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tendency for epiphyseal tissue to respond to HFRT as an “early
reacting” tissue, or both. An interaction between the effect of
HFRT and its use in combination with chemotherapy cannot be
ruled out.
The estimated biologically equivalent dose (BED) of HFRT
relative to STRT on the CNS was calculated on the assumption,
based on rates of radiation-induced necrosis within the CNS, that
a/b Z 2 for the linear (a) and quadratic (b) components of in-
crease in the radiation dose per fraction on the CNS in the linear-
quadratic radiobiological model . On this calculation, the
BED at 2 Gy of HFRT for the CNS was 21.4% higher for the
craniospinal dose outside the boost field (27.0 vs 22.2 Gy BED),
unchanged for the tumor bed (51.0 vs 51.8 Gy BED), and 15%
lower in the remaining posterior fossa boost field, which included
areas of the cerebral cortex adjacent to the cerebellum (45.1 vs
51.8 Gy). The effect on CNS outcomes of these interarm differ-
ences is difficult to predict. The better executive function reported
here is consistent with the encouraging cognitive function reported
in previous uncontrolled studies , but the absence of dif-
ferences in health status, behavior, and QoL suggests similarity of
treatment arms with respect to effects on the CNS. Neither the
absence of difference between treatments in PNET4 with respect
to Event free survival (EFS) nor the greater decrement in
height after HFRT reported here were predicted in advance of
PNET4.
In conclusion, this study highlights the uncertainty of radio-
biological assumptions with respect to early- and late-reacting
tissue components in the normal CNS and bony spine. Although
the present study suggests some benefit to executive function
associated with HFRT, it also showed an absence of associated
benefit to behavior, health status, or quality of life and does not
enable us to reach a final conclusion on whether HFRT was of
greater overall benefit than STRT to QoS. Collation of neuro-
psychometric testing, collected within some participating national
groups on PNET4 survivors, into an international dataset is in
progress. If the neuro-psychometric data also show an association
between HFRT and better cognitive function, a further trial of
HFRT might be discussed. Stratification of HFRT dose by age and
biological risk factor would need to be guided by the present
Table 3 Outcome z-scores by treatment group in all participants stratified by age into those aged <8.0 years and those aged 8.0
years at diagnosis
Outcome
<8.0 y at diagnosis 8.0 y at diagnosis
n1, n2 HFRT STRT
Intergroup mean
difference (95% CI) P n1, n2 HFRT STRT
Intergroup mean
difference
(95% CI) P
Executive function
(BRIEF)
29, 24 0.45 (0.83) 0.39 (1.11) 0.84 (0.31 to 1.38) .003 39, 47 0.09 (0.88) 0.16 (1.03) 0.25 ( 0.17 to 0.67) .24
Health status
(HUI3)
26, 21 0.14 (0.76) 0.09 (1.13) 0.23 ( 0.32 to 0.79) .41 29, 38 0.10 (0.94) 0.17 (1.22) 0.27 ( 0.28 to 0.82) .33
Behavioral
difficulties
(SDQ)
31, 23 0.18 (0.75) 0.30 (1.17) 0.48 ( 0.09 to 1.04) .10 19, 27 0.02 (1.09) 0.05 (1.03) 0.03 ( 0.61 to 0.67) .93
Quality of life
(PedsQL and
QLQ-C30)
20, 17 0.18 (1.04) 0.06 (1.01) 0.23 ( 0.45 to 0.92) .50 42, 49 0.02 (1.01) 0.07 (0.98) 0.10 ( 0.32 to 0.51) .64
Height decrement
from diagnosis
23, 17 1.62 (0.85) 0.91 (0.84) 0.71 ( 1.26 to 0.17) .012 36, 39 1.05 (0.88) 0.82 (0.89) 0.23 ( 0.64 to 0.18) .26
Weight decrement
from diagnosis
24, 19 0.23 (1.13) 0.02 (1.04) 0.25 ( 0.92 to 0.43) .47 35, 41 0.53 (0.93) 0.31 (0.84) 0.21 ( 0.62 to 0.19) .30
Abbreviations: PedsQL Z Quality of Life Inventory; QLQ-C30 Z core 30-item version of the Quality of Life Questionnaire. Other abbreviations as in
and .
Values are mean (SD).
Table 4 Secondary quality-of-survival outcomes by treat-
ment group: Hormone replacement, use of therapy services,
hearing aids, state benefits, and cosmetic outcome
Outcome
n1, n2
(HFRT,
STRT) HFRT STRT
Mean (SD) years to growth
hormone replacement
27, 19 2.98 (0.7) 2.88 (0.6)
Growth hormone
replacement therapy
72, 75 39 (54) 37 (49)
Thyroxine replacement
therapy
71, 76 36 (51) 34 (45)
Physiotherapy 73, 77 46 (63) 56 (73)
Occupational therapy 73, 77 16 (22) 15 (19)
Speech and language
therapy
73, 77 26 (36) 23 (30)
Psychology 73, 77 29 (40) 40 (52)
Special educational
support
72, 77 36 (50) 46 (60)
Educational provision not
suited to child’s needs
60, 66 16 (27) 13 (20)
Uses a hearing aid 70, 74 16 (23) 7 (10
In receipt of state benefits 71, 72 28 (40) 26 (36)
Problems with appearance 71, 74 45 (63) 46 (62)
Hair thinning, patchy hair
loss, or no hair
69, 71 58 (84) 52 (73)
Abbreviations as in .
Values are number (percentage) except where noted. Differences between
treatment arms did not approach statistical significance (P>.1) except
where indicated.
* c2 4.81, PZ.028 for intergroup difference.
Kennedy et al. International Journal of Radiation Oncology Biology Physics 298