Individual changes in neurocognitive functioning and health-related quality of life in patients with brain oligometastases treated with stereotactic radiotherapy

Abstract

Background:
Recently, it has been shown that at group level, patients with limited brain metastases treated with stereotactic radiotherapy (SRT) maintain their pre-treatment levels of neurocognitive functioning (NCF) and health-related quality of life (HRQoL). The aim of this study was to evaluate NCF and HRQoL changes over time at the individual patient level.

Methods:
NCF (seven domains assessed with a standardized test battery) and HRQoL (eight predetermined scales assessed with the EORTC QLQ-C30 and BN20 questionnaires) were measured prior to SRT and at 3 and/or 6 months follow-up. Changes in NCF and HRQoL were evaluated at (1) a domain/scale level and (2) patient level.

Results:
A total of 55 patients were examined, of which the majority showed stable NCF 3 months after SRT, on both the domain level (78-100% of patients) and patient level (67% of patients). This was different for HRQoL, where deterioration in the different scales was observed in 12-61% of patients, stable scores in 20-71%, and improvement in 16-40%, 3 months after SRT. At patient level, most patients (64%) showed both improvement and deterioration in different HRQoL scales. Results were similar between 3 and 6 months after SRT.

Conclusion:
In line with results at group level, most brain oligometastases patients with ≥ 6 months follow-up and treated with SRT maintained their pre-treatment level of NCF during this period. By contrast, changes in HRQoL scores differed considerably at domain and patient level, despite stable HRQoL scores at group level.

Full text

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Journal of Neuro-Oncology (2018) 139:359–368
https://doi.org/10.1007/s11060-018-2868-7
CLINICAL STUDY
Individual changes inneurocognitive functioning andhealth-
related quality oflife inpatients withbrain oligometastases treated
withstereotactic radiotherapy
PimB.vanderMeer1· EstherJ.J.Habets2· RuudG.Wiggenraad3· AntoinetteVerbeek‑deKanter3·
GeertJ.LycklamaàNijeholt4· HannekeZwinkels2· MartinKlein5· LindaDirven1,2· MartinJ.B.Taphoorn1,2
Received: 31 January 2018 / Accepted: 8 April 2018 / Published online: 16 April 2018
© The Author(s) 2018
Abstract
Background Recently, it has been shown that at group level, patients with limited brain metastases treated with stereotactic
radiotherapy (SRT) maintain their pre-treatment levels of neurocognitive functioning (NCF) and health-related quality of
life (HRQoL). The aim of this study was to evaluate NCF and HRQoL changes over time at the individual patient level.
Methods NCF (seven domains assessed with a standardized test battery) and HRQoL (eight predetermined scales assessed
with the EORTC QLQ-C30 and BN20 questionnaires) were measured prior to SRT and at 3 and/or 6months follow-up.
Changes in NCF and HRQoL were evaluated at (1) a domain/scale level and (2) patient level.
Results A total of 55 patients were examined, of which the majority showed stable NCF 3months after SRT, on both the
domain level (78–100% of patients) and patient level (67% of patients). This was different for HRQoL, where deterioration
in the different scales was observed in 12–61% of patients, stable scores in 20–71%, and improvement in 16–40%, 3months
after SRT. At patient level, most patients (64%) showed both improvement and deterioration in different HRQoL scales.
Results were similar between 3 and 6months after SRT.
Conclusion In line with results at group level, most brain oligometastases patients with ≥ 6months follow-up and treated
with SRT maintained their pre-treatment level of NCF during this period. By contrast, changes in HRQoL scores differed
considerably at domain and patient level, despite stable HRQoL scores at group level.
Keywords Health-related quality of life· Neurocognitive functioning· Brain metastases· Stereotactic radiotherapy
Introduction
Brain metastases are a common manifestation of systemic
cancer, with an estimated 9–45% of cancer patients develop-
ing brain metastases [1, 2]. The increasing incidence of brain
metastases is most likely attributable to an aging popula-
tion, the availability of improved imaging to detect smaller
lesions, and better treatment modalities for systemic cancer
which prolong life, thereby increasing the risk of dissemina-
tion of the systemic cancer to the brain [3, 4]. Although a
subgroup of patients experiences longer survival [5], brain
metastases are still incurable for most patients and the focus
of treatment is mainly palliative [6]. Neurocognitive deficits
and a reduced health-related quality of life (HRQoL) are
often observed in patients with brain metastases and may be
caused by the primary tumor, presence of (brain) metasta-
ses themselves, anti-tumor treatment, or supportive medica-
tion [4, 7–10]. Although survival is an important treatment
Pim B. van der Meer and Esther J. J. Habets have contributed
equally to this work.
Electronic supplementary material The online version of this
article (https ://doi.org/10.1007/s1106 0-018-2868-7) contains
supplementary material, which is available to authorized users.
* Pim B. vander Meer
pbvandermeer@lumc.nl
1 Department ofNeurology, Leiden University Medical
Center, PO BOX 9600, 2300RCLeiden, TheNetherlands
2 Department ofNeurology, Haaglanden Medical Center,
TheHague, TheNetherlands
3 Department ofRadiotherapy, Haaglanden Medical Center,
TheHague, TheNetherlands
4 Department ofRadiology, Haaglanden Medical Center,
TheHague, TheNetherlands
5 Brain Tumor Center Amsterdam, Amsterdam,
TheNetherlands
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360 Journal of Neuro-Oncology (2018) 139:359–368
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endpoint for these patients, maintenance or improvement of
neurocognitive functioning (NCF) and HRQoL during the
course of the disease are at least as important [11, 12].
Whole-brain radiotherapy (WBRT) has been the standard
of care in the past decades, but use of stereotactic radio-
therapy (SRT) as an addition to, or as an alternative for,
WBRT have increased considerably in recent years [13]. The
main component of SRT is precise delivery of focal high
dose radiation to a discrete target volume in 1–5 sessions,
while minimizing irradiation of surrounding normal tissue
[8, 14]. This treatment is particularly useful for patients
presenting with limited brain metastases [15], which is the
largest subgroup of patients, considering that 70% of the
patients have three or fewer metastases [16]. SRT alone is
associated with better NCF and HRQoL, while overall sur-
vival (OS) is comparable with WBRT alone or a combina-
tion of WBRT and SRT [5, 17, 18]. In contrast, SRT alone
carries a risk of intracranial recurrences and patients treated
with SRT undergo salvage treatment significantly more often
compared with patients receiving both WBRT and SRT [19].
These salvage treatments may increase the risk of neurologic
deficits and radionecrosis [4, 20].
Habets etal. [21] evaluated NCF and HRQoL prospec-
tively in patients treated with SRT alone for 1–3 brain
metastases and found that at group level, NCF and HRQoL
remained relatively stable during 6months from initial
treatment, with the exception of physical functioning and
fatigue, which worsened over time [21]. Although at group
level patients maintained their pre-treatment levels of NCF
and HRQoL to a large extent, this may not hold true for all
individual patients. Since maintaining or improving NCF
and HRQoL is important for all patients treated with SRT,
we sought to evaluate changes over time in NCF and HRQoL
at the individual patient level.
Materials andmethods
Study population
Patients were eligible if they were ≥ 18years; had ≤ 3
newly diagnosed brain metastases (maximum diameter of
4cm); and were scheduled to undergo SRT, performed on
an out-patient base with a dedicated Linac (Novalis; Brain-
LABAG, Helmstetten, Germany), construction year 2003.
Recruitment of patients took place between January 2009
and February 2012. Exclusion criteria were: prior treat-
ment for metastatic brain tumors; insufficient mastery of the
Dutch language; and Karnofsky Performance Status (KPS)
score < 70. The medical ethics committee of the institu-
tion approved the protocol. All patients provided written
informed consent.
Procedures
The gross tumor volume (GTV) was contoured on a contrast-
enhanced T1-weighted MRI. Planning target volume (PTV)
was created by adding a 2-mm margin by 3D expansion to the
clinical target volume (CTV), which was equal to the GTV.
SRT treatment consisted of 21Gy (PTV < 8cm3) or 18Gy
(PTV 8–13cm3) in a single fraction or 24Gy (PTV > 13cm3
and metastases near the brainstem) in three fractions of 8Gy.
The baseline evaluation of NCF and HRQoL was conducted
in the week preceding SRT. Follow-up assessments took place
3 and 6months after SRT. Patients’ charts were examined to
extract sociodemographic data and clinical variables, includ-
ing primary tumor, treatment status and medication use. At
all time points, MRI scans were made and the status of the
primary disease and the use of medication were monitored.
If patients showed intracranial progression during follow-up
and underwent renewed SRT, provided the number of metas-
tases was ≤ 3, these patients remained in the study. Patients
with intracranial progression who transitioned to WBRT were
excluded from further assessment. Patients were included in
the statistical analysis if they complied for assessment on NCF
and/or HRQoL on at least baseline and 3months, or 3 and
6months.
Study instruments
Neurocognitive functioning
NCF was assessed with a standardized battery of validated
neurocognitive tests found to be clinically relevant in brain
tumor patients (Supplementary Table1) [22–29]. Individual
test scores were combined in seven neurocognitive domain
scores: verbal memory, visual memory, attention, executive
functioning, working memory, information processing speed
and visuoconstruction. Raw individual test scores were con-
verted into standardized z-scores, by using means and standard
deviations of individually matched healthy controls regarding
age, gender, and education level, for four different domains
(verbal memory, attention, executive functioning and informa-
tion processing speed) [30–32]. Published norms were used,
corrected for age and education, for the three other domains
(visual memory, working memory and visuoconstruction) [33,
34]. A change in z-score of ≥ 1.5 standard deviation (SD) was
considered to be clinically meaningful, in line with previous
research in the same population [21].
Health-related quality oflife
HRQoL was evaluated with two validated self-assessment
questionnaires, (1) the for cancer patients developed 30-item
generic European Organisation for Research and Treatment
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361Journal of Neuro-Oncology (2018) 139:359–368
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of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-
C30) and (2) the 20-item brain tumour-specific EORTC
QLQ-Brain Cancer Module (QLQ-BN20) [35, 36]. A
selection of HRQoL scales has been made, based on previ-
ous findings [37], comprising six QLQ-C30 scales (global
health status, physical functioning, emotional functioning,
role functioning, cognitive functioning, and fatigue) and
two BN20 scales (motor dysfunction and communication
deficits). Global health status was rated on a 7-point Likert
scale, ranging from ‘very poor’ to ‘excellent’; the function-
ing and symptom scales were rated on a 4-point Likert scale,
ranging from ‘not at all’ to ‘very much’. Raw scores were
converted linearly into standardized scores ranging from 0
to 100. A higher score on the global health status and the
functioning scales indicates better HRQoL, while on symp-
tom-oriented scales a higher score indicates worse HRQoL.
Difference or change score ≥ 10 points on any given scale
were considered to be clinically meaningful [38].
Statistical analysis
To assess changes in HRQoL and NCF, differences in scores
over time were calculated on (1) a domain/scale level and
(2) patient level. Above described cut-off scores were used
to determine an improvement, deterioration or stable score.
Changes in scores were calculated for two different time
periods: baseline-3months, and 3–6months. A cluster anal-
ysis, using R, was performed to identify whether specific
HRQoL scales clustered.
Statistical analyses were performed using SPSS version
23.0. Statistical significance for intergroup differences were
tested using the χ2 test for categorical variables, the Stu-
dent’s t-tests or Mann–Whitney U-test for two-level continu-
ous variables (depending on the distribution of the data), and
the Kruskal–Wallis test for continuous variables with more
than two levels. Kaplan–Meier curves were used for analyses
of OS, and a log rank test to assess differences in survival.
A p-value of < 0.05 was considered statistically significant.
Domain/scale level
For both time periods (baseline-3months, and 3–6months),
patients were assigned to one of three categories: (1) dete-
rioration, (2) stable score or (3) improvement, separately for
each neurocognitive domain and HRQoL scale. For NCF,
improvement and deterioration were defined as an increase
or decrease in score ≥ 1.5 SD, respectively, and stable score
as < 1.5 SD change. For HRQoL, improvement and dete-
rioration were defined as ≥ 10 points increase or decrease
respectively, and stable score as < 10 points increase or
decrease.
Patient level
At patient level, patients were categorized into four cate-
gories, separately for NCF and HRQoL, applying the same
cut-off scores as in the domain/scale level. These four
categories were as follows: (1) decline, (2) improvement,
(3) both and (4) stable. Decline and improvement were
defined as deterioration or increase in NCF/HRQoL on at
least one domain/scale respectively, while other domains/
scales remained stable. The category ‘both’ included both
a decline and improvement, whereas ‘stable’ was defined
as no detectable change in any neurocognitive domain or
HRQoL scale. Moreover, changes in KPS score, SRT dose
received (biologically higher [single fraction 21 or 18Gy]
versus lower dosis [8Gy in three fractions]), total tumor
volume (as a proxy for GTV), intracranial progression and
active systemic disease were assessed for the four catego-
ries, separately for the two time periods.
Results
Fifty-five out of the original 97 (57%) patients were eligi-
ble for analyses, because they had sufficient data. Baseline
sociodemographic and clinical characteristics of the study
population are summarized in Table1. These baseline soci-
odemographic and clinical characteristics were compared
between patients with and without sufficient NCF/HRQoL
data. At baseline, patients without sufficient data had
more often a lower KPS score (median of 80 [inter quar-
tile range (IQR) = 70–80] vs. 80 [IQR = 80–90]; p = .002)
and shorter OS (median of 3.8months [IQR = 1.6–6.4] vs.
12.0months [IQR = 8.2–12.0]; p < .001) when compared
to patients with NCF/HRQoL data. NCF and HRQoL
scores over time in our subpopulation were similar to the
results as previously reported in the original study popula-
tion (data not shown).
Patient characteristics
The mean age of the 55 included patients was 63years
(SD = 9) and the primary tumor was most frequently
located in the lung (49%). Although the MRI scan showed
a fourth metastasis in two patients, these patients received
SRT because of the small size (< 0.5cm3) and were there-
fore also included. The median total tumor volume at base-
line was 7.3cm3 (IQR = 3.4–12.8) and the 1-year survival
rate was 48%, with all patients still alive after 3months
and 87% after 6months from initial SRT.
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362 Journal of Neuro-Oncology (2018) 139:359–368
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Table 1 Baseline sociodemographic and clinical characteristics of the patient population
Due to rounding, not all percentages add up to 100%
a Level 1–8, NCF neurocognitive functioning, HRQoL health-related quality of life, SD standard deviation, IQR interquartile range, AEDs antie-
pileptic drugs, KPS Karnofsky performance status
Patients with NCF/HRQoL data Patients without NCF/HRQoL data Original study population
Patients included, no. (%) 55 42 97
Age in years, mean ± SD 63 ± 9 64 ± 12 63 ± 11
Sex, no. (%)
Male 25 (45%) 21 (50%) 46 (47%)
Female 30 (55%) 21 (50%) 51 (53%)
Educational levela, median (IQR) 3 (2–4) 2 (2–4) 2 (2–4)
Brain metastases, no. (%)
1 21 (38%) 22 (52%) 43 (44%)
2 23 (42%) 8 (19%) 31 (32%)
3 9 (16%) 9 (21%) 18 (19%)
4 2 (4%) 3 (7%) 5 (5%)
Tumor volume by patient (cm3)
Median (range)/(IQR) 7.3 (0.12–63.9)/(3.4–12.8) 10.2 (0.15-32.0)/(3.6–15.9) 7.8 (0.12–63.9)/(3.5–14.2)
Missing 1 (2%) 0 (0%) 1 (1%)
Primary cancer, no. (%)
Non-small cell lung 27 (49%) 20 (49%) 48 (50%)
Renal cell carcinoma 11 (20%) 1 (2%) 12 (13%)
Melanoma 4 (8%) 5 (12%) 9 (9%)
Colorectal cancer 3 (5%) 6 (15%) 9 (9%)
Breast cancer 3 (5%) 5 (12%) 8 (8%)
Other 7 (13%) 4 (10%) 10 (10%)
Missing 0 (2%) 1 (2%) 1 (1%)
Active systemic disease, no. (%)
Yes 31 (56%) 21 (50%) 52 (54%)
No 24 (44%) 21 (50%) 45 (46%)
Chemotherapy, no. (%)
Yes 6 (11%) 6 (14%) 12 (12%)
No 47 (85%) 33 (79%) 80 (82%)
Missing 2 (4%) 3 (7%) 5 (5%)
Extracranial metastases, no. (%)
Yes 29 (53%) 25 (60%) 54 (56%)
No 25 (45%) 16 (38%) 41 (42%)
Missing 1 (2%) 1 (2%) 2 (2%)
Use of corticosteroids, no. (%)
Yes 48 (87%) 37 (88%) 85 (88%)
No 4 (7%) 4 (10%) 8 (8%)
Missing 3 (5%) 1 (2%) 4 (4%)
Use of AEDs, no. (%)
Yes 12 (22%) 9 (21%) 21 (22%)
No 40 (73%) 32 (76%) 72 (74%)
Missing 3 (5%) 1 (2%) 4 (4%)
KPS
Median (IQR) 80 (80–90) 80 (70–80) 80 (70–90)
KPS ≥ 90, No. (%) 25 (46%) 9 (21%) 34 (35%)
Missing 1 (2%) 0 (0%) 1 (1%)
Survival in months, median (IQR) 12.0 (8.2–12.0) 3.8 (1.6–6.4) 7.7 (3.9–12)
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363Journal of Neuro-Oncology (2018) 139:359–368
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Compliance
During follow-up, compliance dropped from 91% at base-
line (n = 50) to 69% at 3 and 56% at 6months for NCF,
and from 98% at baseline (n = 54) to 93% at 3 and 85%
at 6months for HRQoL assessments (Supplementary
Table2). Patients had several reasons for non-compliance,
such as progression of disease or the assessment being too
demanding.
Neurocognitive functioning
Prior to SRT, half of the patients with neurocognitive data
(25/50, 50%) showed impairments in at least one neurocog-
nitive domain, of which verbal memory was most frequently
affected (10/33, 30%).
Domain level
Three months after initial SRT, deterioration in the differ-
ent neurocognitive domains was observed in 5/7 domains
(3–8% of patients), while in two domains (verbal memory
and visual memory) none of the patients showed deteriora-
tion (Fig.1a). A stable score was observed in all domains
(78–100% of patients), most frequently in verbal memory
and visual memory. Improvement was found in 4/7 domains
(3–17% of patients) and was most profound for visuocon-
struction. Similar results were observed between 3 and
6months after initial SRT [deterioration in 4/7 domains,
8–20% of patients; stable score in all domains, 73–100% of
patients; and improvement in 3/7 domains, 4–8% of patients
(Fig.1b)]. Post-hoc analysis using a less stringent cut-off, a
change in z-score of ≥ 1.0 SD, revealed similar results (Sup-
plementary Fig.1a; Supplementary Fig.1b).
Patient level
Three months after initial SRT, 14% of patients showed a
decline in NCF, another 14% an improvement, 6% both a
decline and an improvement, while 67% had stable NCF
(Fig.1c). The period covering 3–6months after initial
SRT revealed similar results (decline 33%; improvement
13%; both 4%; and stable50%). When using the ≥ 1.0 SD
cut-off, scores differed from the original results, but still
most patients remained stable or improved (Supplementary
Fig.1c).
Changes in KPS scores (Supplementary Table3), SRT
dose received, total tumor volume, intracranial progression
or active systemic disease in individual patients did not
Fig. 1 Changes in neurocognitive functioning (NCF) scores calcu-
lated from a baseline-3months and b 3–6months at domain level and
c patient level. VeM verbal memory; ViM visual memory; AT atten-
tion; EF executive functioning; WM working memory; IPS informa-
tion processing speed; VC visuoconstruction
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364 Journal of Neuro-Oncology (2018) 139:359–368
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differ significantly between the four different categories from
baseline to 3months or from 3 to 6months after initial SRT.
Health‑related quality oflife
Prior to SRT, the vast majority (48/54, 89%) of patients
showed a clinically relevant and statistically significant
impairment in at least one of the six QLQ-C30 scales when
compared to the general population (no reference data avail-
able for the QLQ-BN20 scores) [39], of which physical
functioning was most frequently affected (31/54, 57%).
Scale level
Three months after initial SRT, a decline in all eight dif-
ferent HRQoL scales was observed in 12–61% of patients,
most often in fatigue (Fig.2a). 20–71% of patients had sta-
ble scores and an improvement was shown in 16–40% of
patients most frequently in communication deficit and motor
dysfunction respectively. Comparable percentages were
found between 3 and 6months from initial SRT [deteriora-
tion 8–47% of patients; stable score 18–75% of patients; and
improvement 11–34% of patients (Fig.2b)].
Patient level
A decline in HRQoL in the first 3months was observed in
22% of patients, an improvement in 12%, both worsening
and improvement in 64%, while only 2% had a stable score
(Fig.2c).
Percentages were comparable 6months after initial SRT
(decline 21%; improvement 18%; both 58%; and stable3%).
Changes in KPS scores in individual patients differed signifi-
cantly between the four categories from baseline to 3months
(p = .001) and from 3 to 6 months (p = .036) after initial
SRT, with patients deteriorating in at least one HRQoL scale
(in the ‘both’ and ‘decline’ category) showing most often
worsening in performance status (Supplementary Table3).
No statistical significant differences between categories were
found for SRT dose received, total tumor volume, intracra-
nial progression or active systemic disease (data not shown).
Cluster analysis HRQoL
A heatmap was created to provide insight into changes in
HRQoL at patient level (Fig.3). The most striking pattern
is that fatigue, and to a lesser extent emotional functioning,
were clustered with global health status, indicating that a
change on one scale is likely to be accompanied by a similar
change on the other (i.e. decline, improve, both or remain
stable). In addition, physical and role functioning were clus-
tered, as well as several brain tumor-specific symptoms,
Fig. 2 Changes in health-related quality of life (HRQoL) scores cal-
culated from a baseline-3months and b 3–6 months at domain level
and c patient level. GHS global health status; PF physical function-
ing; EF emotional functioning; RF role functioning; CF cognitive
functioning; FA fatigue; MD motor dysfunction; CD communication
deficits
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365Journal of Neuro-Oncology (2018) 139:359–368
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these were motor dysfunction, communication deficit and
self-perceived cognitive functioning.
Discussion
The aim of this study was to evaluate changes in NCF and
HRQoL at patient level 3 and 6months after SRT, provid-
ing insight in the impact of treatment on the individual
patient level. The overall results, in line with results at
group level [21] and several other studies in patients with
limited brain metastases [19, 40, 41], indicate that most
patients with brain metastases treated with SRT maintained
their pre-treatment levels of NCF for at least 6months.
Although NCF and HRQoL at the group level showed little
variation, this is not necessarily translated into little varia-
tion at domain/scale and patient level. Indeed, changes in
scores on the different HRQoL scales did vary substantially
within patients, and most individual patients showed both a
decline and improvement in separate HRQoL scales in the
first 6months after initial SRT. This finding is in contrast
with the HRQoL findings at group level, in which patients
who deteriorated and improved most likely cancelled each
other out. When informing patients about the impact of a
certain treatment or monitor their disease status, it is not
sufficient to have information at group level only, nor at the
scale level. Clinicians should also be aware that the large
majority of patients will experience both deterioration and
improvement in HRQoL.
An explanation for the relatively unaffected NCF in brain
metastases patients may be that our study population rep-
resents a highly selected group of patients with good func-
tioning. Indeed, patients in our sample had a higher KPS
score and longer survival compared to our patients with-
out sufficient NCF/HRQoL data. This is also supported by
the finding that prior to SRT, only 50% of patients had an
impairment in at least one neurocognitive domain, which
is considerably lower than in previous studies in metastatic
brain tumor patients (67–92%) [40, 42]. Particularly for
neurocognitive testing, compliance rates decreased substan-
tially over 6months’ time. Responsible for non-compliance,
among other things, were poor neurological or physical
functioning and assessment considered too burdensome.
Another explanation is the operational definition of objec-
tive neurocognitive decline, for which different cut-offs have
been suggested [43]. Brown etal. [44], using a ≥ 1.0 SD cut-
off score, found considerably higher neurocognitive deterio-
ration rates compared to our study, with most patients show-
ing cognitive deterioration at 3months after SRT. However,
when using a ≥ 1.0 SD cut-off in our study, still the majority
Fig. 3 Cluster analysis of differences in health-related-quality of
life scores between a baseline-3 months and b 3–6 months. Black
indicates deterioration; dark grey a stable score; light grey improve-
ment; and white a missing value. On the vertical axis all 55 patients
included in this study are displayed. a Patients are also clustered, but
dendrogram is not shown. b Patients and HRQoL scales are similarly
ordered for comparison. EF emotional functioning; FA fatigue; GHS
global health status; PF physical functioning; RF role functioning;
MD motor dysfunction; CD communication deficits; CF cognitive
functioning
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366 Journal of Neuro-Oncology (2018) 139:359–368
1 3
of patients showed no cognitive deterioration, meaning a
different cut-off does only partially explains the difference in
neurocognitive deterioration rates [44]. Taking into account
the aforementioned explanations for the relatively unaffected
NCF, maintenance of NCF over 6months’ time might have
been overestimated in our biased sample and likely limits
generalizability of the results to brain metastases patients
with poor functioning.
Although average HRQoL remained stable at group
level, except for physical functioning and fatigue, this did
not hold true on scale level nor at patient level. On scale
level, patients were relatively similarly distributed over the
three different categories (deterioration; stable score; and
improvement). At patient level, however, the majority of
patients showed both deterioration and improvement in dif-
ferent HRQoL scales after radiotherapy, which has been pre-
viously reported in patients with brain metastases, but com-
parison is difficult because the majority of patients received
WBRT instead of SRT [45, 46]. Caissie etal. [45] reported
that upon follow-up 1month after radiotherapy significant
improvement was seen in several HRQoL scales, includ-
ing communication deficit [45]. On the contrary, Steinmann
etal. [46] reported that upon follow-up 3months after the
start of radiotherapy patients showed a significant and clini-
cally relevant deterioration in several preselected HRQoL
scales, including global health status, physical functioning,
fatigue, motor dysfunction and communication deficit, while
other scales remained unchanged [46]. In our study, the
majority of patients showed a clinically relevant deteriora-
tion between baseline and 3months in physical functioning
(46%), role functioning (54%) and fatigue (61%), reflecting
the findings at group level [21]. Nevertheless, considering
the varying trajectories of changes in HRQoL after SRT, an
important observation is that the majority of our patients
showed both decline and improvement in separate HRQoL
scales. An explanation for the varying trajectories of changes
is that HRQoL measures vastly different concepts, encom-
passing physical, emotional, and social components, and that
this outcome may be influenced by many factors, including
comorbidity, marital status, heterogeneity of the primary
tumor, SRT dose, total tumor volume, progression of the
extracranial cancer and its corresponding supportive or anti-
tumor treatment [47]. Although, SRT dose received, total
tumor volume, intracranial progression and active systemic
disease did not differ significantly between the four differ-
ent categories at patient level, this result must be interpreted
with caution due to our small sample size. As pointed out by
Wilson and Cleary [48] in their model, more distal meas-
ures to the disease or the treatment (i.e. global health status
and the functioning scales) are not only affected by health
status but also by non-medical factors, as opposed to more
proximal measures (i.e. symptoms) [48]. NCF is a proximal
measure, which is mainly influenced by the presence of brain
metastases, or its treatment. Patients who deteriorated on
at least one HRQoL scale did most often have decreased
performance status, suggesting that especially the patients’
overall functioning influences HRQoL. Moreover, Caissie
etal. [49] found that fatigue and emotional functioning were
the two strongest predictors of global health status in brain
metastases patients, which is similar to the findings of our
cluster analysis; deterioration in global health status clus-
ters with increased fatigue and worse emotional function-
ing, suggesting fatigue may be a target for intervention to
improve overall HRQoL [49].
To conclude, in accordance with previous results at group
level, this study showed that most patients with brain oligo-
metastases treated with SRT maintained their pre-treatment
NCF for at least 6months. However, changes in scores for
the various HRQoL scales differed considerably between
and within patients, suggesting that overall functioning
is determined by complex underlying mechanisms which
should be further analysed.
Funding Funding was provided by St. Jacobusstichting, the
Netherlands.
Open Access This article is distributed under the terms of the Crea-
tive Commons Attribution 4.0 International License (http://creat iveco
mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribu-
tion, and reproduction in any medium, provided you give appropriate
credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
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