status; RPA: Recursive partitioning analysis; SRS: Stereotactic radiosurgery.

More recently, Yamamoto et al. reported that, in a larger cohort of 1676 patients managed with Gamma-knife SRS for brain metastases, there was a statistically significant survival difference between patients with a single metastasis and those with more metastases, but that the number of metastases, if greater than one, did not affect survival [31]. In this larger series, the mean and median lesion numbers were seven and three (range: 1–85), respectively. Overall median survival times after SRS were 9.0 months in females and 5.9 months in males (p < 0.0001). The Kaplan–Meier method was used to assess tumor numbers by group: one to four, five to nine, ten to 14, 15–19, 20–24, 25–29, 30–39 and ≥40. The post-SRS median survival times were 8.3, 5.3, 6.9, 5.2, 5.6, 3.0, 5.3 and 4.3 months, respectively (p < 0.0001).

Nam and colleagues evaluated the role of SRS in patients with four or more brain metastases [32]. They looked at 130 patients who underwent SRS, of whom 30 received only SRS, while five had further surgical resection, 78 had WBRT, and 17 had surgery and WBRT. This cohort also had 84 patients presenting with one to three metastases and 46 presenting with four or more metastases. While the survival time for patients with one to three brain metastases was significantly higher than that for patients with less than three brain metastases (48 vs 26 weeks; p = 0.005), the only significant prognostic factor affecting overall survival that was identified in a multivariate analysis was RPA class and not the number of metastases.

Bhatnagar et al. performed a study at the University of Pittsburgh (PA, USA) where the survival outcome of 205 patients treated with SRS for four or more intracranial metastases was examined [33]. Out of all the patients 17% had SRS for the primary management of their metastases, while 46% had WBRT with consolidative SRS and 38% had WBRT with salvage SRS. The median number of metastases was five (range: 4–18). The median overall survival after treatment was 8 months, the 1year local control rate was 71% and the median time to progression or new brain metastases was 9 months. Median overall survival for RTOG RPA classes I, II and III were 18, 9 and 3 months, respectively (p < 0.00001). These survival rates are superior to those reported by the investigators who developed the RTOG RPA scheme for patients treated with WBRT (median survivals of 7, 4 and 2 months for classes I, II and III, respectively) [34]. The multivariate analysis by Bhatnagar et al. revealed that the number of metastases was not a significant prognostic factor for overall survival (p = 0.333). However, this improved outcome may also be the result of selection or referral biases, differences in chemotherapy use or other unknown causes. It is also noteworthy that Bhatnagar et al. found increased treatment volume as a significant prognostic factor in both overall survival and local recurrence, suggesting that future trials should consider total metastasis volume rather than number of metastases as a critical factor.

One of the largest studies to date examining factors influencing survival time in patients with brain metastases after SRS was carried out by Karlsson et al. [35]. This study evaluated 1855 patients who underwent 2448 total SRS treatments. They found that patients with single metastases survived longer than those with multiple metastases. Regardless of the number of metastases (including single metastases), control of primary disease remained the dominant determinant of survival. Furthermore, there was no significant difference in median survival among patients with two, three to four, five to eight, or more than eight metastases. They concluded that primary tumor control and patient age were the most important factors in predicting median survival time and that number of metastases should not be used as a criterion to assess eligibility for SRS.

Serizawa et al. recently reported a study comparing the results of SRS for brain metastases at two institutions in Japan: Gamma House at Chiba Cardiovascular Center (Chiba, Japan) and Mito Gamma House, Katsuta Hospital (Mito, Japan) [36]. The number of metastases ranged from one to 25 or more, and all visible metastases were irradiated with a total skull integral dose of ≤10–12 J. Median survival times were 7.7 months in Chiba and 7.0 months in Mito (p = 0.0635). Significant factors that were identified to predict a poor overall survival on multivariate analysis included active extracranial disease, male gender and low initial KPS (p < 0.0001).

An even larger study was carried out by Yamamoto et al. who merged more data from the Mito and Chiba radiosurgery programs. A total of 3753 patients, who were RTOG RPA class II and had received initial, definitive Gamma-knife SRS, were analyzed [37]. The data from one institution were evaluated to identify four dichotomous prognostic factors that were then tested on the other institution's data. The factors favoring longer survival in RTOG RPA class II patients treated with initial definitive SRS were: KPS (90–100 vs 70–80%), tumor numbers (solitary vs multiple), primary tumor status (controlled vs not controlled) and extracranial metastases (no vs yes). Yamamoto et al. proposed a new index for these patients that is the sum of scores (0 or 1) of these four factors: RPA class II-a, score of 0 or 1; RPA class II-b, score of 2; and RPA class II-c, score of 3 or 4. This new system showed highly statistically significant differences among subclasses in the data from both institutions (p < 0.001 for all subclasses). In addition, this new index was confirmed to be applicable to class II patients with lung, breast, gastrointestinal and genitourinary malignancies.

Japanese Gamma-knife users, based upon the data from the multi-institutional prospective study conducted by Serizawa et al. [24], have embarked upon a prospective multi-institutional trial of Gamma-knife SRS for patients with one to ten newly diagnosed brain metastases that will not incorporate WBRT in the initial management (JLGK0901) [104]. Outcomes for patients, stratified by numbers of brain metastases, will be reported, to determine what differences may exist for patients with varying numbers of metastases.

A retrospective review of 1508 patients who met the eligibility criteria for JLGK0901 identified three groups of patients: group A, single metastases (565 patients); group B, two to four metastases (577 patients); and group C, five to ten metastases (366 patients) [38]. The overall mean survival time was 0.78 years, with patients with a single metastasis having a mean survival of 0.99 years, patients with two to four metastases having a mean survival of 0.68 years and patients with five to ten metastases having a mean survival time of 0.62 years. A multivariate analysis revealed significant prognostic factors for overall survival to be male gender (p < 0.0001), RTOG RPA class (class I vs class II and class II vs class III; both p < 0.0001), primary site (lung vs breast; p = 0.0047) and number of tumors (group A vs group B; p < 0.0001). However, no statistically difference was detected between groups B and C (p = 0.1027; hazard ratio: 1.124; 95% CI: 0.999–1.265). The results of this analysis were predicted to foreshadow the anticipated results of JLGK0901 – noninferiority for survival for SRS alone for patients with five to ten brain metastases, relative to patients with two to four brain metastases.

Finally, while primary site histology has not always been found to be prognostically important by other studies, the most recent publications by Sperduto et al. suggest that in the new era of targeted therapies, significant prognostic factors vary by histological diagnosis [39,40]. The diagnosis-specific prognostic factors from the retrospective analyses by Sperduto et al. for patients with brain metastases for some common cancers are summarized in Table 3.

Table 3. . Summary of prognostic factors influencing median survival in different cancers.

Cancer subtype Prognostic factors
Non-small-cell and small-cell lung cancer Age, KPS, ECM and number of BM
Melanoma KPS and number of BM
Breast cancer KPS, subtype (Lum A, HER2 and Lum B) and age
Renal cell carcinoma KPS and number of BM
GI cancers KPS
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BM: Brain metastases; ECM: Extracranial metastases; GI: Gastrointestinal; KPS: Karnofsky performance status; Lum A: Luminal A; Lum B: Luminal B.

Current opinion on SRS for more than four metastases

The majority of clinical trials described in this review find there is no reduction in overall survival through the use of SRS, although many do find an increased rate of intracranial relapse or new metastases among patients with more than four metastases. Current opinion is divided over whether to use SRS for the treatment of multiple metastases. A recent survey of physicians at two radiosurgery meetings (8th Biennial Congress and Exhibition of the International Stereotactic Radiosurgery Society in San Francisco and the 18th Annual Meeting of the Japanese Society of Stereotactic Radiosurgery in Sendai) included a questionnaire in which respondents were asked questions regarding how many brain metastases they would treat [41]. Results from surveys at both meetings showed that the highest number of metastases physicians were willing to treat with SRS alone was 50. In the San Francisco survey, the mean and median number of metastases physicians considered treating with SRS alone were 6.7 and five, respectively. In Sendai, these numbers were 11 and ten. Furthermore, in San Francisco, 55% of respondents considered treating five or more metastases and 22% considered treating ten or more metastases ‘reasonable’. In Sendai, 83% of respondents considered treating five or more metastases and 57% considered treating ten or more metastases ‘reasonable’. Although there is wide variation in treatment practices and opinions regarding SRS alone, it is noteworthy that more than half the respondents at both meetings were willing to treat patients with five or more metastases. This lack of consensus among expert physicians warrants the need for randomized controlled trials assessing the efficacy of SRS treatment for patients with many brain metastases.

In North America, the American Society for Radiotherapy and Oncology has carried out a systematic evidence-based review of the use of SRS in patients with brain metastases [42]. One of their key findings was that level I to II/III evidence existed that the use of SRS alone as initial therapy does not alter overall survival. Although the clinical trials used to establish this conclusion mainly enrolled patients with one to three brain metastases, the review does not explicitly state the number of metastases appropriate for SRS therapy and instead leaves that decision to the treating physician.

The National Comprehensive Cancer Network, attempting to rely on only the highest quality data for generating universal management recommendations, has promulgated recommendations that WBRT be used as the definitive management for patients with more than three brain metastases [105]. If upon surveillance imaging new or recurrent brain metastases are seen, re-irradiation for salvage (which could presumably include SRS only if there are one to three metastases visualized on the surveillance MRI scan) is listed as a management option. In an interesting juxtaposition to the National Comprehensive Cancer Network's blanket recommendation of WBRT as the only appropriate management approach for patients with more than three brain metastases, repeat SRS is listed as a management option for patients who had presented initially with one to three brain metastases and had been managed with definitive SRS. Presumably patients could, through this approach, have multiple SRS sessions, as long as each time that brain metastases are visualized, only one to three new metastases are seen.

Cancer Care Ontario's Progress in Evidence-Based Care report on the management of brain metastases is under review at present [106]. The extant guidelines, dating back to 2004, do not address the use of SRS as an exclusive treatment or consider the role of SRS in the management of more than four brain metastases [43].

Conclusion

In conclusion, current evidence, based on randomized controlled trials, supports the notion that SRS alone is sufficient to treat patients with one to four brain metastases while avoiding the long-term effects of WBRT. Evidence for the use of SRS for more than four metastases is currently limited to retrospective studies and not randomized controlled trials. However, retrospective studies presented in this review generally suggest that in selected patient populations, such as those with a young age, good KPS scores and primary tumor control, there is no difference in overall survival when comparing SRS with WBRT for multiple metastases. The reasons why the majority of physicians attending radiosurgery meetings would consider it ‘reasonable’ to treat five or more brain metastases with SRS, despite the lack of randomized controlled trial data showing it to be superior to WBRT are unclear, but it is possible that the neurocognitive side effects associated with WBRT and increasing ease of accessing and delivering SRS have led to this increased use of SRS at many medical centers, despite the increased labor and costs associated with SRS. SRS is generally well tolerated by patients and the available randomized controlled trial data on neurocognitive outcomes and quality of life outcomes do not overwhelmingly favor one approach, so it seems with the lack of unarguable data on these end points and since there is no clear survival superiority with the use of SRS compared with WBRT, the next step will be to perform randomized controlled trials comparing SRS alone with WBRT for patients with more than five metastases to truly assess other advantages of SRS treatment for multiple metastases, such as effects on neurocognitive function, quality of life and functional independence. In this vein, the North American Gamma-knife Consortium is opening a randomized controlled trial (NAGKC 12–01) comparing radiosurgery to WBRT for patients with five or more metastases, with neurocognitive status and tumor control as the primary end points [107].

Future perspective

The indications for the use of SRS alone in the treatment of patients with brain metastases continue to evolve even in the minds of the radiosurgeon. Not only is the number of metastases for first-time treatments increasing, but the number of metastases treated at time of salvage after both initial SRS or WBRT is also increasing. As briefly discussed above, the whole-brain dose administered after multiple sessions of radiosurgery to innumerable metastases has not been studied well. Data are very much needed, therefore, in the areas of neurocognition and its impact on quality of life for patients with different durations of survival. Additionally, the cost of treatment needs to be studied in terms of quality-adjusted life years for cancer survivors. Hopefully, trials such as NAGKC 12–01 and JLGK0901 will provide the highest quality evidence to establish the relative roles of SRS and WBRT in the treatment of patients with more than four brain metastases.

Footnotes

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

References

Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

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