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Keywords:

  • brain metastases;
  • stereotactic radiosurgery;
  • whole brain radiotherapy;
  • meta-analysis;
  • neurocognition

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. REFERENCES

BACKGROUND:

To perform a meta-analysis on newly diagnosed brain metastases patients treated with whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) boost versus WBRT alone, or in patients treated with SRS alone versus WBRT and SRS boost.

METHODS:

The meta-analysis primary outcomes were overall survival (OS), local control (LC), and distant brain control (DBC). Secondary outcomes were neurocognition, quality of life (QOL), and toxicity. Using published Kaplan-Meier curves, results were pooled using hazard ratios (HR).

RESULTS:

Two RCTs reported on WBRT and SRS boost versus WBRT alone. For multiple brain metastases (2-4 tumors) we conclude no difference in OS, and LC significantly favored WBRT plus SRS boost. Three RCTs reported on SRS alone versus WBRT plus SRS boost (1-4 tumors). There was no difference in OS despite both LC and DBC significantly favoring WBRT plus SRS boost. Although secondary endpoints could not be pooled for meta-analysis, those RCTs evaluating SRS alone conclude better neurocognition using the validated Hopkins Verbal Learning Test, no adverse risk in deteriorating Mini-Mental Status Exam scores or in maintaining performance status, and fewer late toxicities. We conclude insufficient data for QOL outcomes.

CONCLUSIONS:

For selected patients, we conclude no OS benefit for WBRT plus SRS boost compared with SRS alone. Although additional WBRT improves DBC and LC, SRS alone should be considered a routine treatment option due to favorable neurocognitive outcomes, less risk of late side effects, and does not adversely affect the patients performance status. Cancer 2012. © 2011 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. REFERENCES

Treatment options for selected patients with good prognosis (eg, Karnofsky performance status [KPS] at least 70% or World Health Organization (WHO) performance status of 0-2 and controlled or quiescent extracranial disease1, 2) have evolved over the last few decades. Whole-brain radiation (WBRT)3 and steroids were the standard of care before the development of stereotactic radiosurgery (SRS). As SRS developed into a safe and focal high dose treatment for brain metastases4 to optimize local control, the first question to be tested was the use of SRS as a “boost” to WBRT.5, 6 Two randomized controlled trials (RCTs) were conducted and concluded significant improvements in local control secondary to boost SRS,5, 6 and 1 study reported a modest overall survival (OS) benefit for patients with only a single brain metastasis.5

The question then evolved to test SRS alone with the intent to spare patients the side effects of WBRT, notably neurocognition. The landmark RCT was reported in 2006 by Aoyama et al,7 where patients with 1 to 4 brain metastases were randomized to SRS alone or WBRT and SRS boost. Although WBRT and SRS boost resulted in a modest gain in local control and a lower incidence of new brain metastases, no OS difference was observed (this trial was initially powered for OS; however, halted at the interim analysis with sufficient power to detect a significant difference in brain tumor recurrence rates). It is only recently that 2 RCTs8, 9 have been reported comparing SRS alone to WBRT and SRS boost to further our understanding of the treatment options and expand our knowledge beyond the Aoyama study.7 However, these 2 recent RCTs departed from the traditional design of being powered for brain tumor control or OS and, alternatively, were powered to test functional outcomes as their primary endpoint. The Chang study8 measured neurocognition using the validated Hopkins Verbal Learning Test (HVLT), and the European Organization of Research and Treatment of Cancer (EORTC) study9 measured functional independence as determined by maintaining a WHO performance status of at least 2. The resulting heterogeneity in the primary endpoints among the reported RCTs (Table 1) makes conclusions with respect to local control and OS dependent on a meta-analysis. The purpose of this study was to perform the first meta-analysis incorporating these 2 most recent RCTs with the aim to determine the effectiveness of WBRT and SRS boost versus WBRT alone, and SRS alone versus WBRT and SRS boost.

Table 1. Summary of the Phase III Randomized Controlled Studies Selected for this Meta Analysis
RCT% Single Brain MetsPerformance StatusTumor SizePrimary EndpointLocal ControlDistant ControlOSBaseline NeurocognitionNeurocognitive OutcomesNeurologic Death
  • Abbreviations: HVLT, Hopkins verbal learning test; HR, hazard ratio; KPS: Karnofsky performance status; MMSE: Mini-Mental Status Exam; mo: months; NR, not reported; NSIG, not significant; SRS, stereotactic radiosurgery; TV, total volume; WBRT, whole-brain radiotherapy; WHO, World Health Organization; yr: year.

  • a

    Note: ∼44% and 42%, respectively, were not reviewed for local control analysis.

  • bThe primary endpoint intended was OS but patient accrual was insufficient for this endpoint at the interim analysis and sufficient only to detect a significant difference in brain tumor recurrence rates.

  • cNote for patients with more than 1 metastases the breakdown consisted of 72 patients in the WBRT + SRS arm and 73 in the WBRT-alone arm. dThe survival data are based on those randomized to observation as opposed to WBRT after surgery or radiosurgery and not specific to SRS alone versus SRS plus WBRT, however, no significant difference was observed for adjuvant WBRT in any of the subgroups.

Aoyama:7 SRS (n = 67) vs WBRT + SRS (n = 65)49% vs. 48%52% KPS 90-100 vs. 66% KPS 90-100Median: 1.3 cm (0.2-3.0 cm) vs. 1.4 cm (0.2-3.0cm)Brain tumor recurrenceb72.5% vs 88.7% at 1 y (P = .002)36.3% vs 58.5% at 1 y (NSIG)28.4% vs 38.5% at 1 y (NSIG)Average MMSE: 26.7 vs 27.13 point deterioration in MMSE (NSIG)19.3% vs 22.8% (NSIG)
Chang:8 SRS (n = 30) vs WBRT + SRS (n = 28)60% vs. 54%100% KPS ≥70 (each arm)Median TV: 1.4 cc (0.1- 20) vs. 2.3 cc (0.05-27)Neuro-cognition: HVLT at 4 months67% vs 100% at 1 y (P = .012)45% vs 73% at 1 y (P = .02)63% vs 21% at 1 y (P = .003)Baseline scores providedMean posterior probability of decline at 4 months: 24% vs 52% (SIG)HR: 2.1 (NSIG)
Kocher:9 SRS (n = 100) vs WBRT + SRS (n = 99)68% vs. 66%100% WHO status 0-2 (in each arm)Median: 2.0 cm (0.4-4.0 cm) vs. 1.8 cm (0.5-3.4 cm)Duration of functional independence69% vs 81% at 2 y (P = .008)52% vs 67% at 2 y (P = .023)NSIGaNRNRNR
Kondziolka:6 WBRT + SRS (n = 13) vs WBRT (n = 14)0%100% KPS ≥70 (each arm)All tumors <2.5 cmLocal control92% vs 0% at 1 y (P = .0016)NRMedian: 11 mo vs. 7.5 mo (NSIG)NRNRNR
Andrews:5 WBRT + SRS (n = 164) vs WBRT (n = 167)56% vs. 56%57% KPS 90-100 vs. 63% KPS 90-10050.5% ≤2 cm and 49.5% >2 cm vs. 59% ≤2 cm and 41% >2 cmOverall Survival89% vs 83% at 3 mo;a 82% vs 71% at 1 y (P = .01)NRMedian Single mets: 6.5 mo vs. 4.9 mo (P = .04) Multiple mets: NSIGMMSE: ∼85% 25-30 (both arms)Worse or Unchanged: 38% vs. Worse or unchanged: 48% (NSIG)NSIG

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. REFERENCES

A literature search was carried out for RCTs comparing WBRT and SRS boost versus WBRT alone, and RCTs comparing SRS alone versus WBRT and SRS boost for the initial management of adult (age >18) patients with newly diagnosed brain metastases (single or up to 4). We excluded prospective nonrandomized or retrospective cohort studies, and studies reported only in abstract form. All patients had to have single fraction SRS with either Gamma Knife (Elekta, AB, Stockholm, Sweden) or linac based technologies. MEDLINE (1966-Nov. 3, 2010), EMBASE (1980-2010, week 46), and the CENTRAL databases (issue 4, 2010) were searched. The search strategies resulted in 1826 publications, 597 publications, and 425 publications (search strategy courtesy of the Cochrane Library), respectively. One trial was excluded as the trial was closed prematurely as accrual was insufficient, and despite being published, no conclusions could be drawn.10 This left 5 published RCTs5-9 and the details of each are summarized in Table 1. Importantly, for the RCT by Kocher et al9 the treatment arms randomizing to surgery alone versus surgery followed by WBRT were excluded for this analysis, and only the data from the SRS alone versus WBRT and SRS boost randomization were included.

The primary outcome measures for this meta-analysis were OS, local control (based on the outcome of the treated brain metastases with SRS or of those brain metastases present at the time of WBRT), and distant brain control (defined as control of brain metastases not treated with SRS). Secondary outcomes included neurocognitive function, quality of life (QOL), and treatment-related toxicity.

Data Collection and Analysis

All eligible studies were retrieved and evaluated by 2 reviewers (MT, AS). The Generic inverse variance method and fixed effects model in Review Manager (RevMan 5) were used for this meta-analysis. The meta-analytic method makes fewer assumptions about the similarity of the studies in design and execution. The fixed effects analysis is a classical meta-analysis technique on the pooled database. It applies tests of heterogeneity on whether the participating studies are sufficiently similar to be combined in a meta-analysis. The outcome measures considered for data pooling were the log hazard ratio (lnHR) and its variance, which were estimated using Hazard Ratio Meta-analysis Tool Box.11 Forest plots were provided with pooled hazard ratios (HRs), and corresponding 95% confidence intervals (CIs). The meta-analyses were applied separately on OS, local control, and distant brain control.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. REFERENCES

Study Characteristics

A summary of pertinent outcomes from each of the 5 analyzed RCTs are summarized in Table 1. Patient factors at the time of randomization were similar among the studies where most patients had a Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA1) class of I or II (8), KPS of 70 or greater and/or a WHO performance status (PS) ranging from 0 to 2, stable systemic disease, and the maximum diameter of the individual brain target(s) did not exceed approximately 4 cm in size.

RCTs Comparing WBRT and SRS Boost versus WBRT Alone

Primary outcomes

Two RCTs (5, 6) evaluated WBRT and SRS boost versus WBRT alone. However, the RTOG Andrews5 study (5) included patients with 1 to 3 brain metastases, and the Kondziolka6 study included patients with 2 to 4 brain metastases. As such, results for single brain metastasis patients could not be pooled. For multiple brain metastases, the pooled analysis of a total 172 participants (Fig. 1) yielded no difference in OS with a HR of 1.63 (95% CI 0.72-3.69; P = .24). For single brain metastases, the Andrews5 study did report an OS advantage favoring WBRT and SRS boost over WBRT alone by univariable analysis (median survival 6.5 months vs 4.9 months; P = .0393), and P = .053 on multivariable analysis. Pooled analysis for local control (all patients included for a total 358 participants) yielded a significant difference favoring WBRT and SRS boost compared with WBRT alone (Fig. 2) with an HR of 2.88 (95% CI 1.63-5.08; P = .0003). We could not pool results for the risk of new brain metastases as these data were not explicitly reported.

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Figure 1. Overall survival: whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) boost versus WBRT alone.

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Figure 2. Local Control: WBRT and SRS boost versus WBRT alone.

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Secondary outcomes

Neurocognitive outcomes were not reported in the Kondziolka6 study. In the Andrews5 study, no difference in mental status was reported (3) between the 2 arms based on the Mini-Mental Status Exam (MMSE). Neither trial reported on QOL outcomes using a validated QOL instrument. In the Andrews et al5 study, no patient experienced acute grade 3 or 4 toxicities in the WBRT alone arm, whereas 2% grade 3 and 1% grade 4 acute toxicities were observed in those treated with WBRT and SRS boost. There were 2% grade 3 and 1% grade 4 late toxicities in the WBRT alone arm, and 3% grade 3 and 3% grade 4 late toxicities in the WBRT and SRS boost arm. Kondziolka et al6 reported no neurologic or systemic morbidity related to SRS, however, after WBRT patients developed mild scalp erythema and hair loss.

RCT Comparing SRS Alone versus WBRT and SRS Boost

Primary outcomes

Three RCTs evaluated patients treated with either SRS alone or WBRT and SRS boost7-9. The pooled analysis (Fig. 3) for OS could only be performed on data from the Aoyama7 and Chang8 study for a total 190 participants, and yielded no OS difference with a HR of 0.98 (95% CI 0.71-1.35, p = 0.88). In the Kocher9 study, they reported OS such that we could not isolate the SRS alone arm from the WBRT plus SRS boost arm. The study reported no significant difference in OS amongst those treated with WBRT as compared to observation (median survival of 10.9 months versus 10.7 months, respectively), importantly, they state that adjuvant WBRT did not confer any significant advantage for OS in any of the subgroups (this would include those randomized to SRS alone and those to WBRT plus SRS boost). We were able to pool data from all three studies for local control and distant brain control. We observe significant differences favoring WBRT and SRS boost in local control of the treated brain metastases (Fig. 4) with a HR of 2.61 (95% CI 1.68-4.06, p<0.0001), and in distant brain control (Fig. 5) with a HR of 2.15 (95% CI 1.55-2.99, p <0.00001).

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Figure 3. OS: SRS alone versus WBRT plus SRS boost.

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Figure 4. Local Control SRS alone versus WBRT plus SRS boost.

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Figure 5. Distant brain control: SRS alone versus WBRT plus SRS boost.

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Secondary outcomes

Chang et al8 evaluated neurocognition using the HVLT as the primary endpoint of the study. Patients assigned to WBRT and SRS boost were significantly more likely to show a decline in learning and memory function compared with those assigned to SRS alone. In the Aoyama7 study, neurocognitive function was optionally assessed using the MMSE and not an a priori endpoint of the study. No significant difference in MMSE scores on follow-up were observed between the 2 arms. As these neurocognitive tests are not directly comparable, and the MMSE is not regarded an appropriate measure of neurocognition but of dementia,12 the results were not pooled.

QOL outcomes were specifically reported by Chang et al.8 At 4 months, the mean FACT-BR score was 58 for the WBRT and SRS boost arm and 65.6 for the SRS alone arm. The mean difference between the groups at 4 months compared with baseline was 2.8 (95% CI = −26-21; P = .76) favoring SRS alone. However, conclusions due to the wide CIs associated with the measurements resulted in the inability to render definitive support for the SRS alone arm. Although the QOL component to the Kocher9 study has yet to be reported, the study concludes that treatment was not a predictive factor in the ability for a patient to maintain a WHO performance status of at least 2, which was the primary endpoint of the study.

With respect to serious toxicities, in the Aoyama study7 grade 3 acute neurologic toxicity was observed in 1/65 (3%) patients receiving WBRT and SRS boost compared with 2 of 67 (3%) patients treated with SRS alone (no grade 4 events reported). Grade 3 and 4 late neurologic toxic effects were observed in 4 of 65 (6%) patients treated with WBRT and SRS boost (2 grade 3 and 2 grade 4) compared with 2 of 67 (3%) patients treated with SRS alone experiencing a grade 4 neurotoxic event (no grade 3 events). Any grade of radiographic leukoencephalopathy was observed in 11% of patients (7 of 65) treated with WBRT and SRS boost compared with 3% patients (2 of 67) treated with SRS alone. No grade 4 events were reported in either arm, and grade 3 events were limited to those (2 of the 9 events) treated with WBRT plus SRS boost. In the Chang8 study, there was 1 case of grade 3 toxicity (seizures, motor neuropathy, decreased level of consciousness) in the WBRT and SRS boost arm compared with 1 case of grade 3 toxicity (aphasia) in the SRS alone arm. Two cases of grade 4 toxicity were observed in the SRS alone arm, which manifested as pathologically proven radiation necrosis. Kocher et al9 reported contrast-enhancing lesions suspicious of radiation-induced breakdown of the blood-brain barrier in 8% following SRS and in 13% following WBRT plus SRS boost, and one patient likely died from radionecrosis following WBRT plus SRS boost.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. REFERENCES

RCTs Comparing WBRT and SRS Boost versus WBRT Alone

The 2 RCTs comparing WBRT to WBRT and SRS boost5, 6 fundamentally ask the question of the role in optimizing local control by adding SRS as a boost when overall brain control is maximized by WBRT. Our meta-analysis was able to pool OS data for those treated with multiple brain metastases only, as the Kondziolka6 study restricted entry to patients with 2 to 4 brain metastases and the Andrews5 study reported data for those with single versus multiple brain (2 or 3) metastases separately. For multiple metastases, we conclude no OS advantage with the use of SRS as a boost to WBRT with an HR of 1.63 (95% CI 0.72-3.69; P = .24) (Fig. 1). However, the Andrews5 study reported a significant difference in OS for those patients with a single brain metastasis treated with WBRT and SRS boost compared with WBRT alone (median survival of 6.5 months vs 4.9 months, P = .0393). Importantly, this RCT was powered for OS and a priori for patients with single brain metastasis.5 Although OS for a treated single brain metastasis significantly favored WBRT and SRS boost (compared with WBRT alone) in the univariable analysis, the multivariable analysis yielded a P = .053 for treatment compared with P < .0001 for class 1 RPA status.5

Pooled results for local control from both RCTs5, 6 resulted in a statistically significant improvement in local control with an HR of 2.88 (95% CI 1.63-5.08; P = .0003) (Fig. 2) favoring WBRT and SRS boost. However, this result should be interpreted with caution as there are potential sources of bias. For example, the local failure rate with WBRT in the Kondziolka6 study was unexpectedly high at 100%, which has not been reproduced. Furthermore, this study was stopped early with only 14 patients randomized to WBRT alone and 13 to WBRT and SRS boost. Alternatively, the Andrews5 study completed with a much larger sample size with 164 patients randomized to WBRT and SRS boost and 167 patients randomized to WBRT alone. Although, they report local control favoring the addition of SRS boost with an 82% vs 71% local control rate at 1 year, missing data on local control was a confounding factor. The authors reported at the 3 month follow-up time point that only 60% of patients had imaging available for central review. Although, a local control benefit would not be unexpected given that additional dose to the tumor should indeed improve tumor control.

With respect to distant brain control, we could not pool the results from the 2 studies as data were not reported specifically for this endpoint. However, overall brain control (considering both local and distant brain failures) was described as the median time to any brain failure in the Kondziolka6 study. Failure occurred at 5 months in those treated with WBRT and 34 months for those treated with WBRT and SRS boost (P = .002).6 In contrast, Andrews et al5 report no significant differences between those treated with WBRT and SRS boost versus WBRT alone with respect to overall time to intracranial progression (P = .1278). Therefore, it is unclear from the 2 published trials whether there is a significant difference in the development of new brain metastases for patients treated with WBRT and SRS boost versus WBRT alone. However, intuitively as both arms are treated with WBRT, one would expect a similar risk of new distant brain metastases.

Therefore, we can conclude that SRS as a boost improves local control compared with WBRT alone, and for patients with single brain metastasis (as opposed to multiple) the local control benefit translates into a gain in OS. Hence, if local control is not optimized using SRS, then only is there potential for an OS advantage when the alternative is WBRT alone (and in patients with favorable prognostic factors, that is, RPA1 class 1 status).

SRS alone versus WBRT plus SRS boost

Fundamentally, those RCTs evaluating SRS alone to WBRT plus SRS boost7-9 were designed to answer the question of the need for WBRT when local control is optimized by using SRS in each treatment arm. The clinical aim of SRS alone was to avoid the potential side effects associated with WBRT, notably neurocognitive decline. We conclude based on our meta-analysis that the addition of WBRT to SRS significantly improves distant brain control with an HR of 2.15 (95% CI 1.55, 2.99; P < .00001) (Fig. 5), and local tumor control with an HR of 2.61 (95% CI 1.68-4.06; P < 0001) (Fig. 4). These results are biologically sound as subclinical microscopic disease in the brain remains untreated without WBRT, resulting in a greater risk of new brain metastases with time. This observation has been confirmed by RCTs evaluating prophylactic cranial irradiation (PCI) in lung cancer patients,13-15 as a lower incidence of brain metastases has been reported in those prophylactically radiated as opposed to those observed. The reported improvement in local tumor control is also expected given that the additional dose delivered by the WBRT serves to intensify the SRS dose given to the tumor.

However, despite these observed benefits of WBRT to SRS alone, we conclude no OS advantage for adjuvant WBRT based on the pooled data from the Chang8 and Aoyama7 study with a HR of 0.98 (95% CI 0.71-1.35, p = 0.88, Figure 3). This result confirms the Kocher9 study who reported no significant advantage for adjuvant WBRT in any of the subgroup arms, and that would include those randomized to SRS alone and WBRT plus SRS boost. As the OS curves were not reported for each subgroup independently, we could not pool their data for meta-analysis. The lack of OS advantage to WBRT can be explained by considering several factors. First, these studies were designed to optimize local control in both the experimental and control arms using SRS, as opposed to the Andrews5 and Kondziolka6 study where the control arm consisted of patients treated suboptimally for local control with WBRT alone. Second, the result likely reflects the observation that OS is determined according to those powerful prognostic factors such as primary cancer type,2 age,1 performance status,1 systemic disease status,1 and use of systemic chemotherapy,8 as opposed to overall brain control. Last, that OS survival is not compromised in patients treated with SRS alone as long as patients are followed closely and treated with salvage radiation (further SRS or WBRT) when appropriate at the time of intracranial relapse.7, 8, 9 Therefore we confirm, and provide updated robust HRs for the selected primary endpoints, those results from the initial Aoyama7 study such that WBRT plus SRS improves local control, distant brain control, and does not impact OS.

Although we could not pool the data for meta-analysis for the secondary endpoints proposed in this study, it is the interpretation of those secondary endpoints that provide insight as to why some have been such strong advocates of SRS alone. First, with respect to neurocognitive outcomes, the Chang study8 used a validated neurocognitive instrument to determine the impact of WBRT on cognition. This study was uniquely powered for this intent as the primary endpoint was based on the HVLT. Chang8 reported a significant improvement in learning and memory function at 4 months in those treated with SRS alone, and the benefit persisted at 6 months. With respect to longer term neurocognitive adverse sequelae of WBRT, a negative impact on learning and memory was recently reported even up to 1 year after WBRT after PCI again based on HVLT assessments.16 This PCI RCT16 on patients with lung cancer is highly relevant as neither arm had brain metastases at baseline, and worse learning and memory neurocognitive function was observed despite the lower incidence of metastases in the PCI arm compared with the controls. Therefore, one can conclude that it is the treatment effect of WBRT that affects neurocognition as opposed to the conjecture that brain metastases recurrence is the major source of neurocognitive decline.

Although the Aoyama study7 did evaluate neurocognition using the MMSE tool, this was not an a priori endpoint and optionally assessed. In 28 of the 44 patients who lived at least 1 year after treatment, MMSE scores were available at least once at the median follow-up times of 30.5 months in the WBRT plus SRS boost arm (16 patients) and 20.7 months in the SRS alone arm (12 patients).7 Aoyama reports no significant difference in MMSE scores between the 2 arms.7 However, the MMSE is a dementia screening tool and is considered at best a poor measure of neurocognition in brain metastases patients.12 Therefore, we could not pool the MMSE data with the formal neurocognitive HVLT results from the Chang8 study, and the latter remains the only study with outcomes based on a validated instrument to test neurocognition.

With respect to maintaining good performance status over time, as defined by a WHO score of at least 2, Kocher et al9 reported no significant difference among those treated with WBRT plus SRS boost compared with SRS alone. This study was specifically powered for this endpoint. A similar result was observed in the Aoyama et al7 RCT, where systemic functional preservation rates as measured by a KPS of ≥70 were not significantly different in those randomized to WBRT plus SRS boost and those to SRS alone (P = .53). Furthermore, in those studies reporting the risk of neurologic death according to the treatment arm, there has been no significant difference favoring 1 treatment approach over another. The relevant data from the RCTs are summarized in Table 1. Therefore, one can conclude that despite a greater risk of new brain metastases and risk of local tumor progression when treating with SRS alone, there is no adverse impact for patients in preserving their functional independence or in their cause of death. We postulate that this observation is associated with the timely use of salvage brain treatments before symptomatic manifestation of the recurrent tumors, which is possible as patients are followed with frequent imaging and clinical follow-up on study. However, we cannot validate this hypothesis within the reported RCT data.

With respect to QOL, the lack of reported data in the RCTs makes any conclusion of potential benefits of 1 treatment approach over another impossible. Although the Chang8 study did report better QOL scores for the SRS alone cohort, the wide CI in the data made the result inconclusive. With respect to toxicity, serious adverse events based on the individual RCTs may favor use of SRS alone. In particular, an increased risk of radiation necrosis with WBRT plus SRS boost has been reported compared with SRS alone by Kocher et al.9 Furthermore, leukoencephalopathy as a late effect was observed more in patients treated with WBRT as reported by Aoyama et al.7 Last, we learned from the Chang8 study that patients treated with SRS alone were treated sooner with systemic therapy and with more cycles of systemic therapy, and this may be a potential benefit for patients treated with SRS alone to consider. This imbalance in the treatment arms may have been a factor in the reported longer OS observed in the SRS alone arm compared with the WBRT and SRS boost arm in that study; however, based on meta-analysis and the Kocher study9 we observe no OS difference according to treatment arm.

For selected patients with up to 4 brain metastases eligible for SRS, our meta-analysis concludes no OS benefit for WBRT plus SRS boost compared with SRS alone despite significant gains in both local and distant brain tumor control with WBRT. SRS alone may allow patients to optimally retain their neurocognitive function, experience fewer serious late side effects, and are not at adverse risk with respect to maintaining performance status. Therefore, we conclude that SRS alone with frequent magnetic resonance imaging (MRI)-based follow-ups in order to salvage recurrent brain metastases before symptomatic manifestations, should be routinely offered to selected patients as a treatment option to consider.

FUNDING SUPPORT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. REFERENCES

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. REFERENCES
  • 1
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    Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009; 10: 1037-1044.
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    Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol. 2010; 29: 134-141.
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    Roos DE, Wirth A, Burmeister BH, et al. Whole brain irradiation following surgery or radiosurgery for solitary brain metastases: mature results of a prematurely closed randomized Trans-Tasman Radiation Oncology Group trial (TROG 98.05). Radiother Oncol. 2006; 80: 318-322.
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    Meyers CA, Wefel JS. The use of the mini-mental state examination to assess cognitive functioning in cancer trials: no ifs, ands, buts, or sensitivity. J Clin Oncol. 2003; 21: 3557-3558.
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