1622 / 1708
comparing hyperfractionated
radiation therapy with stan-
dard radiation therapy, com-
bined with a chemotherapy
regimen common to both
treatment arms, in children
and young adults with me-
dulloblastoma. We observed
a possible benefit of hyper-
fractionated radiation ther-
apy to executive function but
greater restriction of spinal
growth and no significant
benefit to health status,
behavior, or quality of life.
Methods and Materials:
Participants in the PNET4 trial and their parents/caregivers in 7 participating
anonymized countries completed standardized questionnaires in their own language on executive func-
tion, health status, behavior, health-related quality of life, and medical, educational, employment, and
social information. Pre- and postoperative neurologic status and serial heights and weights were also
recorded.
Results:
Data were provided by 151 of 244 eligible survivors (62%) at a median age at assessment of
15.2 years and median interval from diagnosis of 5.8 years. Compared with standard radiation therapy,
hyperfractionated radiation therapy was associated with lower (ie, better)
z
-scores for executive func-
tion in all participants (mean intergroup difference 0.48 SDs, 95% confidence interval 0.16-0.81,
P
Z
.004), but health status, behavioral difficulties, and health-related quality of life
z
-scores were
similar in the 2 treatment arms. Data on hearing impairment were equivocal. Hyperfractionated radi-
ation therapywas also associatedwith greater decrement in height
z
-scores (mean intergroup difference
0.43 SDs, 95% confidence interval 0.10-0.76,
P
Z
.011).
Conclusions:
Hyperfractionated radiation therapy was associated with better executive function and
worse growth but without accompanying change in health status, behavior, or quality of life.
2014 Elsevier Inc.
Introduction
Survivors of childhood central nervous system (CNS) tumors have
shown impairments of quality of survival (QoS) in multiple do-
mains of function, persisting or worsening many years after
completion of treatment
(1-5). Medulloblastoma survivors,
particularly if treated before age 8 years, have impaired health-
related quality of life (HRQoL)
d
a multidimensional concept
that includes physical, social, cognitive, and emotional func-
tioning
(6-8), with underlying difficulties in neurocognition,
attention, executive function
(9-13), growth, fertility, thyroid
function
(14-18), educational attainment, employment, and for-
mation of long-term relationships. Rates of stroke, second tumors,
and premature aging are increased
(14, 19-25) .The HIT-SIOP PNET4 phase 3 European randomized controlled
treatment trial (RCT) for medulloblastoma compared hyper-
fractionated radiation therapy (HFRT) comprising 2 smaller frac-
tional doses of 1 Gy per day, separated by an interval of at least 8
hours, with conventionally fractionated standard treatment (STRT)
of 1 1.8-Gy fraction per day. Smaller fractional radiation therapy
doses produce a redistribution of proliferating tumor cells, with
some cells entering a radiosensitive stage and thus providing a better
tumor cell kill. Nonproliferating tissues, such as normal brain,
should be spared this effect of redistribution and thereby potentially
be protected by HFRT according to a linear-quadratic formula
relating fraction size to biological effect
(26). This sparing effect of
HFRT may account for the higher full-scale intelligence quotient
after treatment with twice-daily HFRT without chemotherapy than
that observed in historical controls treated with once-daily STRT
previously reported by Carrie et al
(27)and Gupta et al
(28)in
medulloblastoma survivors
(29). These studies were not, however,
experimental in design and relied on historical controls, rather than
random allocation of treatment, to provide comparison groups.
The HFRT regimen used in PNET4 was predicted to be bio-
logically more effective in its effects on tumor tissue than STRT,
but this was not supported by a 5-year event-free survival rate
(0.79 0.02) in both treatment arms
(30). It was also predicted
that the HFRT in PNET4 would produce long-term CNS effects
that were either similar or possibly, by reduction of the posterior
fossa HFRT boost outside the tumor bed, less deleterious than
those observed after STRT.
In-depth assessment of CNS outcomes in multicenter clinical
trials has typically been associated with ascertainment rates below
30%
(31)and attrition bias
(1) .Booklets of standardized ques-
tionnaires for completion by participants and parents, however,
achieved ascertainment rates of 73% in United Kingdom survivors
enrolled in the PNET3 study of medulloblastoma at 7 years from
diagnosis
(32). PNET4 provided an opportunity to establish
whether cross-cultural adaptations of the same questionnaires
could be applied across Europe. We report here on a cross-
sectional follow-up study of the CNS and endocrine outcomes
in surviving PNET4 participants.
Methods and Materials
Patients
Between 2001 and 2006, 338 participants aged 4-21 years in 10
countries had been randomly allocated to receive either HFRT or
STRT treatment trial for M0 medulloblastoma in PNET4. Standard
radiation therapy comprised 23.4Gy to the craniospinal axis and 54Gy
to the posterior fossa and was given over 42 days in 30 daily fractions
of 1.8Gy for 5 days perweek. Hyperfractionated radiation therapywas
given in 68 fractions: 1.0 Gy twice per day with an 8-hour interval
between fractions, given over 48 days. The total craniospinal dose was
36 Gy, and the whole posterior fossa dose was 60 Gy, with a further
boost to 68 Gy to the tumor bed. In both treatment arms a maximum of
8 doses of vincristine 1.5 mg/m
2
(maximum 2 mg) was given once per
week during radiation therapy and adjuvant chemotherapy. Eight
cycles of cisplatin 70 mg/m
2
intravenously, lomustine 75 mg/m
2
on
day 1, and vincristine 1.5 mg/m
2
intravenously on days 1, 8, and 15,
began 6weeks after the end of RT, with a 6-week interval between each
cycle
(30) .The 244 survivors from France, Germany, Italy, The
Netherlands, Spain, Sweden, and the United Kingdom who remained
in remission during the 2010-2011 9-month cross-sectional follow-up
study period in the QoS study were eligible for the present QoS study.
Procedure
Written consent for QoS data collection had been obtained as part
of the PNET4 treatment trial by the treating clinician, who provided
Volume 88 Number 2 2014
Quality of survival in the PNET4 study
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