Full Scale IQ (FSIQ) Changes in Children Treated with Whole Brain

Transcription

Strahlentherapie
und Onkologie © Urban & Vogel 2000
Originalarbeit
Full Scale IQ (FSIQ) Changes in Children Treated
with Whole Brain and Partial Brain Irradiation
A Review and Analysis
Martin Fuss1, Karin Poljanc2, Eugen B. Hug3
Purpose: Neuropsychological impairment has been reported following whole brain and partial brain irradiation in children. The purpose of this analysis was to assess current knowledge, with focus on correlation with radiation dose, irradiated volume and age.
Method: Full Scale IQ (FSIQ) data, representing 1,938 children, were derived from 36 publications and analyzed as to
radiation dose, irradiated volume, and age.
Results: FSIQ after whole brain irradiation showed a non-linear decline as dosage increased. The dose-effect relationship was age-related, with more pronounced FSIQ decline at younger age. FSIQ test results below the normal level
(< 85) were found at doses higher than 24 and 36 Gy in children under age 3, and older than age 6, respectively. Mean
FSIQ test result after 18 Gy was 100, thus at the mean standard value; a minor decline was detectable only when compared to test results of a control group. Young children scored at this dose in the low normal range. Partial brain irradiation caused minor FSIQ decline, with measurable effects at dose levels > 50 Gy.
Conclusion: The collected data suggest that whole brain irradiation doses of 18 and 24 Gy have no major impact on intellectual outcome in children older than age 6, but may cause impairment in younger children. Doses > 24 Gy comprise
a substantial risk for FSIQ decline, even in older children. At equal dose levels, partial brain irradiation is less damaging than whole brain irradiation. The authors are well aware of limitations in the interpretation of data collected for the
current review. Thus, further research is required to evaluate the effect of low-dose whole brain irradiation as well as
partial brain irradiation on FSIQ development.
Key Words: Children · Radiation therapy · Brain · Cognitive function · Full Scale IQ
Full-Scale-IQ-(FSIQ-)Veränderungen nach Ganz- und Teilhirnbestrahlung des kindlichen Gehirns.
Review und Analyse
Hintergrund: Störungen der neurokognitiven Entwicklung sind nach Ganz- und Teilhirnbestrahlung kindlicher zerebraler Tumoren berichtet worden. Diese Arbeit bestimmt den momentanen Wissensstand und analysiert kausale Zusammenhänge von Bestrahlungsdosis, bestrahltem Volumen und dem Alter der Kinder zur Zeit der Bestrahlung.
Methode: Aus 36 englischsprachigen Publikationen wurden Full-Scale-IQ-(FSIQ-)Daten von 1 936 Kindern gewonnen
und bezüglich Bestrahlungsdosis, bestrahltem Volumen und dem Alter der Kinder analysiert.
Ergebnisse: Die FSIQ-Werte fielen nicht linear mit steigenden Bestrahlungsdosen ab (Abbildungen 1 und 2). Die Dosisbeziehung war altersbezogen, wobei jüngere Kinder einen ausgeprägteren Abfall der Testwerte zeigten. Bei Kindern
unter drei Jahren lagen die Testergebnisse nach 24 Gy Ganzhirnbestrahlung unterhalb des Normalwertbereichs (FSIQ
90 bis 110), wohingegen die Werte bei Kindern über sechs Jahren erst nach 36 Gy im selben Maße abfielen. Der mittlere Testwert nach 18 Gy Ganzhirnbestrahlung lag bei 100; das bedeutet, auf dem standardisierten Mittelwert der FSIQTests war nur ein geringer Abfall der Testwerte im Vergleich zur ebenfalls getesteten Kontrollgruppe (Mittelwert 104)
zu erheben (Tabelle 1). Kleine Kinder wurden nach 18 Gy Ganzhirnbestrahlung im niedrig normalen Bereich getestet.
Teilhirnbestrahlungen verursachten geringe Abfälle der FSIQ-Testwerte nach Gesamtdosen > 50 Gy.
Schlussfolgerung: Die gesammelten Daten zeigen, dass Ganzhirndosen von 18 und 24 Gy keinen oder nur einen geringen Einfluss auf die intellektuelle Entwicklung von Kindern über sechs Jahren haben. Bei jüngeren Kindern wird nach
diesen Dosen jedoch bereits eine Schädigung nachweisbar (Tabelle 2). Dosen 24 Gy können die kognitive Leistungsfähigkeit auch bei älteren Kindern erheblich beeinträchtigen. Die Dosis-Wirkungs-Beziehung ist nicht linear mit
stärkerer Schädigung bei höheren Dosen in allen Altersgruppen. In vergleichbaren Dosen ist die Teilhirnbestrahlung
weniger schädigend als eine Ganzhirnbestrahlung. Datensammlung und Auswertungsmethode zeigen bestehende
1
Department of Radiation Oncology, University of Heidelberg, Heidelberg, Germany,
Atomic Institute of the Austrian Universities, Technical University Vienna, Vienna, Austria,
3
Departments of Radiation Medicine and Pediatrics, Loma Linda University Medical Center, Loma Linda, CA.
2
Submitted: 10 Apr 2000; accepted: 12 Sep 2000.
Strahlenther Onkol 2000;176:573–81 (Nr. 12)
573
Fuss M, et al. Full Scale IQ (FSIQ) after Cranial Irradiation
Limitationen auf und weisen auf mögliche Interpretationsfehler hin. Weitere Testungen und prospektive Studien sind
erforderlich, um den Einfluss niedriger Dosen in der Ganzhirnbestrahlung sicherer bestimmen zu können. Der erwartete normalgewebsschonende Effekt zunehmend eingesetzter 3-D-geplanter Teilhirnbestrahlungen sollte bezüglich der
Entwicklung der kognitiven Leistungsfähigkeit dokumentiert werden.
Schlüsselwörter: Ganzhirnbestrahlung · Teilhirnbestrahlung · Kinder · Full-Scale-IQ · Kognitive Funktionen · Gehirn
A
s modern therapy regimens improve long-term survival
rates for childhood cancer, long-term sequelae relating
to such treatment has become an important field of research
in recent years. Quantitative reports of decline in intellectual
functioning following whole brain irradiation for intracranial
malignancies and for prophylaxis in childhood acute lymphoblastic leukemia date back almost 25 years. Numerous investigations have resulted in controversial findings, ranging
from direct attribution to radiation of severe detriment of
neuropsychological functioning, to lack of causal relationship between radiation therapy and central nervous system
complications [22].
In recent years 2 reviews have attempted to address this
problems by integrating data from several studies so as to
gain sufficient numbers of patients for multivariate analysis
[6, 31]. Both reports concluded on impaired cognitive functioning following cranial radiation, with more pronounced
effect in the younger child. However, no relation to radiation
dose prescribed was analyzed. A more recent review [38]
suggested that whole brain irradiation doses of 18 to 24 Gy
result in mild intellectual deficit and that it may be more deleterious than local irradiation. The young age at treatment
was found to be associated with higher damage. Accompanying factors such as sex, tumor type and location, combined
treatment modalities, and psychosocial factors have been
found to contribute to radiation induced sequelae [37, 39, 44,
45].
Studies focusing on IQ deficit following partial brain radiation are rare, but of high interest. Modern radiation treatment concepts for localized brain tumors intend to spare
healthy normal brain tissue by conforming radiation doses to
the tumor outline and are expected to reduce the rate of
treatment associated sequelae.
Normal tissue complication probabilities correlate highly
with dose distribution, and several mathematical models
have been developed to calculate values that offer additional
information for decision-making and treatment selection.
Empirical clinical data with well-accepted radiation dose to
volume relationship are available for a variety of endpoints,
such as functional loss and necrosis for many organs [1, 10].
However, the current lack of data in terms of intellectual
functioning after radiation therapy to the child’s brain, handicaps the physician’s ability to estimate or calculate the probability of possible cognitive deficits.
This study reviewed literature on intellectual functioning following whole brain and partial brain irradiation with regard
to Full Scale IQ (FSIQ) in order to collect data and report
the status of current knowledge. We intended to derive a
clearer statement of dose effects on FSIQ, including a correlation of age at radiation therapy. In addition we investigated
574
the influence of methotrexate (MTX) therapy with or without radiation therapy. In order to permit estimation of normal tissue complication probabilities we tried to establish a
data-base that allows modeled calculation of FSIQ change
after whole brain irradiation and partial brain irradiation,
dependent on dose and irradiated volume.
Methods
We identified 36 publications written in English language
providing information of FSIQ in relation to radiation doses
prescribed for whole brain and/or partial brain irradiation.
These data constituted the basis of this analysis and included
1,938 children. A minimum follow-up of 3 years was reported by 30 publications; 6 reports provided data based on an
observation period of minimum 1 year and up to 3 years.
We excluded reports that did not report one or both of the
following: absolute, mean or median FSIQ data, radiation
dose prescribed in cGy or Gy. In reports involving updated
information or with longitudinal design, the most recent data
with the longest follow-up were chosen for analysis. Studies
with a follow-up shorter than 1 year were excluded from this
analysis.
Data Basis for FSIQ Development after Whole Brain
Irradiation
Of the 36 publications reviewed 33 [2–5, 8, 9, 11–17, 19, 20, 23,
25–30, 32, 34, 35, 37, 39, 40, 43–45] specifically reported FSIQ
values (absolute, mean, or median) with respect to dose following whole brain irradiation. Thirteen studies [8, 12, 13, 15,
18, 19, 27, 29, 35–37, 42, 44], either in addition or separately,
provided data on percentage of children tested with an FSIQ
of < 90 and/or < 80. Number of children and FSIQ test results
according to radiation dose are displayed in Table 1. Publications reporting changes of FSIQ but without reproducible
documentation of radiation dose delivered were excluded
from this analysis.
Age-at-treatment was derived from 16 publications [8, 9, 13,
15–17, 19, 23, 27–29, 35, 37, 39]. We grouped these data by 3
age ranges: less than 3 years, ages 3 through 6, and older than
6 years. Although most publications reported on age-dependent treatment effects, not every study provided data reflecting the chosen age ranges in this study.
Data Basis for FSIQ after Partial Brain Irradiation
FSIQ values after partial brain irradiation were reported for
136 children in 6 publications [3, 7–9, 15, 28]. The number of
patients and dose levels reported by these authors are displayed in Table 1. Grouping the data by partial brain irradiation dose ranges of 49 to 52 Gy, and 54 to 55 Gy did not implicate finding of significantly different dose effects at such
Dose range
(Gy)
n
Weighted wmFSIQ Significance # of
mean
(FSIQ-drop) reports
dose (Gy)
Control
0 baseline test
0 ALL
0 glioma
0 non CNS
0 healthy
0 whole group
261
405
25
126
145
962
0
0
0
0
0
0
104.3
104.7
100.4
103.3
104.0
104.2
WBI
18
20–24
25–30
31–36
37–45
54 (24+30)
532
365
67
110
22
5
18.0
23.8
28.9
33.9
39.6
54.0
100.0
97.6
88.3
88.3
73.6
80.4
p = 0.37
p < 0.001
p < 0.001
p < 0.001
p < 0.001
p < 0.001
13
15
5
7
6
1
PBI
49–52
54–55
70.2
Total n
50 51.9
92.8
p < 0.001
81 54.4
95.0
p = 0.003
5 70.2
85.0
p < 0.001
2199–261 (baseline) = 1938
3
4
1
36
to level of radiation dose for whole brain irradiation: from 0
Gy (control group) to 18 Gy, 20 to 24 Gy, 25 to 30 Gy, 31 to
36 Gy and 37 to 45 Gy; partial brain irradiation data were
grouped according to 49 to 52 Gy, 54 to 55 Gy and 70.2 Gy.
Statistics
25
Table 1. Dose and treatment volume dependency of FSIQ outcome.
Tabelle 1. FSIQ Entwicklung in Abhängigkeit von Behandlungsdosis und -volumen.
slightly different dose levels. However, the clear attribution
of the children to the prescribed doses, suggested this classification.
The primary tumors in the cases studied were mostly astrocytoma or glioma (n = 62) and pituitary or parasellar tumors (n
= 59). Other histologies were reported in 15 children. None
of these children received whole brain irradiation. Tumor or
target volumes were specified in only 1 study [3]. Lack of
provided data in the reports prohibited further evaluation of
possible age dependency.
In order to weight the data at each dose level in respect to the
number of children attributing to each data point, and, thus, to
exclude unproportional high influence of single absolute FSIQ
values, we calculated the weighted mean dose, and weighted
mean FSIQ (wmFSIQ) for each dose range. Thus, data points
derived of studies with many children at a certain dose level
had a higher impact than data from single children or small patient groups. Using this statistical method, however, prohibited the calculation of standard error or standard deviation as
usually not all base data for each child tested was provided in
a report. The calculated weighted mean values were listed in a
database according to topic of interest. Significance of FSIQdrop was calculated by use of Student’s t test.
We did not attempt to employ statistical methods recommended for metaanalysis. The intend of this present review
was a comprehensive yet basically simple display of dose effects on outcome in terms of FSIQ test scores in children following cranial radiation therapy.
Data Calculation of Normal Tissue Complication
Probabilities
Assuming that FSIQ drop after radiation therapy below a
certain level may indicate a critical dose for the occurrence of
late side effects, the TD5 and TD50 for children with FSIQ
< 90 and < 80 can be calculated. According to models of
normal tissue complication probabilities of Lyman [21] and
Niemierko et al. [33] the complication probability can be
calculated by fitting the slope parameter m and the volume
parameter n.
Results
Control Groups
Control Groups and Baseline Values
Several groups of children who received no cranial radiation
therapy were identified as controls. They were divided into 2
groups: those with intracranial malignancies and those with
extracranial malignancies after oncological treatment, both
groups being followed after therapy. Results of baseline before undergoing radiation therapy was available for 261 children. In addition, a third control group consisting of healthy
children, such as siblings or normal population, was included
for evaluation of non-radiation related FSIQ changes. In Table 1 each of these groups is classified as to number of children, baseline results, and tumor type or “healthy”.
Data were collected on 962 children who received no cranial
irradiation or were tested before undergoing radiation therapy. The data were evaluated in 3 groups: children with malignant diseases of the central nervous system (glioma), those
with acute lymphoblastic leukemia, and those with extracranial malignant diseases (non-central nervous system) after
appropriate treatment. Baseline data were obtained from 10
studies in which 261 children were tested prior to undergoing
whole brain irradiation or chemotherapy. Thus an initial
FSIQ status was obtained in about 21% of all children who
underwent radiation therapy, and were tested for FSIQ during follow-up. No significant difference in wmFSIQ was
found between these groups, all data being within a normal
FSIQ range of 100 ± 10 points. Data of each group and the
whole group of controls are summarized in Table 1. These
values are plotted in Figure 1 at the 0 Gy level.
Data Management
Data sheets were coded for each study with the following parameters: number of children; radiation dose and, if available, error of the dose and dose range; absolute, mean or median FSIQ with standard deviation and range; FSIQ drop;
percentage of children with FSIQ < 90 and < 80; evaluation
of other IQ qualities; specification for control groups; age,
error in age; tumor specification and combined MTX therapy. For evaluation purposes we grouped these data according
Dose and Treatment Volume Dependency of FSIQ
Development
Results of the evaluation of those 36 publications that provided data of FSIQ development in correlation to respective
575
Figure 1. FSIQ drop in relation to increasing
dose after whole brain irradiation and partial
brain irradiation. Display of absolute, mean, or
median FSIQ derived from 36 studies. The
curves represent the weighted mean FSIQ after
whole brain irradiation and partial brain irradiation. FSIQ: Full Scale IQ, WBI: whole brain irradiation, PBI: partial brain irradiation.
120
PBI
100
WBI
FSIQ
80
Abbildung 1. Abfall der FSIQ-Testwerte in Bezug auf Gesamtdosis bei Ganz- und Teilhirnbestrahlung. Dargestellt sind Einzel-, Mittel- und
Medianwerte aus 36 Publikationen. Die Kurven
folgen den gewichteten Mittelwerten. FSIQ: Full
Scale IQ, WBI: Ganzhirnbestrahlung, PBI: Teilhirnbestrahlung.
60
WBI
PBI
wm WBI
wm PBI
WBI 24 + 30 Gy
40
20
0
0
6
12
18
24
30
36
42
48
54 60
66
72
dose [Gy]
radiation doses after whole brain and partial brain irradiation are summarized in Table 1. Figure 1 displays mean, median, or discrete FSIQ values derived from all 36 studies. The
number of data points in this figure is not consistent with the
number of publications because some reports provide data of
FSIQ at several dose levels. Data published by Longeway et
al. [20] are displayed separately, since they represent children treated 2 times with whole brain irradiation, first as prophylactic treatment (24 Gy) and again after diagnosis of recurrent disease (30 Gy). Thus the data point of 54 Gy
(triangle) represents the sum of both whole brain irradiation
doses. The curves in Figure 1 display the decrease of FSIQ
after whole brain and partial brain irradiation according to
the wmFSIQ, relative to radiation dose. As mentioned
above, calculation of error bars were prohibited due to the
used statistical wmFSIQ values. The initial value of the
curves was defined as 100, because all FSIQ tests are normalized to this value. The endpoints of the curves were lined out
to the highest dose level at which data were available.
whole group resulted in comparable FSIQ decline dependent
on whole brain irradiation dose as in the whole evaluated
population. When compared for FSIQ change, the change
was mostly negatively correlated to whole brain irradiation,
but no significantly different FSIQ decrease with increasing
dose was found. No report provided data for age analysis according to our requirement.
Age at Diagnosis
Age group
Number of children, dose levels of whole brain irradiation,
and wmFSIQ are displayed in Table 2. Figure 2 displays
wmFSIQ according to whole brain irradiation dose. The
curves represent the decrease of wmFSIQ values according
to age and whole brain irradiation doses.
WmFSIQ and curves are superimposed on data from Silber
et al. [41], who developed a model of FSIQ decline after doses of 18 Gy, 24 Gy, and 36 Gy whole brain irradiation, according to age. The linear FSIQ decline for age 2, age 4, age
6, age 8, and age 10 is plotted, as predicted by the model.
However, data collected for the present review suggest a
non-linear decline of FSIQ after whole brain irradiation with
more pronounced dose effects for the group of younger children (< 3 years, and 3 to 6 years), but substantial decline at
higher dose levels for older children (> 6 years) as well.
Percentage of Children Tested with FSIQ < 90, and < 80
A Gauss bell-shaped plot of normal distribution of FSIQ
shows certain percentages of the normal population below
the expected mean value of 100. An FSIQ < 90 is expected in
25% of all children examined, and an FSIQ < 80 in 8.9% of
the normal population. An increase of the percentage of children with FSIQ test results less than 90 and 80 points was observed with increasing whole brain irradiation radiation
dose. Figure 3 displays curves derived of weighted mean percentages of children below the chosen FSIQ level according
Dose (Gy)
0–3 years (n = 79) 0
18
20–24
25–30
31–36
37–45
3–6 years
0
18
20–24
25–30
31–36
37–45
Over 6 years
0
18
20–24
25–30
31–36
37–45
wmFSIQ
97
92
90.4
n/a
75.6
46.5
106.9
n/a
91.1
87.0
n/a
59.0
100.6
110.0
97.4
n/a
92.0
80.8
Significance
(FSIQ-drop)
p<0.001
p = 0.02
n/a
p<0.001
p<0.001
n/a
p = 0.07
p = 0.02
n/a
p<0.001
no drop
p = 0.36
n/a
p = 0.17
p = 0.02
Prospective Comparison of FSIQ Development
Table 2. Significance of age and dose on FSIQ.
FSIQ values were available in 10 studies for 261 children, before and after whole brain irradiation. Evaluation of the
Tabelle 2. Signifikanz von Alter und Behandlungsdosis auf FSIQ
Entwicklung.
576
of the derived curves is about linear and the curves are parallel; therefore, m = 4.7 can be calculated from these data.
This slope expresses that in the respective dose ranges an increase of whole brain irradiation dose of 1 Gy results in an increase of approximately 4.7% of children with post treatment
FSIQ < 90 and < 80, respectively. Based on this slope and the
baseline of 25% and 8.9% for healthy children with FSIQ
< 90 and < 80%, respectively, the dose causing 50% probability for FSIQ below defined threshold value can be estimated.
According to the evaluated data and the calculated slope we
suggest a 50% probability at 30 Gy whole brain irradiation for
FSIQ < 90 and at 38.5 Gy whole brain irradiation for FSIQ
< 80. The estimated error for the slope within the respective
dose limits is assumed not to exceed 10%.
to whole brain irradiation doses. The mathematical source of
the curves at dose 0 Gy represents the expected percentage
of healthy children. In addition discrete or mean percentages
of children below age 3 are plotted which were tested with an
FSIQ < 90; the vast majority of these data points are distributed above the FSIQ < 90 curve, thus indicating that this subgroup is at even higher susceptibility for radiation induced
FSIQ drop. Further evaluation for age relationship to percentages below given threshold values was limited by lack of
reported data.
For comparison, the percentage of children below given
FSIQ values after partial brain irradiation was plotted in Figure 3 indicating a minor FSIQ decline at substantial higher
doses when compared to whole brain irradiation.
Estimation of 5% increase of percentage of FSIQ < 90 and
< 80 is far more uncertain since the data do not suggest a linear relationship between increase of whole brain irradiation
dose and FSIQ decline at these points. Coarse approximation indicates a dose of about 22.5 Gy whole brain irradiation
to increase the percentage of children below FSIQ 90 by 5%
and 26 Gy for FSIQ < 80. The error of the slope at this point
might be as high as 25%.
Approximation of Normal Tissue Complication Probabilities
Derived from data contributing to Figure 3 the 5% and 50%
increase of percentage of children below defined FSIQ values
following whole brain irradiation can be approximated. At
whole brain irradiation dose ranges of about 26 Gy to 36 Gy
for FSIQ < 90 and 34 Gy to 44 Gy for FSIQ < 80, the slope (m)
Figure 2. FSIQ drop after whole brain irradiation in relation to increasing dose and according
to age < 3, 3–6, and > 6 years. Superimposed to a
model calculation by Silber et al. [41]. FSIQ: Full
Scale IQ.
100
FSIQ
Abbildung 2. Abfall der FSIQ-Testwerte in Bezug auf Gesamtdosis und Alter zur Zeit der
Strahlentherapie. Die Kurven für die Altersgruppen < 3 Jahre, drei bis sechs Jahre und
> 6 Jahre wurden einer Modellkalkulation von
Silber et al. [41] überlagert. FSIQ: Full Scale IQ.
120
wm FSIQ < 3 yrs
wm FSIQ 3 to 6 yrs
wm FSIQ > 6 yrs
Silber < 2 yrs
Silber 2 to 4 yrs
Silber 4 to 6 yrs
Silber 6 to 8 yrs
Silber 8 to 10 yrs
80
60
40
0.0
6.0
12.0
18.0
24.0 30.0
dose [Gy]
36.0
42.0 48.0
100
wm WBI < 90
wm WBI < 80
< 3 yrs
PBI < 90
PBI < 80
90
Abbildung 3. Gewichtete mittlere prozentuale
Anteile der Kinder, die nach Ganzhirnbestrahlung mit FSIQ-Werten < 90 und < 80 getestet
wurden. Zusätzlich wurden Testwerte für Kinder < 3 Jahre nach Ganzhirnbestrahlung und
prozentuale Anteile nach Teilhirnbestrahlung
unterhalb der gewählten Schwellwerte aufgetragen. FSIQ: Full Scale IQ, WBI: Ganzhirnbestrahlung, PBI: Teilhirnbestrahlung.
80
WBI
70
%
Figure 3. Weighted mean percentage of children
tested with FSIQ < 90, and < 80, after whole
brain irradiation in relation to dose. For comparison, display of percentage of children < 3 years
with FSIQ < 90 after whole brain irradiation and
percentage of children after partial brain irradiation with FSIQ < 90 and < 80. FSIQ: Full Scale
IQ, WBI: whole brain irradiation, PBI: partial
brain irradiation.
60
50
40
PBI
30
20
10
0
0
6
12
18
24
30 36 42
dose [Gy]
48
54 60
66
72
577
Influence of MTX Administration with and without Whole
Brain Irradiation
The influence of MTX effects in combination with radiation
therapy could not be evaluated in this study, since at the 18,
24, and 36 Gy dose level nearly all children received a combined therapy regimen, with only a limited number of children known to have undergone radiation therapy without
combination with any form of MTX therapy. Interestingly,
adding up the available data on children receiving MTX
without radiation therapy versus healthy children, did not
demonstrate a significant difference in FSIQ. MTX treated
children were tested with a wmFSIQ of 104.5, compared to
the group of healthy children with a wmFSIQ of 104.9.
Discussion
Intellectual functioning can be assessed by testing for a variety of parameters. The focus on FSIQ, therefore, represents
only one result of a complex and not necessarily standardized
testing procedure. The majority of studies provides data concerning FSIQ, some report other IQ data, such as Performance IQ (PIQ) or Verbal IQ (VIQ), as well. Not all of these
IQ may be found similar impaired after radiation therapy.
Other functional qualities, such as memory and attention
may well be deficient without significant expression in other
test scores. Thus, focus of this review on FSIQ was given by
the broad data basis and the fact that FSIQ represents a general assessment of intellectual functioning with defined mean
value and standard distribution of test values in the normal
population. FSIQ tests are available for several age groups
and in different languages; the results are therefore internationally comparable.
Whole Brain Irradiation
Mulhern et al. [30] found in a review of 22 studies (403 children) that mean FSIQ after whole brain irradiation was 82.9,
with children under age 4 and older than 4 scoring at mean
values of 73.4 and 87.0, respectively. Whereas these authors
found a correlation between irradiated volume (whole brain
irradiation vs partial brain irradiation) and decline in FSIQ,
no analysis in regard to radiation doses was provided.
The present review analyzed FSIQ development after
whole brain and partial brain irradiation. Analysis of 36
studies and more than 1,900 children showed a clear correlation between test results and radiation dose and volume.
In the whole group of children, the mean FSIQ after 18 and
24 Gy whole brain irradiation was within the normal range.
At doses higher than 24 Gy a negative correlation with increasing doses was found. Age at diagnosis had high impact
on FSIQ development with children under age 3. They
scored at low normal levels after 18 and 24 Gy and showed
significant decline in intellectual functioning at higher doses. Children older than age 6 at diagnosis were tested with
mean normal and low normal values after whole brain irradiation doses of up to 36 Gy, substantial FSIQ decline was
found at higher doses.
Silber et al. [41] introduced a model for dose, age, and
change of FSIQ in dependency of initial IQ. Their model assumed a patient with an initial score of 100 and whole brain
irradiation treatment with 18, 24, and 36 Gy at ages from 2 to
578
10 and predicts a linear decrease with increasing dose. Our
findings rather support a non-linear decline for all age groups
with steeper decline at increasing doses. The dose-effect relationship is shown to be age-related with more pronounced
dose effects at younger age. For the younger children (less
than age 6) the estimated value at 18 and 24 Gy from the
model and our compiled data almost overlap, but at higher
doses the documented decline exceeds by far the prediction
of the model. For children older than age 6 Silber’s model
would overestimate the dose effects at dose levels between
18 and 36 Gy, when compared to the collected data.
Many authors prefer the expression of FSIQ point difference
for comparison between 2 groups of children or in comparison to a control group. Cousens et al. [6] describe in their
metaanalysis a 10-point decline of the irradiated group compared to the control group that scored at a mean FSIQ of
109. Thus the irradiated group scored at a normal mean level. Unusual high mean test scores in their control group may
suggest their conclusion that whole brain irradiation causes
decline in intellectual functioning. However, most studies
test their control groups at values around 100. Evaluation of
the control groups in the present review found the whole
group as well as all subgroups at FSIQ levels of about 104.
No significant difference was found between healthy children and children with brain tumors or acute lymphoblastic
leukemia, either before or after undergoing sufficient treatment but without radiation therapy.
The definition of 100 as the baseline for calculation of FSIQ
drop and as the starting point of the curves may be controversial, but to ensure comparability of all collected data we
decided to use the standardized mean value of all IQ tests.
However, this may have consequences if a drop is calculated
in the collected data, with possible underestimation of detrimental effects, this with special respect to FSIQ impairment
following a whole brain irradiation dose of 18 Gy. The
wmFSIQ in this review of 100.0 points was exactly as high as
the expected mean value in a normal population, but 4.2
points lower than the mean score of all control groups.
Therefore, a minor effect of radiation therapy with 18 Gy
could not be excluded with certainty.
The influence of the findings and interpretation of a single
study on possible discrete drop in cognitive functioning following whole brain irradiation with 18 Gy in this review may
be documented. A recent longitudinal study [14] evaluated
129 children with acute lymphoblastic leukemia following 18
Gy whole brain irradiation in combination with MTX containing chemotherapy in comparison to a second group of 74
children which were only treated with intravenous and intrathecal MTX. As specified, the last available FSIQ test value
at longest follow-up was chosen to apply for this review. The
high number of children in this study represents about a
quarter of all children treated with 18 Gy in this analysis. After a follow-up of more than 7 years, the irradiated children
scored with a mean FSIQ of 95, compared to 104.5 in children treated with chemotherapy alone. The difference was
therefore 9.5 points. As the mean follow-up of all children
ranged between 6.4 years (18 Gy) and 5.8 years (chemo) only a subgroup of children can have contributed to this last test
value. If test results were compared after a follow-up of 6 to
7 years the difference between both groups was only 2 points
with the groups scoring at 102 (18 Gy) and 104 points
(chemo). Again only a subgroup of the 129 children can have
been tested in this follow-up interval. It would have been of
great interest to compare the latest test results of the subgroup with longest follow-up with their own initial score.
This documents a common dilemma; test results at different
times after therapy and from different subgroups may lead to
significantly different conclusions. The evaluation of a large
number of children, such as in this review may have the power to detect differences in FSIQ scores which do not appear
in studies with small numbers of children, on the other hand
may such an analysis enhance differences based only on a
subgroup of all examined children.
Longeway et al. [20] provide in their study data for intellectual outcome after 2 courses of whole brain irradiation with initial doses of 24 Gy and additional doses of 30 Gy at the time
of recurrent disease. The mean FSIQ score of 80.4 corresponded to a value expected to be equivalent to a single whole
brain irradiation course of about 38 Gy. Although the authors
did not report the time gap between the 2 whole brain irradiation treatment courses this seems to demonstrate a splitcourse effect with considerable reduction of expected FSIQ
detriment. Nonetheless, the outcome for 3 of these 5 children
was in the mentally defective range. But also the only reported child scoring over 120 after a whole brain irradiation dose
higher than 38 Gy belonged to this group of children.
Partial Brain Irradiation
FSIQ testing after local cranial radiation therapy (partial
brain irradiation) shows substantial reduced impairment.
Mulhern et al. [28] tested children after hyperfractionated radiation therapy of brain stem gliomas and doses of 70.2 Gy.
Their test scores correspond to test results after about 36 Gy
whole brain irradiation. This may confirm the hypothesis
that hyperfractionation can reduce functional detriment.
Tumor localization and histology can have a major impact on
FSIQ following partial brain irradiation with substantial impairment in children with hypothalamic tumor extension [18]
and tumors of the parapituitary region [15]. In contrast, Cavazzuti et al. [3] reported that primary radiation treatment for
children with craniopharyngeoma resulted in superior FSIQ
scores when compared to children who underwent surgery
and radiation therapy. FSIQ test results are undoubtedly associated with factors, such as hydrocephalus [15, 18], extend and
number of surgeries [3], and degree of neurological deficit and
disability [18, 28]. These factors themselves can result in cognitive impairment and add to radiation induced sequelae.
Although multi-factor dependent, the data support the obvious fact that partial brain irradiation at equal dose levels is
less damaging than whole brain irradiation. Overall, the paucity of current data on cognitive functioning following partial
brain irradiation does not allow definitive conclusions regarding dose-effect relationship.
Data-Base for Normal Tissue Complication Probabilities
Calculation
In order to define radiation treatment doses that are both,
sufficient for tumor control or central nervous system proStrahlenther Onkol 2000;176:573–81 (Nr. 12)
phylaxis, yet can safely avoid normal tissue complications,
precise knowledge of tumoricidal dose and tolerance doses
of normal tissue is required. Unfortunately, not all complication endpoints are clearly attributed to radiation doses and
their multi-factorial origin further complicates risk estimation. Calculation of normal tissue complication probabilities
(NTCP) offers an additional estimate of the increase of risk
for the occurrence of deterministic and therefore doseand/or volume-dependent radiation induced sequelae. Typically, an increase in risk of 5% and 50% for a follow-up time
of 5 years is calculated.
The data for TD5/TD50 were approximated from curves derived from data of several publications. However, mainly the
slope of these curves has to be interpreted with caution. Data
contributing to this estimation are quite inhomogeneous;
children with whole brain irradiation doses up to 30 Gy have
mostly been treated for acute lymphoblastic leukemia, at
higher doses the leading diagnosis was medulloblastoma. We
could not account for the influence, and thus possible immanent errors, of primary tumor and cofactors such as surgery,
combined toxicity of chemotherapy and effects caused by
different daily fractionation regimens. We tried to account
for the age at treatment as an important factor by excluding
the children younger than age 3 for this approximation; still
the data reflect a wide age-range at the time of treatment.
Thus, an average effect of whole brain irradiation on rate of
children with post-treatment FSIQ < 90 and < 80 points has
been estimated. The usefulness of derived data for normal
tissue complication probabilities calculation and clinical
appropriateness of calculated values will be subject to a
separate report.
The current data collection suggests that the risk to increase
the percentage of children tested with an FSIQ < 90 and < 80
points to 50% is correlated to a dose of 30 Gy whole brain irradiation, and 38.5 Gy, respectively. For clinical practice, the
dose causing a 5% increase might be of greater interest as
this complication rate limits prescribed doses to many organs
in various treatment protocols. Approximation of this value
risk had an even higher degree of uncertainty, with doses of
22.5 Gy and 26 Gy possibly causing a 5% increase of children
with an FSIQ < 90, and < 80, respectively.
To our knowledge, Miralbell et al. [24] were the only other
group that tried to estimate a dose relationship to the percentage of children with an FSIQ < 90. They calculated,
based on 5 publications [8, 13, 26, 41, 44] the TD50 for an
FSIQ < 90 at a dose level of 41 Gy. This would suggest a substantially minor steep dose-effect relationship than observed
in the present evaluation where about 90% of reported children were tested below 90 points at this high dose level. As in
the present review, the authors reported a correction of the
given values by the probability of this endpoint in the general population. Differences in both studies might be explained
by different baselines for children with FSIQ lower than 90 in
the normal population (25% vs. 20% assumed by Miralbell)
and obvious misinterpretation of base-data by the authors.
Definition of normal tissue complication probabilities as
complication probability after radiation therapy does not expressively define if the observation of an event or only the
new occurrence of this event has to be taken into account.
579
Based on complication endpoints, such as necrosis which usually do not occur in a normal population there is no need for
this discrimination. The focus on a complication event that is
already observed in the normal population may need more
precise definition. With the intent to offer comparable data
we calculated the dose level at which in 50% of the observed
group the event FSIQ < 90 was reported. Calculation for 50%
new events would result in slightly higher dose levels.
Increase of percentage of children with test results < 90 and
< 80 points was also documented after localized cranial irradiation. However, the limited number of children with
FSIQ data after these treatment courses restricts the validity of a statement. Young age at treatment and tumor extension into mid brain structures can be associated with
measurable detriment after partial brain irradiation. The
only reliable conclusion based on current data is that there
is an increase in the percentage of children with FSIQ < 90
and < 80 following local cranial irradiation, whereas, although, far less pronounced as expected after comparable
whole brain irradiation doses. The link of dose and its effects at conventionally fractionated doses higher than 54 Gy
remains yet unclear; also if this function may be linear or
non-linear.
Conclusion
The intent of the present study was to improve knowledge of
the causal correlation of cranial radiation therapy and intellectual development. The collected data suggest that whole
brain irradiation doses of 18 to 24 Gy cause no major impairment of intellectual development in children older than age
6, but may be already correlated to an impairment in children
younger than age 3. Doses higher than 24 Gy prescribed to
the total brain comprise a substantial risk for intellectual impairment, even in older children. partial brain irradiation significantly reduced FSIQ decline.
Results of the current review may be interpreted with caution. Several limitations, such as inhomogeneous primary tu-
mors, influence of cofactors and treatment parameters as
well as the criteria to collect and analyze the data might initiate critical discussion.
Thus, we support suggestions by others of a standardized test
design with evaluation of various, comparable essential data,
such as FSIQ, PIQ, and VIQ. Any report should clearly correlate observed IQ values with radiation dose, irradiated volume, primary tumor and age of children. Since all studies
evaluate basic data, at least the mean and median FSIQ
should be documented. Lack of these data prohibited inclusion of a large number of children reported in numerous publications into this study. Including them might have influenced our conclusions.
In order to detect a possible effect following whole brain irradiation with 18 Gy, further data collection is required.
Baseline testing in form of a prospective study design is required to clarify if the small FSIQ decline compared to FSIQ
of the control group, as found in this review, represents a reproducible effect. Evaluation of the dose-effect relationship
at this dose level may influence future protocol developments. Whole brain irradiation with 18 Gy is currently recommended as standard dose in the prophylactic treatment of
children with high-risk acute lymphoblastic leukemia (WBC
count >25,000) and the rationale to exclude cranial radiation
therapy in the prophylaxis for acute lymphoblastic leukemia
is based on the studies reporting intellectual detriment. Reevaluation of the large group of children treated with whole
brain irradiation doses > 36 Gy in the past, and now with significant long-term follow-up, could provide essential, additional information, as inhomogeneous data situation at this
dose level requires further research.
Acknowledgement: The authors wish to thank Dr. John O. Archambeau for reviewing this paper and offering helpful suggestions and
Mr. Chris Oeinck, C. R. A., for his assistance in the preparation of
the manuscript.
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Address for Correspondence: Dr. Martin Fuss, UTHSC/Dept. of
Radiation Oncology, 7703 Floyd Curl Drive, San Antonio,
Texas 78284-7800, USA,
Phone (+1/210) 616 5648, Fax 949 5085,
e-mail: [email protected]
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Full Scale IQ (FSIQ) Changes in Children Treated with Whole Brain

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