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Summary
In the PNET4 randomized
controlled treatment trial,
cognitive performance of
children and young adults
with standard risk medullo-
blastoma allocated to un-
dergo hyperfractionated
radiation therapy (HFRT)
followed by standard
chemotherapy was compared
to that of subjects allocated
to receive standard radiation
therapy (STRT) followed by
standard chemotherapy
regimen. Treatment with
HFRT was associated with a
trend toward better verbal
outcomes in children
younger than 8 years of age
at diagnosis, but no signifi-
cant differences in other
cognitive measurements.
Purpose:
In the European HIT-SIOP PNET4 randomized controlled trial, children
with standard risk medulloblastoma were allocated to hyperfractionated radiation
therapy (HFRT arm, including a partially focused boost) or standard radiation
therapy (STRT arm), followed, in both arms, by maintenance chemotherapy. Event-
free survival was similar in both arms. Previous work showed that the HFRT arm
was associated with worse growth and better questionnaire-based executive function,
especially in children
<
8 years of age at diagnosis. Therefore, the aim of this study
was to compare performance-based cognitive outcomes between treatment arms.
Methods and Materials:
Neuropsychological data were collected prospectively in 137
patients. Using the Wechsler Intelligence Scales, Kaufman Assessment Battery for
Children, and Raven’s Progressive Matrices, we estimated full-scale intelligence quo-
tient (FSIQ) and, when available, verbal IQ (VIQ), performance IQ (PIQ), working
memory index (WMI), and processing speed index (PSI).
Results:
Among the 137 participants (HFRT arm n
Z
71, STRT arm n
Z
66, 63.5%
males), mean ( SD) ages at diagnosis and assessment respectively were 9.3 ( 3.2)
years of age (40.8%
<
8 years of age at diagnosis) and 14.6 ( 4.3) years of age. Mean
( SD) FSIQ was 88 ( 19), and mean intergroup difference was 3.88 (95% confidence
interval: 2.66 to 10.42,
P
Z
.24). No significant differences were found in children
>
8 years of age at diagnosis. In children
<
8 years of age at diagnosis, a marginally
significant trend toward higher VIQ was found in those treated in the HFRT arm; a
similar trend was found for PSI but not for PIQ, WMI, or FSIQ (mean intergroup dif-
ferences were: 12.02 for VIQ [95% CI: 2.37-21.67;
P
Z
.02]; 3.77 for PIQ [95% CI:
5.19 to 12.74;
P
>
.10]; 5.20 for WMI [95% CI: 2.07 to 12.47;
P
>
.10]; 10.90 for
PSI [95% CI: 1.54 to 23.36;
P
Z
.08]; and 5.28 for FSIQ [95% CI: 4.23 to
14.79;
P
>
.10]).
Conclusions:
HFRT was associated with marginally higher VIQ in children
<
8 years
of age at diagnosis, consistent with a previous report using questionnaire-based data.
However, overall cognitive ability was not significantly different.
2015 Elsevier Inc.
All rights reserved.
Introduction
Extensive research has consistently recognized longitudinal
impairments associated with medulloblastoma (MB), the
most frequent malignant brain tumor of the central nervous
system (CNS) during childhood
(1-3). Standard treatment
includes surgical resection, postoperative radiation therapy
(RT) and adjuvant chemotherapy. MB survivors experience
significant health-related problems, namely endocrine and
growth morbidity and reduced fertility
(4, 5) ,second tu-
mors
(6), hearing loss
(7), and long-term neurological
deficits
(8-10). Among the major complications arising
from the tumor and its treatment, predominantly RT and
especially when given with chemotherapy, are the high rate
of neurocognitive deficits, possibly attributable to the
deleterious effects of radiation on white matter develop-
ment
(11, 12). MB survivors typically achieve scores below
the mean for age-matched peers in measurements of intel-
ligence quotient (IQ), verbal and performance IQ (VIQ,
PIQ), processing speed index (PSI), working memory index
(WMI), and sustained attention
(13-16). Importantly, defi-
cits in these core cognitive domains tend to worsen over
time
(16-18). To improve tumor control and quality of
survival, hyperfractionated RT (HFRT) capitalizes on the
fact that proliferating tumor cells are more sensitive than
normal tissue to a given dose of RT if it is administered in a
larger number of fractions of smaller size. This enhances
the antitumor effects of RT while sparing normal tissues
(19-22). Compared with standard fractionated RT (STRT),
HFRT can be used either to maintain a given antitumor
effect while decreasing unwanted effects on the CNS or to
increase the antitumor effect without increasing unwanted
effects on the CNS. Previous uncontrolled studies by Carrie
et al
(22)and Gupta et al
(23)reported higher posttreatment
full-scale IQ in patients receiving twice-daily HFRT than
that in historical controls receiving once-daily STRT.
However, using historical controls instead of a controlled
experimental randomized design limits interpretation of
these data.
Furthermore, we could hypothesize that the lack of a
significant IQ decline could be related to improved quality
of posterior fossa irradiation, even in STRT, with less ra-
diation to the temporal and occipital lobes.
The HIT-SIOP PNET4 phase 3 European randomized
controlled treatment trial (RCT) for MB was designed to
investigate the hypothesized biological advantage of HFRT
relative to STRT. Five-year event-free survival was similar
between the 2 arms
(24) .A subsequent cross-sectional study
Volume 92 Number 5 2015
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