Effect of Radiosurgery Alone vs Radiosurgery With
Whole Brain Radiation Therapy on Cognitive Function
in Patients With 1 to 3 Brain Metastases
A Randomized Clinical Trial
Paul D. Brown, MD; Kurt Jaeckle, MD; Karla V. Ballman, PhD; Elana Farace, PhD; Jane H. Cerhan, PhD; S. Keith Anderson, MS; Xiomara W. Carrero, BS;
Fred G. Barker II, MD; Richard Deming, MD; Stuart H. Burri, MD; Cynthia Ménard, MD; Caroline Chung, MD; Volker W. Stieber, MD; Bruce E. Pollock, MD;
Evanthia Galanis, MD; Jan C. Buckner, MD; Anthony L. Asher, MD
IMPORTANCE Whole brain radiotherapy (WBRT) significantly improves tumor control in the
brain after stereotactic radiosurgery (SRS), yet because of its association with cognitive
decline, its role in the treatment of patients with brain metastases remains controversial.
OBJECTIVE To determine whether there is less cognitive deterioration at 3 months after SRS
alone vs SRS plus WBRT.
DESIGN, SETTING, AND PARTICIPANTS At 34 institutions in North America, patients with 1 to 3
brain metastases were randomized to receive SRS or SRS plus WBRT between February 2002
and December 2013.
INTERVENTIONS The WBRT dose schedule was 30 Gy in 12 fractions; the SRS dose was 18 to
22 Gy in the SRS plus WBRT group and 20 to 24 Gy for SRS alone.
MAIN OUTCOMES AND MEASURES The primary end point was cognitive deterioration (decline
>1 SD from baseline on at least 1 cognitive test at 3 months) in participants who completed the
baseline and 3-month assessments. Secondary end points included time to intracranial failure,
quality of life, functional independence, long-term cognitive s tatus, and ov er all survival.
RESULTS There were 213 randomized participants (SRS alone, n = 111; SRS plus WBRT,
n = 102) with a mean age of 60.6 years (SD, 10.5 years); 103 (48%) were women. There was
less cognitive deterioration at 3 months after SRS alone (40/63 patients [63.5%]) than when
combined with WBRT (44/48 patients [91.7%]; difference, −28.2%; 90% CI, −41.9% to
−14.4%; P < .001). Quality of life was higher at 3 months with SRS alone, including overall
quality of life (mean change from baseline, −1.3 vs −10.9 points; mean difference, 9.6; 95% CI,
3.6-15.6 points; P = .002). Time to intracranial failure was significantly shorter for SRS alone
compared with SRS plus WBRT (hazard ratio, 3.6; 95% CI, 2.2-5.9; P < .001). There was no
significant difference in functional independence at 3 months between the treatment groups
(mean change from baseline, −1.5 points for SRS alone vs −4.2 points for SRS plus WBRT;
mean difference, 2.7 points; 95% CI, −2.0 to 7.4 points; P = .26). Median overall survival was
10.4 months for SRS alone and 7.4 months for SRS plus WBRT (hazard ratio, 1.02; 95% CI,
0.75-1.38; P = .92). For long-term survivors, the incidence of cognitive deterioration was less
after SRS alone at 3 months (5/11 [45.5%] vs 16/17 [94.1%]; difference, −48.7%; 95% CI,
−87.6% to −9.7%; P = .007) and at 12 months (6/10 [60%] vs 17/18 [94.4%]; difference,
−34.4%; 95% CI, −74.4 % to 5.5%; P = .04).
CONCLUSIONS AND RELEVANCE Among patients with 1 to 3 brain metastases, the use of SRS
alone, compared with SRS combined with WBRT, resulted in less cognitive deterioration at 3
months. In the absence of a difference in overall survival, these findings suggest that for patients
with 1 to 3 brain metastases amenable to radiosurgery, SRS alone may be a preferred strategy.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00377156
JAMA. 2016;316(4):401-409. doi:10.1001/jama.2016.9839
Corrected on August 7, 2018.
Editorial page 393
Supplemental content at
jama.com
Author Affiliations: Author
affiliations are listed at the end of this
article.
Corresponding Author: Paul D.
Brown, MD, Department of Radiation
Oncology, Mayo Clinic, 200 First St
SW, Rochester, MN 55905
(brown.paul@mayo.edu).
Research
Original Investigation
(Reprinted) 401
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A
pproximately 30% of patients with cancer develop brain
metastases, and the incidence of these lesions is
rising.
1,2
Most patients present with oligometastatic dis-
ease, which is to say limited intracranial metastases, usually
defined as 1 to 3 lesions.
3
Stereotactic radiosurgery (SRS) is an
effective and commonly used treatment for brain metasta-
ses, but intracranial tumor progression is frequent after SRS
alone, primarily because of the development of new meta-
static lesions.
1,4,5
Previous randomized clinical trials (RCTs)
have consistently demonstrated improved intracranial tu-
mor control with the addition of whole brain radiotherapy
(WBRT) to SRS for cerebral oligometastases; the clinical sig-
nificance of this observation, however, remains unclear. None
of these prospective analyses have demonstrated a survival ad-
vantage to adjuvant WBRT, and a single RCT has reported a sur-
vival disadvantage.
1,4,5
Additionally, central to this issue is
whether tumor progression anywhere in the brain is more det-
rimental to a patient’s well-being than the potential deterio-
ration of cognitive function and quality of life (QOL) associ-
ated with WBRT.
4,6,7
Because more than 200 000 individuals
in the United States alone are estimated to receive WBRT each
year,
8
it is important that the potential benefits and risks of ad-
juvant WBRT be clearly defined. To address ongoing knowl-
edge gaps, N0574, a multi-institutional RCT, investigated the
role of adjuvant WBRT in patients with 1 to 3 brain metasta-
ses treated with SRS (see trial protocol in Supplement 1).
Methods
Study Design and Participants
Adult patients (≥18 years of age) with 1 to 3 brain metastases,
all smaller than 3 cm in diameter, were eligible for the trial. Eli-
gibility criteria included Eastern Cooperative Oncology Group
performance status (score of 0, no symptoms; 1, mild symp-
toms; 2, symptomatic, <50% in bed during the day), and patho-
logic confirmation of extracerebral tumor site (eg, lung, breast,
prostate) from either the primary site or a metastatic lesion.
Exclusion criteria included pregnant or nursing women, men
or women of childbearing potential unwilling to use ad-
equate contraception, inability to complete a magnetic reso-
nance imaging scan with contrast, prior resection of cerebral
metastasis, chemotherapy within 7 days of preregistration or
planned chemotherapy during the radiotherapy, prior cranial
radiotherapy, leptomeningeal metastases, lesion located within
5 mm of the optic chiasm or within the brainstem, or metas-
tases from primary germ cell tumor, small cell carcinoma, or
lymphoma. Prior to patient enrollment, each participating in-
stitution provided institutional review board approval and each
patient provided written informed consent.
Randomization and Masking
Eligible adult patients were enrolled at 34 participating insti-
tutions in the United States and Canada and were randomly
assigned in a 1:1 ratio to undergo either SRS plus WBRT or SRS
alone. Randomization was performed using a dynamic mini-
mization strategy with stratification according to age (<60 vs
≥60 years), duration of extracranial disease control (≤3 vs >3
months), number of brain metastases (1 vs 2 vs 3), and treat-
ment center. Randomized assignment to the treatment group
was done electronically. Neither patients nor clinicians were
blinded to treatment assignment, although the neuropsycholo-
gists grading the cognitive assessments were blinded to treat-
ment assignment.
Study Treatment
Patients randomly assigned to receive SRS alone received 24 Gy
in a single fraction if lesions were less than 2.0 cm or 20 Gy if
lesions were 2 to 2.9 cm in maximum diameter. Patients ran-
domly assigned to undergo SRS plus WBRT received 22 Gy in
a single fraction if lesions were less than 2.0 cm or 18 Gy if le-
sions were 2 to 2.9 cm in maximum diameter. The dose was
prescribed to the highest isodose line encompassing the tar-
get, ranging from 50% to 80% of the maximum dose. Pa-
tients randomly assigned to SRS plus WBRT received 30 Gy in
12 fractions of 2.5-Gy WBRT delivered 5 days a week. Whole
brain radiotherapy began within 14 days of SRS.
Assessments
Before registration and randomization, each patient under-
went baseline evaluation consisting of history and physical ex-
amination, neurological examination, magnetic resonance
imaging, and assessment of cognitive function, QOL, and per-
formance status. Race/ethnicity data were collected as man-
dated on all National Cancer Institute (NCI)–sponsored trials
by patient self-report. All baseline evaluations as well as as-
sessment of adverse events were repeated at week 6 and
months 3, 6, 9, 12, 16, 24, 36, 48, and 60. Quality of life was
assessed using the Functional Assessment of Cancer Therapy–
Brain, for which the range is from 0 to 200 and higher scores
indicate better QOL.
9
Functional independence was assessed
by the Barthel Index of Activities of Daily Living (ADL Index),
for which a score of 100 implies complete independence and
a lower score suggests that the patient requires some super-
vision and/or assistance.
10
A well-established battery of cog-
nitive tests was used to assess learning and immediate memory
(Hopkins Verbal Learning Test–Revised [HVLT-R] Immediate
Recall; range, 0-12, for which higher values indicate better per-
formance), fine motor control (Grooved Pegboard Test; range,
0-650 seconds, for which higher values denote worse perfor-
mance), verbal fluency (Controlled Oral Word Association Test;
range, 0-60 words, for which higher values reflect better
Key Points
Question What is the effect of whole brain radiotherapy in
addition to stereotactic radiosurgery on cognitive function of
patients with 1 to 3 brain metastases?
Findings In this randomized clinical trial that included 213 adults
with metastases amenable to radiosurgery, there was less
cognitive deterioration at 3 months after stereotactic radiosurgery
alone (64%) than after stereotactic radiosurgery plus whole brain
radiotherapy (92%), a significant difference.
Meaning In patients with 1 to 3 brain metastases, stereotactic
radiosurgery alone may be the preferred strategy.
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402 JAMA July 26, 2016 Volume 316, Number 4 (Reprinted) jama.com
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performance), processing speed (Trail Making Test Part A
[TMT-A]; range, 0-180 seconds, for which higher values indi-
cate worse performance), executive function (TMT Part B
[TMT-B]; range, 0-300 seconds, for which higher values de-
note worse performance), delayed memory (HVLT-R Delayed
Recall; range, 0-12, for which higher values reflect better per-
formance), and recognition (HVLT-R Recognition; range, −12
to 12, for which higher values indicate better performance).
11,12
The cognitive testing was administered by a trained, certified
member of the site study team. All treatment-related toxic ef-
fects and adverse events were recorded according to NCI Com-
mon Terminology Criteria for Adverse Events, version 3.0.
End Points
The primary end point was cognitive deterioration (progres-
sion), defined as a decline of greater than 1 SD from baseline
on at least 1 of the 7 cognitive tests (all tests are standardized
based on published norms and transformed so that higher val-
ues represent improved cognition) at the 3-month post-SRS
evaluation. Secondary end points included time to intracra-
nial failure (eTable 1 in Supplement 2), QOL, toxic effects, func-
tional independence, cognitive outcomes for individual cog-
nitive assessments, long-term cognitive status, and overall
survival. Because of concerns regarding the accuracy of
assigning a cause of death, cause-specific survival was not
assessed.
13,14
Intracranial tumor control rates at 3 months
(a post hoc analysis) were reported because these rates tem-
porally corresponded with the primary end point. Local fail-
ure was defined as an increase of greater than 25% in the size
of the perpendicular diameters of the treated lesion. Distant
brain failure was defined as the development of new, noncon-
tiguous lesions. Intracranial progression was defined as either
local or distant brain failure.
Statistical Analysis
The trial was closed on December 10, 2013, after meeting ac-
crual goals. Data for this analysis were frozen on April 23, 2015.
According to the sample size calculation, 112 evaluable pa-
tients (56 in each group) were required. This was based on a
type I error probability of .10 (2-sided), 85% power, an as-
sumed 3-month cognitive deterioration rate of 0.65 for the con-
trol group (SRS plus WBRT), and a minimal detectable abso-
lute decrease in the 3-month cognitive deterioration of 0.25.
The study was powered to detect a change in the anticipated
3-month cognitive deterioration rate of 0.65 for the SRS plus
WBRT group, based on a clinical trial of patients with brain me-
tastases treated with WBRT who were prospectively assessed
at baseline and over time with a cognitive battery, to 0.40 or
lower for the SRS group.
7
A .10 level of significance was used
because it was believed that SRS plus WBRT would cause more
cognitive deterioration and the focus was ensuring that there
was a .05 1-sided level to detect this. The trial was designed
to keep accruing until the necessary number of evaluable pa-
tients was obtained. The study used a completers analysis,
which was specified in a protocol amendment prior to analy-
sis to make cognitive deterioration the primary end point. The
basis for using a completers analysis rather than imputation
was lack of reliability of imputation methods given the small
number of patients. In addition, a separate sensitivity analy-
sis was conducted in which it was assumed that all noncom-
pleters had experienced a cognitive decline. A patient was
deemed a completer if he/she had completed baseline and
3-month cognitive tests; patients who did not complete the
3-month evaluation were not part of the primary analysis.
For primary analysis of the 3-month cognitive deteriora-
tion end point, we used a Fisher exact 2-group binomial test
to compare the proportion of evaluable patients with 3-month
cognitive deterioration between the 2 groups and report point
estimate for the difference with a 90% confidence interval (cor-
responding to the .10 level of significance). One preplanned
interim analysis was performed when 50% of the target num-
ber of evaluable patients was accrued (see the protocol in
Supplement 1 for details). Accrual was not stopped during the
interim analysis, and interim results did not cross the stop-
ping boundaries. As directed by the Alliance data and safety
monitoring board, because there was an imbalance in the pro-
portion of completers in each study group, a separate, post hoc
sensitivity analysis was performed that treated noncom-
pleters as experiencing a 3-month cognitive deterioration.
Time to intracranial failure (local and distant failure) was
analyzed using Cox proportional hazards and competing risks
models. In the competing risk models, death counted as a com-
peting risk.
15
Overall survival, defined as the time from ran-
domization until death due to any cause, was compared be-
tween the groups using stratified log-rank tests. Planned
subgroup analyses, specified by the stratification factors, were
conducted. A long-term survivor was defined as one who had
a cognitive evaluation 12 months or longer after randomiza-
tion. Multivariable Cox models, also used to compare overall
survival between the groups, contained the stratification vari-
ables and other prognostic variables, such as location of
primary tumor. The QOL scores were transformed to a 0- to
100-point scale (with 100 being most favorable), in which a
10-point change was considered clinically significant.
16
We
compared the intergroup proportion of patients with signifi-
cant QOL deterioration using an exact binomial test, and in-
tergroup changes in QOL scores were compared using a
2-sample t test. Toxic effect rates in the 2 groups were com-
pared using the Fisher exact test. In addition to point esti-
mates, 95% confidence intervals are provided, except for the
primary end point, for which a 90% confidence interval is re-
ported. All secondary analyses used a 2-sided .05 level of sig-
nificance. There was no adjustment for multiple compari-
sons for the secondary end point analyses, so these results
should be interpreted as exploratory. All analyses were per-
formed using either SAS version 9.3 (SAS Institute Inc) or R ver-
sion 3.1.1 (R Core Team 2014).
17
Results
Study Patients
Between February 2002 and December 2013, 213 patients
were enrolled and randomly assigned to treatment with SRS
alone (n = 111) or SRS followed by WBRT (n = 102) (Figure 1).
For the primary end point, after excluding patients who died
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prior to the 3-month evaluation, who did not return for the
3-month or a subsequent evaluation, or who did not com-
plete the required baseline tests, 151 patients were alive and
111 patients were evaluable (73.5% overall completion rate)
(Figure 1). The completion rate was 66.7% (48/72) in the SRS
plus WBRT group and 79.7% (63/79) in the SRS alone group
(difference, −13.1%; 95% CI, −28.4% to 2.3%; P = .096).
Median follow-up for all patients was 7.2 months (range,
0.0-62.5 months), and for the 111 evaluable patients it was
11.6 months (range, 2.7-62.5 months). Baseline characteris-
tics were well balanced in the groups for both the total study
population (Table 1) and the patients evaluable for the pri-
mary end point. Baseline characteristics were also well bal-
anced between evaluable and nonevaluable patients except
for worse baseline verbal fluency in the nonevaluable
patients (Controlled Oral Word Association Test, −0.8 [SD,
1.1] points vs −1.3 [SD, 1.2] points; P = .003). At baseline,
mean and median cognitive scores were below population
norms, ranging from mild to severe impairment.
Primary Analysis and Secondary Cognitive Outcomes
Cognitive deterioration, the primary end point in evaluable
patients at 3 months, was less frequent after SRS alone than
after SRS plus WBRT (40/63 [63.5%] vs 44/48 [91.7%],
respectively; difference, −28.2%; 90% CI, −41.9% to −14.4%;
P < .001). There was more deterioration in the SRS plus
WBRT group on each cognitive test (Table 2), reaching statis-
tical significance for immediate memory (30.4% vs 8.2%,
respectively; difference, 22.2%; 95% CI, 5.4%-39.1%;
P = .004), delayed memory (51.1% vs 19.7%, respectively;
difference, 31.4%; 95% CI, 12.1%-50.7%; P < .001), and verbal
fluency (18.6% vs 1.9%, respectively; difference, 16.7%; 95%
CI, 2.4%-31.0%; P = .01). Analyzing by the mean change from
baseline in normalized z scores revealed similar results, with
cognitive deterioration more pronounced after SRS plus
WBRT vs after SRS alone (eTable 2 in Supplement 2). Post
hoc analyses using different definitions of cognitive deterio-
ration (eg, 1.5-SD decline in at least 2 tests; 2-SD decline in
1 test; 3-SD decline in 1 test; eTable 3 in Supplement 2)
revealed similar results: more frequent cognitive deteriora-
tion and deterioration on each cognitive test were docu-
mented in patients treated with SRS plus WBRT.
7,12
In addi-
tion, in post hoc analysis, if patients who did not complete a
3-month assessment were counted as having cognitive dete-
rioration, the results remained the same: patients treated
with SRS plus WBRT were more likely to experience cogni-
tive deterioration than those treated with SRS alone (94.6%
[88/93] vs 74.8% [77/103], respectively; difference, 19.9%;
95% CI, 9.3%-30.4%; P < .001).
QOL and Functional Independence
There were 71 and 53 patients in the SRS and SRS plus WBRT
groups, respectively, for whom QOL data were available
from baseline and from at least 1 subsequent evaluation.
There was better QOL at 3 months with SRS alone, including
overall QOL (mean change from baseline, −1.3 vs −10.9
points; mean difference, 9.6 points; 95% CI, 3.6-15.6 points;
P = .002) and functional well-being (mean change from
baseline, 0.4 vs −21.9 points; mean difference, 21.5 points;
95% CI, 4.6-38.4; P = .03) (eTable 4 in Supplement 2). Bar-
thel ADL Index scores remained high at 3 months with no
significant difference between the treatment groups (mean
change from baseline, −1.5 points with SRS alone vs −4.2
points with SRS plus WBRT; mean difference, 2.7 points;
95% CI, −2.0 to 7.4 points; P = .26).
Intracranial Tumor Control
Time to intracranial failure was significantly shorter for SRS
alone compared with SRS plus WBRT (hazard ratio, 3.6; 95%
CI, 2.2-5.9; P < .001). Intracranial tumor control rates at 3
months were 93.7% (89/95) with SRS plus WBRT and 75.3% (79/
105) with SRS alone (difference, 18.4%; 95% CI, 7.8%-29.0%;
P < .001) and were also significantly higher at 6 and 12 months
in patients who received WBRT (P < .001 for competing risk)
(Figure 2 and eTable 5 in Supplement 2). The 6- and 12-
month local and distant tumor control rates were also signifi-
cantly higher in patients who received WBRT (eTable 5). Fewer
patients underwent salvage therapy after SRS plus WBRT than
after SRS alone (7.8% vs 32.4%, respectively; difference,
−24.6%; 95% CI, −35.7% to −13.5%; P < .001) (eTable 6 in
Supplement 2).
Survival Outcomes
A survival comparison was performed on an intention-
to-treat basis using the entire study population. Despite a
higher intracranial tumor control rate associated with WBRT,
Figure 1. Participant Flow in the N0574 Trial
213 Randomized
111 Randomized to receive
stereotactic radiosurgery
alone
102 Randomized to receive
stereotactic radiosurgery
plus whole brain radiotherapy
105 Completed baseline tests
5 Other reasons
6 Did not complete baseline tests
1 Cancelation
97 Completed baseline tests
1 Ineligible
1 Disability or language problem
2 Other reasons
5 Did not complete baseline tests
1 Refused testing
79 Patients had 3-mo evaluation
3 Had follow-up <90 d
23 Died prior to 3-mo evaluation
72 Patients had 3-mo evaluation
6 Had follow-up <90 d
19 Died prior to 3-mo evaluation
63 Included in primary end-point
analysis
48 Included in primary end-point
analysis
16 Patients withdrawn from study
after 3-mo evaluation
3 Refused tests
2 Staff unavailable
2 Other medical problems
1 Missed visit
1 Testing done late
7 Reasons not available
24 Patients withdrawn from study
after 3-mo evaluation
5 Refused tests
7 Other medical problems
4 Patient withdrawals
2 Missed visit
1 Staff unavailable
5 Reasons not available
The number of patients screened for eligibility and the number excluded are not
available.
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404 JAMA July 26, 2016 Volume 316, Number 4 (Reprinted) jama.com
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no improvement in survival occurred; whereas the median
overall survival for SRS plus WBRT was 7.4 months, it was
10.4 months for SRS alone (hazard ratio, 1.02; 95% CI, 0.75-
1.38; P =.92)(Figure 3). Analysis by the 3 stratification fac-
tors of age, extracranial disease status, and number of brain
metastases revealed no survival benefit in any subset, nor
did post hoc analysis by time era (2002-2006 vs 2007-2013).
Median overall survival for evaluable and nonevaluable
patients was 13.5 months and 3.0 months, respectively (post
hoc analysis hazard ratio, 3.3; 95% CI, 2.4-4.5; P < .001).
Long-term Survivors
There were 34 long-term survivors (16%) overall (19 in the
SRS plus WBRT group and 15 in the SRS alone group). Long-
term survivors were defined as evaluable patients who sur-
vived for 12 months after randomization (eTable 7 in
Supplement 2). Intracranial tumor control, analyzed in this
cohort of long-term survivors, was 94.7% (95% CI, 7.3%-
100%) at 3 months, 89.5% (95% CI, 85.2%-100%) at 6
months, and 89.5% (95% CI, 85.2%-100%) at 12 months for
SRS plus WBRT and was 73.3% (95% CI, 54.0%-99.5%),
60.0% (95% CI, 39.7%-90.7%), and 20.0% (95% CI, 7.3%-
55.0%) for SRS alone, respectively (P < .001 for competing
risk) (eTable 8 in Supplement 2). In this subset, cognitive
deterioration occurred more frequently after SRS plus
WBRT, reaching statistical significance for executive func-
tion at 12 months (TMT-B: 42.9% vs 0.0%, respectively; dif-
ference, 42.9%; 95% CI, 7.8%-77.9%; P = .05) (eTable 9 in
Supplement 2). Analyzing by the mean change from baseline
in normalized z scores (eTable 10 in Supplement 2), cognitive
deterioration was more pronounced in the SRS plus WBRT
group for immediate memory at 3 months (difference, −0.8
points; 95% CI, −1.7 to 0.1 points; P = .04) and fine motor
control at 6 months (difference, −2.2 points; 95% CI, −4.3 to
−0.1 points; P = .03). The incidence of cognitive deteriora-
tion (ie, at least a 1-SD decrease in 1 test score) was less after
SRS alone at 3 months (5/11 [45.5%] vs 16/17 [94.1%]; differ-
ence, −48.7%; 95% CI, −87.6% to −9.9%; P = .007) and at 12
Table 1. Baseline Characteristics in the N0574 Trial
Characteristics
SRS Alone
(n = 111)
SRS Plus WBRT
(n = 102)
Age, mean (SD), y 59.8 (10.4) 61.4 (10.6)
Age group, y, No. (%)
18 to 59 53 (47.7) 44 (43.1)
≥60 58 (52.3) 58 (56.9)
Sex, No. (%)
Female 57 (51.4) 46 (45.5)
Male 54 (48.6) 55 (54.5)
Race, No. (%)
White 95 (86.4) 85 (83.3)
Nonwhite 15 (13.6) 17 (16.7)
Months of systemic disease control,
No. (%)
≤3 81 (73.0) 75 (73.5)
>3 30 (27.0) 27 (26.5)
No. of brain metastases, No. (%)
1 55 (49.5) 56 (54.9)
2 39 (35.1) 36 (35.3)
3 17 (15.3) 10 (9.8)
ECOG performance score, No. (%)
a
0 49 (44.5) 49 (48.0)
1 50 (45.5) 45 (44.1)
2 11 (10.0) 8 (7.8)
Primary tumor site, No. (%)
Breast 11 (9.9) 7 (6.9)
Colorectal 7 (6.3) 4 (4.0)
Lung 80 (72.1) 66 (65.3)
Skin/melanoma 3 (2.7) 9 (8.9)
Bladder 1 (0.9) 1 (1.0)
Kidney 1 (0.9) 4 (4.0)
Gynecologic 2 (1.8) 3 (3.0)
Other 6 (5.4) 7 (6.9)
Cranial nerves, No. (%)
Normal 102 (91.9) 92 (91.1)
Abnormal 9 (8.1) 9 (8.9)
Sensation, No. (%)
Normal 105 (94.6) 96 (96.0)
Abnormal 6 (5.4) 4 (4.0)
Motor, No. (%)
Normal 97 (87.4) 89 (88.1)
Abnormal 14 (12.6) 12 (11.9)
Cerebellar, No. (%)
Normal 92 (82.9) 85 (84.2)
Abnormal 19 (17.1) 16 (15.8)
(continued)
Table 1. Baseline Characteristics in the N0574 Trial (continued)
Characteristics
SRS Alone
(n = 111)
SRS Plus WBRT
(n = 102)
FACT-Br total score, mean (SD)
b
146.6 (24.0) 141.7 (27.7)
Cognitive test scores, mean (SD)
c
HVLT-R
Immediate recall −1.4 (1.4) −1.7 (1.3)
Delayed recall −1.3 (1.8) −1.6 (1.7)
Recognition −0.8 (1.9) −0.9 (1.8)
TMT-A time to complete −1.7 (3.6) −1.9 (3.1)
TMT-B time to complete −2.8 (4.3) −3.2 (4.3)
COWAT total −1.0 (1.2) −1.1 (1.2)
GPS total, mean (SD), s −6.2 (8.6) −5.4 (6.0)
Abbreviations: COWAT, Controlled Oral Word Association Test; ECOG, Eastern
Cooperative Oncology Group; FACT-Br, Functional Assessment of Cancer
Therapy–Brain; GPS, Grooved Pegboard Test; HVLT-R, Hopkins Verbal Learning
Test–Revised; SRS, stereotactic radiosurgery; TMT, Trail Making Test;
WBRT, whole brain radiotherapy.
a
ECOG performance status scores range from 0 to 5, with higher numbers
indicating greater disability; a score of 0 indicates no symptoms; 1,
mild symptoms; and 2, symptomatic (<50% in bed during the day).
b
FACT-Br scores range from 0 to 200; higher scores indicate better quality
of life.
c
Cognitive tests are reported as standardized scores (z scores, transformed
so that higher scores indicate better cognitive performance): (patient
value – published-norm mean value)/published-norm standard deviation value .
SRS With or Without WBRT and Cognitive Function in Patients With Brain Metastases Original Investigation Research
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