VOLUME 24 䡠 NUMBER 8 䡠 MARCH 10 2006

JOURNAL OF CLINICAL ONCOLOGY R E V I E W A R T I C L E

Whole-Brain Radiotherapy in the Management of

From the University of Wisconsin,
Madison, WI; and the Mayo Clinic,
Rochester, MN.
Submitted October 14, 2005; accepted
November 28, 2005.
Authors’ disclosures of potential
conflicts of interest and author contribu-
tions are found at the end of this
article.
Brain Metastasis
Deepak Khuntia, Paul Brown, Jing Li, and Minesh P. Mehta
A B S T R A C T
Brain metastases are an important cause of morbidity and mortality, afflicting nearly 170,000 Americans annually.
The prognosis for these patients is poor, with median survival times measured in months. In this review article, we
present the standard treatment approach of whole-brain radiotherapy and discuss new directions, including the role
of chemical modifiers and the management and prevention of neurocognitive deficits.
J Clin Oncol 24:1295-1304. © 2006 by American Society of Clinical Oncology

Address reprint requests to Minesh P.
Mehta, MD, Department of Human
Oncology, University of Wisconsin, 600
Highland Avenue, Madison, WI 53792;
e-mail: mehta@humonc.wisc.edu.
© 2006 by American Society of Clinical
Oncology
0732-183X/06/2408-1295/$20.00
DOI: 10.1200/JCO.2005.04.6185
INTRODUCTION
Brain metastases represent an important cause of
morbidity and mortality, and are the most common
intracranial tumors in adults, occurring in approxi-
mately 10% to 30% of adult cancer patients.1 It is
estimated that up to 170,000 new cases of brain
metastases occur in the United States each year.2,3 It
is speculated that the annual incidence is rising for
several reasons, including an aging population, bet-
ter treatment of systemic disease, and the improved
ability of imaging modalities, such as magnetic res-
onance imaging (MRI), to detect smaller metastases
in asymptomatic patients.1
The risk of developing brain metastases varies
according to primary tumor type, with lung cancer
accounting for approximately one half of all brain
metastases.4 Other malignancies commonly associ-
ated with brain metastases are breast cancer (15% to
20%), unknown primary (10% to 15%), and mela-
noma (10% to 15%). Patients may experience sin-
gle, few, or several brain metastases. Melanoma and
lung cancer are frequently associated with multiple
metastases while solitary metastases are more com-
monly seen in patients with breast, colon, and renal-
cell carcinoma.5
The prognosis of patients with brain metas-
tases is poor; the median survival time of un-
treated patients is approximately 1 month.6 With
treatment, the overall median survival time after
diagnosis is approximately 4 months.7 The Radi-
ation Therapy Oncology Group (RTOG) recursive
partitioninganalysis(RPA)describesthree prognostic
classes, defined by age, Karnofsky performance
score (KPS), and disease status.8 RPA class 1 pa-
tients are younger (⬍ 65 years) and have higher
KPS scores (ⱖ 70 years), no other sites of metas-
tases, controlled extracranial disease, and the
longest median survival (Table 1).
Cancer patients with brain metastases present
significant neurologic, cognitive, and emotional dif-
ficulties, and once diagnosed, generally convey a
poor outcome. In this article, we will review stan-
dard treatment approaches with whole-brain radio-
therapy (WBRT) and discuss new directions in brain
metastasis therapy, specifically focusing on the role
of chemical modifiers of the radiation effect. Since
neurocognitive dysfunction after WBRT is a major
concern, we will focus a significant portion of our
discussion on this issue.
TREATMENT OPTIONS
The most widely used treatment for patients with
multiple brain metastases is WBRT. The appropri-
ate use of WBRT can provide rapid attenuation of
many neurologic symptoms, improve quality of life,
and is especially beneficial in patients whose brain
metastases are surgically inaccessible or when other
medical considerations remove surgery from the list
of appropriate options.9,10 The use of adjuvant
WBRT after resection or radiosurgery has been
proven to be effective in terms of improving local
control of brain metastases, and thus, the likelihood
of neurologic death is decreased.11 The majority of
patients who achieve local tumor control die from
progression of extracranial disease, whereas the
cause of death is most often due to CNS disease in
patients with recurrent brain metastases.12
Attempts are being made in three areas of in-
vestigation to improve the survival of patients with
unresectable brain metastases: (1) WBRT in con-
junction with radiosurgery (RS), an area that is fur-
ther explored in another manuscript in this issue;

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 Khuntia et al

metastases who received WBRT alone, with median survival ranges

Table 1. Median Survival According to RPA Class After WBRT8
RPA Class (median survival, months)
Treatment No. of Patients Class 1ⴱ Class 2† Class 3‡
WBRT§ 1,176 7.1 4.2 2.3
Abbreviations: RPA, recursive partitioning analysis; WBRT, whole-brain radio-
therapy; KPS, Karnofsky performance score.
ⴱ
Primary controlled, age ⬍ 65 years, no extracranial metastases, KPS ⱖ 70.
†Primary uncontrolled or age ⱖ 65 years, or extracranial metastases.
‡KPS ⬍ 70.
§Radiation Therapy Oncology Group phase III trials.
(2) radiosensitizers; and (3) new chemotherapeutic agents that
synergize (or are additive) with radiotherapy. Previous radiosensi-
tizers have not resulted in clinical benefits,13,14 but two newer
agents, efaproxaril (Efaproxyn, Allos Therapeutics Inc, Westmin-
ster, CO; RSR-13)15 and motexafin gadolinium (Xcytrin, Pharma-
cyclics Inc, Sunnyvale, CA)16 reflect continued interest in this area
of clinical research. Other promising developments in the treat-
ment of brain metastases include new chemotherapy agents such as
temozolomide (Temodar, Schering-Plough Corp, Kenilworth,
NJ), which crosses the blood-brain barrier. Advances in the use of
interstitial chemotherapy agents, such as bis-chlorethylnitrosourea
(BCNU) polymer wafers (Gliadel Wafer, MGI Pharma Inc, Bloom-
ington, MN), provide highly focused local chemotherapy in the
brain without increasing systemic toxicity, and their combination
with WBRT is also being evaluated.
WBRT
In patients who have brain metastases that impinge on eloquent areas,
or are too large, numerous, or disseminated for surgery or RS, WBRT
alone remains the treatment of choice and provides effective symptom
relief in the majority of cases.17 Although response rates after WBRT
vary, complete or partial responses have been documented in more
than 60% of patients in randomized controlled studies conducted by
the RTOG. Table 2 summarizes results of different dose and fraction-
ation schedules from eight randomized studies in patients with brain
from 2.4 to 4.8 months. The consensus from these studies of fraction-
ation schedules is that differences in dose, timing, and fractionation
have not significantly altered the median survival time for WBRT
treatment of brain metastases. Currently, the most common WBRT
regimen uses 30 Gy in ten 3 Gy fractions. Though this dose is clearly
inadequate for long-term tumor control, except in the most radiosen-
sitive histologies such as germinoma and lymphoma, this lower dose
has traditionally been used to minimize the toxicity of WBRT. An
analysis of RTOG trials shows that this results in control of disease in
approximately 50% of patients at 6 months.
A second major use of WBRT is as an adjuvant after surgery or
radiosurgery. MRI reveals that approximately 80% of patients have
more than one metastasis, and approximately 50% have three or more
metastases. Moreover, 70% of patients with brain metastases experi-
ence relapse after resection, if WBRT is omitted.26
It is important to recognize that there are some arguments
against the use of WBRT. Some question its ability to reverse neuro-
logic symptoms27 and its use has been putatively associated with
debilitating complications in long-term survivors.28 These data, how-
ever, are relatively weak and WBRT remains the standard of care for
patients with multiple brain metastases and also for patients after
radiosurgery or resection in the adjuvant setting.
Chemical Modifiers of WBRT
Historically, chemical modifiers of radiation effect, both true
sensitizers, as well as synergistic or additive cytotoxic agents, have had
little impact on overall median survival times in human trials of brain
metastases. Misonidazole, bromodeoxyuridine (BUdR), lonidamine,
nimustine, fluorouracil, and others have failed to show significant
benefit in randomized trials.15 Recent developments suggest a new
interest in this approach with two compounds that show promise as
radiosensitizers: motexafin gadolinium and efaproxaril.
Motexafin-Gadolinium
Motexafin-gadolinium (MGd) is a metalloporphyrin redox
modulator that demonstrates selective tumor localization and cat-
alyzes the oxidation of a number of intracellular reducing metabo-
lites, such as ascorbate, glutathione, and nicotinamide adenine
dinucleotide phosphate, thereby generating reactive oxygen spe-
cies, and depleting the pools of reducing agents necessary to repair

Table 2. Dose Fractionation Schemes of WBRT in Various Tumor Types

Random Assignment
Group 1 Group 2 Group 3
No. of No. of No. of No. of Median Survival
Studyⴱ Year Patients Gy Fractions Gy Fractions Gy Fractions (months)
Harwood and Simpson18 1977 101 30 10 10 1 4.0-4.3
Kurtz19 1981 255 30 10 50 20 3.9-4.2
Borgelt20 1980 138 10 1 30 10 40 20 4.2-4.8
Borgelt21 1981 64 12 2 20 5 2.8-3.0
Chatani22 1986 70 30 10 50 20 3.0-4.0
Haie-Meder23 1993 216 18 3 43 13 4.2-5.3
Chatani24 1994 72 30 10 50 20 2.4-4.3
Murray25 1997 445 54.4 34 30 10 4.5

Abbreviation: WBRT, whole-brain radiotherapy.

ⴱ
Randomized trials of WBRT alone for brain metastases.

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 WBRT for Brain Metastasis

cytotoxic damage.29 Selective uptake of MGd in tumors, but not in

normal tissues, has been shown in patients using MRI because of its
paramagnetic characteristics (Fig 1).30-33 Preliminary studies in pa-
tients with brain metastases treated with MGd and WBRT demon-
strated radiologic responses in 68% to 72% of patients.16,30 A large
randomized phase III study of MGd in 401 patients did not show a
significant increase in median survival (5.2 v 4.9 months; P ⫽ .48) or
median time to neurologic progression (9.5 v 8.3 months; P ⫽ .95).
When analyzed by tumor type, MGd significantly improved time to
neurologic progression in the prespecified stratum of 251 patients
with brain metastases from non–small-cell lung cancer (NSCLC; Fig
2).34 A confirmatory randomized phase III trial in patients with
NSCLC has completed accrual and results are pending.
Efaproxaril Fig 2. Kaplan-Meier neurologic progression-free survival curve from the pre-
Efaproxaril is a synthetic small molecule that noncovalently specified stratum of 251 patients with brain metastases from non–small-cell lung
cancer treated with motexafin gadolinium (solid line) or control (dotted line). D,
binds to hemoglobin and decreases its oxygen binding affinity and
days; HR, hazard ratio; M, months; MGd, motexafin-gadolinium; NR, not reached;
shifts the oxygen dissociation curve to the left, increasing p50 and WBRT, whole-brain radiotherapy.
tissue pO2. It exerts its effects based on an increase in tumor
oxygen levels, thereby circumventing restrictions due to the blood-
brain barrier.15,35-38
proximately 30% of plasma concentrations.40 In limited preclinical
Shaw et al15 conducted a phase II, open-label, multicenter study
studies, some synergy with radiotherapy has been demonstrated.41
of efaproxaril plus WBRT in 57 patients with brain metastases. The
results were retrospectively compared with the RTOG RPA brain Temozolomide has demonstrated modest activity in patients
metastases database; the median survival time for the efaproxaril- with recurrent42,43 or newly diagnosed44,45 brain metastases from var-
treated patients was 6.4 months compared with 4.1 months for the ious malignancies. Recent trials of temozolomide with radiotherapy
database (P ⫽ .0174). Subsequently, a phase III randomized, open- suggest a significant increase in response rates, especially for metasta-
label, comparative study of standard WBRT plus supplemental oxy- ses from lung cancer. Antonadou et al studied 52 patients with brain
gen with or without efaproxaril, was conducted in 538 RPA class 1 or metastases from solid tumors randomly assigned to temozolomide
2 patients with brain metastases.39 This study did not show a signifi- plus WBRT compared with WBRT alone.44 In the study from the
Hellenic Radiation Oncology Group, the objective response was 96%
cant increase in median survival for efaproxaril versus control (5.3 v
(38% complete response; 58% partial response) for temozolomide
4.5 months; P ⫽ .17), but median survival was increased in the sub-
plus WBRT compared with 66% (33% complete response; 33% par-
group of 115 patients with breast cancer (8.7 v 4.6 months; P ⫽ .061).
tial response) for WBRT alone (P ⫽ .017). A larger phase III trial has
A second study of efaproxaril in women with brain metastases from
been completed by the same group, and awaits publication. Histology
breast cancer began enrollment in 2004 with a target of 360 patients.
appears to have a bearing on the effect of temozolomide, as well as
Temozolomide when it is used with radiotherapy. For example, in a phase II study of
Temozolomideisasecond-generationoralalkylatingprodrugthatis dose-intense alternating weekly regimen of temozolomide, the re-
converted to its active metabolite, 5-(3-methyltriazen-1yl)imidazole-4- sponse rate was 24% for NSCLC, 19% for breast cancer, and 40% for
carboximide, and has nearly 100% bioavailability. It readily crosses melanoma.46 This differential activity could putatively be associated
the blood-brain barrier producing CSF concentrations that are ap- with methylation of the promoter region of the MGMT gene, which

Fig 1. T1-weighted brain magnetic reso-

nance imaging scans of a patient with
non–small-cell lung cancer: (left) noncon-
trast scan at baseline; (right) noncontrast
scan after the 10th administration of
motexafin-gadolinium.

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 Khuntia et al
synthesizes MGMT, the enzyme responsible for repairing the lethal
methylation lesion produced by temozolomide. Therefore it is possi-
ble to consider a future treatment strategy with temozolomide, based
on the MGMT promoter-region methylation status of the tumor. The
frequency of this finding ranges from 36% to 42% in squamous and
adenocarcinoma (of the lung), respectively.47 Thus, temozolomide
and radiotherapy may have promise in patients with brain metastases,
especially for those with lung cancer and melanoma.
CONTROVERSY SURROUNDING THE USE OF
WBRT WITH RADIOSURGERY
Radiosurgery after WBRT has been validated with level 1 evidence as a
standard of care option in the management of patients with single
brain metastases.48 As radiosurgery has increased in popularity, a new
trend has been emerging in the management of patients with brain
metastases; in this approach, patients with a limited number of brain
metastatic lesions (the exact definition of limited is based on institu-
tional preference and varies from three to ten or more) are treated with
radiosurgery without WBRT, and are then closely monitored, which
involves monthly or every other month MRIs. Repeat radiosurgery, is
performed for new intracranial metastases, with the intent being
avoidance or delay of WBRT in as many patients, and for as long as
possible. The putative rationale for this is the avoidance of significant
neurotoxicity from WBRT; unfortunately, this approach has not been
validated in controlled clinical trials, and its application dramatically
increases the overall cost of managing these patients, with multiple
and expensive imaging studies (total charges of easily $2,000 per study
or more) and repeat radiosurgical procedures (often $20,000 to
$40,000 total charge per procedure).
In this section, we will discuss the elements that drive this debate.
We summarize the arguments as follows: (1) most patients have oli-
gometastatic disease; (2) survival is unaltered whether upfront WBRT
is used or not; (3) radiosurgery is good enough for local control; and
(4) the neurologic status and quality of life of patients in whom WBRT
is withheld is superior.
A proposition in support of withholding WBRT is that most
patients have oligometastatic disease. Older autopsy and computed
tomography (CT) imaging studies suggest that the rate of multiple
brain metastases ranges from 58% to 86%, with a mean of 66%, but
these studies have been criticized on several grounds. Few prospective
brain metastases trials have mandated routine MRIs, and therefore
these data are sparse. In one MRI-based study, only 19% of the 336
patients had a single lesion; the percentage of patients with two, three,
four, and five or more lesions was 16%, 13%, 10% and 40%, respec-
tively. In most trials of radiosurgery, three is considered the upper
limit in terms of the definition of oligometastases, and in this trial,
50% of patients had more than three lesions on their MRIs.49 There-
fore, most reports would suggest that only approximately 20% of
patients have one brain metastasis, and this is especially important, as
evidence-based data suggest no survival benefit from aggressive local
treatments, such as surgery or radiosurgery in patients with more than
one metastatic lesion.50
A second contention is that survival is unaltered whether
upfront WBRT is used or not. In a disease process where the
occurrence of brain metastases represents only one component of
systemic spread, it is unlikely that local control of disease in one
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compartment will alter overall survival, and decisions regarding
local disease control are not driven by the impact on survival, but
rather on the value of local control.51 Not surprisingly, trials (that
were not designed to answer an overall survival question) of local
therapies that have excluded WBRT show no difference in overall
survival.11 However, a cautionary observation is provided by a
retrospective analysis from Germany; Pirzkall et al reported that
for brain metastases patients without extracranial disease, (ie, pa-
tients with a much lower likelihood of dying from systemic metas-
tases) the median survival after radiosurgery alone with WBRT
used for salvage was 8.3 months compared with 15.4 months for
similar patients treated up front with radiosurgery plus WBRT.52
Similar results were seen in a retrospective study from the Mayo
Clinic with a survival benefit for adjuvant WBRT limited to pa-
tients without systemic disease—5-year survival rates of 21% for
those who received adjuvant WBRT compared to 4% for those
patients who did not.53 These observations are crucial, implying
that for those patients where prolonged survival is likely, failure to
control the intracranial disease by omitting or delaying WBRT
could potentially result in a negative survival impact.
It has been proposed, primarily based on retrospective institu-
tional chart reviews, that radiosurgery is good enough for local con-
trol. In the prospective randomized Japanese trial, JROSG 99-1,
patients were randomly assigned to radiosurgery alone, versus WBRT
and radiosurgery. The actuarial 6 month freedom from new brain
metastases was 48% in the radiosurgery alone arm, and 82% in the
radiosurgery and WBRT arm (logrank, P ⫽ .003). Actuarial 1 year
brain tumor control rate for the lesions treated with radiosurgery was
70% in the radiosurgery alone arm and 86% in the radiosurgery and
WBRT arm (log-rank, P ⫽ .019).54 Another randomized trial55 com-
pared radiosurgery alone, WBRT alone, or WBRT and radiosurgery.
The local brain control rate was highest in the radiosurgery plus
WBRT arm. A prospective single arm, multi-institutional ECOG
phase II study of radiosurgery alone for radioresistant histologies
(melanoma, sarcoma, renal cell carcinoma) in patients with one to
three brain metastases has recently been reported.56 At 6 months,
39.2% failed within the radiosurgery volume and 39.4% failed outside
the radiosurgery volume, thereby defining the limited benefit from
radiosurgery alone. Clinical trial-based assessments therefore suggest
high rates of intracranial failures and reduced local control rates when
WBRT is omitted or delayed.
It has been speculated that the neurologic status and quality of
life of patients in whom WBRT is withheld is superior. The only
randomized data available in this context are from a recent Japa-
nese trial, not yet fully published. In that study, patients were
randomly assigned to radiosurgery alone or with WBRT; detailed
neurocognitive assessments were not performed, and the primary
assessment was by an evaluation of performance score and neuro-
logic functional status using RTOG criteria. There were no differ-
ences in these end points between the two study arms, belying the
claims of worse neurologic outcomes in the WBRT arm.54 In fact,
many have argued that the converse might be true, (ie, withholding
WBRT increases intracranial failure and neurologic deterioration
is more directly related to disease progression in the brain.57) In a
recent phase III trial of WBRT with or without the radiosensitizer,
MGd, the most significant predictor for neurologic and neurocog-
nitive decline, as well as deterioration in quality of life was disease
progression in the brain.58
JOURNAL OF CLINICAL ONCOLOGY
 WBRT for Brain Metastasis

Therefore, the switch to omitting WBRT has largely been made in

the absence of prospective randomized data and needs to be consid-
ered carefully. In large measure, it is fair to say that this switch has been
made because physicians have observed some patients experiencing
neurocognitive and neurologic decline (the causes for which could in
fact be multifactorial).

NEUROCOGNITIVE AND NEUROLOGIC DECLINE

Neurocognitive Function: Baseline, Post-WBRT, and

Predictive Variables.
Patients with brain metastasis may suffer a certain degree of
neurocognitive function (NCF) impairment from multiple factors
including the tumor, WBRT, neurosurgical procedures, chemother-
apy and other neurotoxic therapies (including anticonvulsants and
steroids), or from paraneoplastic effects induced by the malignancy.59 Fig 3. Change of mean normalized memory scores (delayed recall) over time.
The scores were normalized to individual patient’s baseline. Each point repre-
Furthermore, radiotherapy variables (eg, total dose, volume of brain sents mean normalized score ⫾ SE. Spearman correlation coefficient between
irradiated, fraction size) and the interaction with other treatment (eg, mean scores and the time is 0.704 (P ⫽ .011).
concurrent chemotherapy) or patient variables (ie, age, diabetes mel-
litus) all influence the incidence of radiation-induced injury to the
brain and may account for the differences in reported incidences of
domains of NCF testing (memory, fine motor, executive function) at
cognitive deficits.60,61 For example, two studies have not found signif-
baseline are predictive of survival, whereas multivariate analysis
icant cognitive decline if whole brain fraction size was less than 3 Gy.28
showed that only memory score was an independent predictor.58
In addition, in a phase III clinical trial that compared WBRT (30 Gy in
Similar results were obtained in patients with recurrent brain tumors,
10 fraction) versus WBRT plus MGd in patients with brain metastasis,
where memory test score was found to be highly related to survival by
analysis of NCF data demonstrated that 90.5% of patients had signif-
multivariate analysis.67 Interestingly in this patient population, cogni-
icant impairment (⬎1.5 SDs from the age-adjusted population nor-
tive deterioration occurred almost 6 weeks before radiographic failure,
malized score) in one or more neurocognitive domain at the time of
highlighting the sensitivity and survival predictive value of NCF
diagnosis of brain metastasis, with 42% of the patients having impair-
changes.68 Our preliminary analysis of patients with brain metastasis
ment in at least four out of the eight tests.58,62,63 This result is consis-
treated with WBRT has also shown that certain functions may deteri-
tent with previous reports where baseline neurocognitive and
orate earlier in the course of the disease than others. If confirmed,
neuropsychological test scores were impaired in patients with small-
these results may help to further streamline NCF tests that are more
cell lung cancer (even in the absence of overt brain metastases) before
sensitive in predicting subsequent QOL changes and survival.
receiving WBRT.64,65
Studies involving NCF deterioration should be interpreted cau-
On reviewing NCF data from patients with brain metastases who
tiously. NCF decline in the literature is often defined statistically and
received WBRT alone,63 we found that at 3 months, the mean NCF
there is little consensus as to the actual clinical relevance of a statistical
test scores appear to be unchanged or slightly reduced. However, 3
definition. Use of different definitions may artificially change the
months later, gradual recovery is observed (Fig 3). To determine if this
sequence of events, suggesting a further need for a statistical model
recovery is due to patient selection effect, we compared groups of
that allows use of early test scores to predict later events without
patients who were alive at 4 months after treatment with patients who
requiring such predefined statistical windows. In addition, conven-
were alive at 15 months after treatment. We found that 4-month
tionally used measures such as the Folstein mini-mental examination
survivors had a sharp drop in their mean NCF scores in the first few
(MMSE) are rather crude and it is crucial to develop sensitive and
months, whereas 15-month survivors had stable NCF with gradual
practical NCF testing to characterize these changes. In particular, the
improvement over time. Although both groups of patients had reduc-
sensitivity of MMSE has been shown to be problematic in detecting
tion in mean tumor volume from WBRT in the first 4 months, greater
subtle neurocognitive dysfunction69 in patients with brain metastasis
reduction was observed in the long-term survivors, which may explain
where clinically apparent WBRT-induced dementia is rare (1.9 to
their relatively stable NCF (J. Li, manuscript in preparation). These
5.1%).28,70 Recent evidence indicates that a battery of validated,
findings are consistent with a previous report that NCF decline corre-
language-specific, and population-normalized NCF tests evaluating
lates with tumor growth.58 In addition, these results suggest that the
memory, fine motor coordination, and executive functions confers
initial changes in patients’ NCF test scores, as well as radiologic evi-
more accurate and comprehensive measurement of NCF changes in
dence of tumor regression, may be predictive of overall survival. Al-
patients with brain metastasis.66
though it is possible that the improvement in NCF scores in long-term
survivors may also result from increased familiarity with retesting, the Correlation Between NCF and Quality of Life
battery of NCF tests utilized in this study was designed to have mini- Although neurocognitive function is believed to have a major
mal effect from repetitive testing.66 impact on the quality of life (QOL) in patients with many medical,
A more definitive predictor of survival in patients with brain mental, or psychiatric diseases71-73 this relationship has not been
metastasis is baseline NCF. Univariate analysis has shown that all three adequately evaluated in patients with brain metastases. An early

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 Khuntia et al
study in patients with primary brain tumors did show that NCF
impairment caused a decline in functional independence more
often than physical disability. This suggests that any treatment that
would reduce the severity of or prolong the time to NCF deterio-
ration could lead to increased functional status in these patients.74
The recent development of brief, comprehensive, and validated
measurements for NCF and cancer-specific QOL has made it pos-
sible to explore the nature of the relationship between NCF and
functional performance in anticancer clinical trials.66,75,76
In patients with brain metastasis who received WBRT alone,63
our analysis has shown that at baseline each individual NCF test score
is correlated with functional measures such as FACT-Br (Functional
Assessment of Cancer Therapy–Brain, brain-specific QOL), Barthel
Index, or KPS. The strength of these correlations ranges from weak to
moderate, but all are statistically significant. Interestingly, the correla-
tions became stronger 4 months after treatment, and the highest
correlation coefficient is observed between memory and Barthel Index
(Fig 4). The correlations remain strong at 6 months although statistical
significance diminishes due to patient loss (J. Li, manuscript in prep-
aration). These results clearly demonstrate that there is an association
between NCF and QOL in patients with brain metastasis. In addition,
these results suggest that therapy that preserves patients’ NCF, espe-
cially memory, may have a positive impact on patients’ quality of life.
The sensitivity of the Barthel index and FACT-Br for detecting
decline in functional status in patients with brain metastasis or pri-
mary brain tumors has been questioned. In fact, it appears from the
literature, that gross decline in QOL, especially in terms of severe
impairment in activities of daily living may indeed be a late
event.63,66,67 Even with the relative insensitivity of current QOL tools,
in patients with brain metastasis receiving WBRT, we consistently
detected a correlation between NCF and QOL, suggesting that more
sensitive QOL testing could help potentially delineate changes in pa-
tient’s functional status at an earlier point in time.
Mechanism of Neurocognitive Dysfunction
The response to radiotherapy has been classically divided into
three categories based on the timing of onset of symptoms: acute,
Fig 4. Spearman correlation coefficient for memory test scores (delayed recall)
and QOL measures Barthel index (solid line) and Brain-subscale of FACT-Br
(dotted line). (*) Represents statistical significance with P value ⬍ .05. NCF,
neurocognitive function; QOL, quality of life; FACT-Br, Functional Assessment of
Cancer Therapy–Brain.
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subacute, and late.77 Acute effects occur during the first few weeks
of treatment and are often characterized by drowsiness, headache,
nausea, vomiting, and worsening focal deficits. Often, cerebral
edema is the cause of these symptoms and corticosteroids may
improve these symptoms. Subacute encephalopathy (early delayed
reaction) occurring at 1 to 6 months after completion of radio-
therapy may be secondary to diffuse demyelination.78,79 Symptoms
include headache, somnolence, fatigability, and deterioration of
pre-existing deficits that resolve within several months. Late de-
layed effects appear more than 6 months after radiotherapy and are
generally irreversible and progressive.80 This may be a result of
white matter damage due to vascular injury, demyelination, and
necrosis. Symptoms range from mild lassitude to significant mem-
ory loss and severe dementia.81 The pathophysiology of radiation-
induced neurocognitive damage is complex and involves inter- and
intracellular interactions between vasculature and parenchymal
cells, particularly oligodendrocytes, which are important for my-
elination. Oligodendrocyte death occurs either due to direct p53-
dependent radiation apoptosis or due to exposure to radiation-
induced tumor necrosis factor alpha (TNF␣).82,83 Postradiation
injury to the vasculature involves damage to the endothelium
leading to platelet aggregation and thrombus formation, followed
by abnormal endothelial proliferation and intraluminal collagen
deposition.60,84 In addition, hippocampal-dependent functions of
learning, memory, and spatial information processing seems to be
preferentially affected by radiation.85 Animal studies reveal that
doses as low as 2 Gy can induce apoptosis in the proliferating cells
in the hippocampus, leading to decreased repopulative capacity.86
Management and Prevention of Neurocognitive
Deficits As a Result of WBRT
Treatment (or prophylaxis) of cognitive sequelae of cranial radi-
ation is limited at this time. Methylphenidate has been used in a several
small series of patients exhibiting neurobehavioral slowing with lim-
ited response.87-89 Patients who develop psychomotor slowing, de-
cline in executive functioning, or general apathy may benefit in
particular.88 Although these studies suggest beneficial effects with
methylphenidate, they have several limitations including small sample
size and lack of a blinded control, and therefore the widespread use of
methylphenidate should not be considered standard of care.
Erythropoietin has been shown to be a CNS protectant in a
number of studies, and this has generated considerable interest in
the utilization of this agent.90,91 A blinded, randomized trial of
erythropoietin (compared with saline) found significantly less mo-
tor impairment in erythropoietin treated rats 2 days after 100 Gy
was delivered to the right striatum; by day 10 the erythropoietin
treated rats had returned to near control levels while the deficits
persisted in the saline-treated rats.92 A similar study found that
erythropoietin delivered 1 hour after WBRT (17 Gy in one frac-
tion) was neuroprotective in mice.93
There has been some interest in using Alzheimer’s therapeutic
agents to treat radiation-induced injury, since in some aspects
radiation-induced injury is clinically and radiographically similar to
Alzheimer’s dementia. In a trial from Wake Forest University
(Winston-Salem, NC), 24 previously irradiated brain tumor patients
were treated for 24 weeks with donepezil.94 Neurocognitive tests were
performed at baseline, 6, 12, 24, and 30 weeks. Verbal fluency, verbal
memory, attention, and figural memory scores significantly improved
JOURNAL OF CLINICAL ONCOLOGY
 WBRT for Brain Metastasis

between baseline and week 24, but there was no change on global
cognitive function or executive function. No significant worsening of
performance was noted on any measures. The limitations of this study
include the small sample size and the potential (and uncontrolled)
impact of practice (ie, neurocognitive measures repeated over multi-
ple evaluations) and placebo effect.
Prior studies have suggested beneficial effects of vitamin E for
patients with Alzheimer’s disease.95 Researchers at the Queen Eliz-
abeth Hospital in Hong Kong treated 19 patients with temporal
lobe radionecrosis with a daily megadose of vitamin E for 1 year,
whereas 10 other patients with temporal lobe radionecrosis served
as controls (treatment assignment was decided on a voluntary
basis).96 Significant improvement in global cognitive ability, mem-
ory, and executive function occurred among patients in the treat-
ment group after a 1-year medication period. However, as noted by
Chan et al,96 limitations of this study were that the patients were
not randomly assigned or blinded to treatment, and therefore the
results should be considered preliminary.
Although a neurocognitive conceptual framework for under-
standing the effects of radiotherapy is currently limited,97 it seems that
the pathophysiology of late RT injury is dynamic, complex, and a
result of inter- and intracellular interactions between the vasculature
and parenchymal compartments, and injury is most likely multifacto-
rial (ie, demyelination, proliferative and degenerative glial reactions,
endothelial cell loss, and capillary occlusion).85 The vascular hypoth-
esis is probably the most recognized and longest standing premise as
the primary cause of radiation-induced damage.98 The vascular hy-
pothesis of radiation-induced injury attributes accelerated atheroscle-
rosis and mineralizing microangiopathy that result in vascular
insufficiency and infarction to radiation-induced injury and inflam-
mation. Taken together, these mechanisms result in a picture similar
to the small vessel disease, as is often seen with vascular dementia.99
For this reason there is interest in using pharmaceutical agents that are
effective in the treatment of vascular dementia for irradiated brain
tumor patients. One of these agents is memantine, a N-methyl-D-
aspartate (NMDA) receptor antagonist, that blocks excessive NMDA
stimulation that can be induced by ischemia and lead to excitotoxicity.
It is believed that agents that block pathologic stimulation of NMDA
receptors may protect against further damage in patients with vascular
dementia.100 Thus, NMDA receptor antagonists such as memantine
may be neuroprotective and prevent neuronal injury associated with
radiation-induced ischemia. In addition, the physiologic function of
the remaining neurons could be restored, resulting in symptomatic
improvement.101 Preclinical in vitro and in vivo data support this
hypothesis.102-105 Phase III clinical trials of memantine in patients
with vascular dementia demonstrated clinical benefit, with the sub-
group of patients with small-vessel disease responding better to me-
mantine than other types of dementia.106,107 In addition, anecdotal
Fig 5. Hippocampus avoidance with intensity modulated radiotherapy via
helical tomotherapy.
experience using memantine in primary CNS lymphoma patients
with cognitive dysfunction after radiotherapy has shown dramatic
clinical improvement (I. Robbins, personal communication, October
2005). With the beneficial findings of these studies and the limitations
of treatment of cognitive decline after radiotherapy, the RTOG plans a
trial of memantine directed at preventing the detrimental effects of
cranial radiation.
Besides pharmaceutical interventions, others are considering
modifying how WBRT is delivered to decrease the risk of neurotoxic-
ity. As mentioned earlier, doses of 2 Gy or less can damage the
hippocampus.78As a result, current investigations are underway using
new technology to avoid the hippocampus conformally. With the use
of intensity modulated radiotherapy, it is possible to create isodose
distributions that treat the majority of the brain to full dose, while
keeping the radiation dose to the hippocampus relatively low (Fig 5).
However, prospective trials with detailed NCF testing will be needed
to determine if sparing of the hippocampus alone is beneficial or if
other parts of the limbic system will also need to be spared.
DISCUSSION
In summary, WBRT continues to be a standard and efficacious treat-
ment in the management of brain metastasis. Despite the use of
WBRT, outcomes are poor and efforts are being made to incorporate
multimodality approaches including surgery, radiosurgery, chemo-
therapy, and radiotherapy sensitizers to improve survival. Patients
with brain metastasis are susceptible to deficits in neurocognition
because of their disease and potentially from the treatment for their
brain metastasis. Innovative strategies for preventing and treating
neurocognitive deficits are actively under investigation.

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Authors’ Disclosures of Potential Conflicts of Interest

Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs
or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about
ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other
Minesh P. Mehta Schering-Plough
Corp (A);
Pharmacyclics Inc
(A)
Dollar Amount Codes (A) ⬍ $10,000 (B) $10,000-99,999 (C) ⱖ $100,000 (N/R) Not Required

Author Contributions

Conception and design: Deepak Khuntia, Paul D. Brown, Jing Li, Minesh P. Mehta
Administrative support: Deepak Khuntia, Minesh P. Mehta
Provision of study materials or patients: Deepak Khuntia, Jing Li, Minesh P. Mehta
Collection and assembly of data: Deepak Khuntia, Paul D. Brown, Jing Li, Minesh P. Mehta
Data analysis and interpretation: Deepak Khuntia, Paul D. Brown, Jing Li, Minesh P. Mehta
Manuscript writing: Deepak Khuntia, Paul D. Brown, Jing Li, Minesh P. Mehta
Final approval of manuscript: Deepak Khuntia, Paul D. Brown, Minesh P. Mehta

1304 JOURNAL OF CLINICAL ONCOLOGY

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