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age-appropriate booklets of questionnaires to eligible participants.
The study was approved by ethics committees in all participating
countries.
Outcome measures
The 4 principal QoS outcome measures were z-scores on stan-
dardized age-appropriate questionnaires. These assessed executive
function in everyday life, health status, behavioral difficulties, and
HRQoL. In participants aged <18 years at assessment, the ques-
tionnaires were parent-report versions of the Behavior Rating
Inventory of Executive Function (BRIEF) ; the Health Utili-
ties Index (HUI3) ; the Strengths and Difficulties Question-
naire (SDQ) ; the Pediatric Quality of Life Inventory
(PedsQL) ; and, if aged 11-17 years, self-report versions of the
HUI3, SDQ, and PedsQL. Survivors aged 18 years provided
self-report versions of the BRIEF, the HUI3, and the 30 core
question version of the European Organization for Research and
Treatment of Cancer Quality of Life measure (QLQ-C30) .
Reduction in height z-score compared with that at diagnosis,
known to vary with radiation treatment dose , was the pre-
specified principal endocrine outcome. Height, weight, and
mid-parental height were expressed as z-scores, age- and sex-
standardized against United Kingdom British 1990 growth refer-
ence values to allow inter- and intragroup comparisons.
Baseline demographic and secondary outcome information was
provided by clinicians using adapted versions of the Medical
Examination Form and by adult participants and parents of
child participants using the Medical, Educational, Employment
and Social questionnaire .
Statistical analysis
Univariate analyses of HFRT and STRT group scores were con-
ducted using Mann-Whitney U tests or t tests. Quality of survival
questionnaire scores in age-specific subgroups, governed by the
age ranges of questionnaires, were converted to a single dataset of
z-scores in all participants where mean Z 0, SD Z 1 for scores of
all study participants on that measure. Proxy-report z-scores for
children and self-report z -scores for adults for BRIEF and HUI3
were thus used to create a single “executive function z -score”
variable and a single “health status z -score” variable, respectively.
Proxy-report SDQ z-scores, available only in participants aged
<18 years, provided behavioral difficulties z -scores. Finally, child
self-report z-scores for PedsQL and adult self-report z-scores for
the QLQ-C30 were used to create a single “HRQoL z -score”
variable. Statistical analysis of QoS was thus simplified into 4
analyses relating to these 4 prespecified principal QoS outcomes.
Analyses of questionnaire subscales were conducted only when
total scores differed.
A regression model, including sex, younger age (3-7.9 years)
or older age (8.0-20.8 years) at diagnosis, and cerebellar mutism
(or, in an alternative model, perioperative complications including
cerebellar mutism), was used to increase the precision of the
estimate of the effect of treatment on principal QoS outcomes and
on decrement since diagnosis in height z-score. Sensitivity ana-
lyses were used to examine possible confounding by baseline
characteristics. Statistical significance testing (SPSS version 19.0;
SPSS, Chicago, IL) was 2-tailed with a 1% significance level to
adjust for multiple testing .
Results
Baseline characteristics
Outcomes were ascertained in 151 of 244 eligible survivors
(61.9%) (74 of 117 [63.2%] and 77 of 127 [60.6%] that had
received HFRT and STRT, respectively) at a median interval from
diagnosis of 5.8 (range, 4.2-9.9) years. Participants and non-
participants in the QoS study receiving HFRT were similar with
respect to sex, age at diagnosis, pre- and postoperative charac-
teristics, chemotherapy received, and interval between diagnosis
and assessment of QoS to those receiving STRT; there was a small
excess of neurologic deficits of extraocular movement in those
allocated to HFRT and of premorbid developmental impairment in
those allocated to STRT . The radiation therapy actually
delivered to PNET4 QoS study participants corresponded well to
that prescribed in both treatment arms: quality assurance included
both fields (checked in at least 68 of 151 [45%]) and dose
delivered (checked in at least 51 of 151 [34%]).
Outcomes at posttreatment evaluation
There were significant (P<.01) correlations between all of the
outcome measures, including strong positive correlations (0.58-
0.80) between proxy- and self-report scores, between health status
and HRQoL scores, and between executive function and behav-
ioral difficulties scores ( Supplementary Table e1, available on-
line). Female participants had poorer HRQoL z -scores than males
(group mean difference 0.48, 95% confidence interval [CI] 0.13-
0.84, PZ.008) but were similar to males with respect to executive
function, health status, and behavioral difficulties.
Effect of HFRT on executive function, behavior,
health status, and HRQoL
Scores in subgroups governed by questionnaire age ranges showed
no statistically significant differences between treatment arms
other than lower (better) adult self-report BRIEF executive func-
tion scores in those aged 18 years at assessment ). In the
merged single dataset of z -scores for all participants for the 4
principal outcome measures, executive function (BRIEF) z-scores
were significantly lower (better) after HFRT than after STRT
(group mean difference 0.48, 95% CI 0.16-0.81, PZ.004)
), but health status, behavioral difficulties, and HRQoL of
all participants were similar in the 2 treatment arms (group mean
z-score differences 0.26, 0.23, and 0.14, respectively, with 95%
CIs including the null point, P .25) ). The intergroup
differences in executive function (BRIEF) Global Executive
Composite z-scores seemed to be general effects reflected in sta-
tistically significant intergroup differences for both the Behavioral
Regulation Index, carried by inhibition, shift, and emotional
control subscales, and also for the Meta-cognitive Index, carried
by monitoring, working memory, and planning/organizing
subscores (Supplementary Table e2).
Effect of HFRT on growth
Compared with STRT, the mean group decrement since diagnosis
in height z-score after HFRT was greater by 0.43 (95% CI
Kennedy et al. International Journal of Radiation Oncology Biology Physics 294