UNSCEAR 1993 Report - Annex I - United Nations Scientific

SOURCES AND EFFECTS
OF IONIZING RADIATION
United Nations Scientific Committee on the Effects
of Atomic Radiation
UNSCEAR 1993 Report to the General Assembly,
with Scientific Annexes
UNITED NATIONS
New York, 1993
NOTE
The report of the Committee without its annexes appears as Official Records of the
General Assembly, Forty-eighth Session, Supplement No. 46 (N48/46).
ll1e designation employed and the presentation of material in this publication do not imply
tl1e expression of any opinion whatsoever on the part of tlie Secretariat of the United Nations
concerning the legal status of any country, territory, city or area, or of its authorities, or concerning
tl1e delimitation of its frontiers or boundaries.
The country names used in this document are, in most cases, those tliat were in use at the
time the data were collected or the text prepared. In other cases, however, the names have been
updated, where tliis was possible and appropriate, to reflect political changes.
UNITED NATIONS PUBLICATION
Sales No. E.94.IX.2
ISBN 92-1-142200-0
ANNEX I
Late deterministic ef'fects in children
CONTENTS
Page
INTRODUCTION
I.
..........................................
870
........ 871
I1 . RADIATION EFFECTS IN TISSUES AND ORGANS ............. 872
A. BRAIN ........................................... 872
1 . Organic effccts .................................. 872
2. Ncuropsychologic effects ........................... 875
3. Neuroendocrine effects ............................. 877
B. THYROID GLAND .................................. 881
C. OVARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .884
D. TESTIS ........................................... 886
DETERMINISTIC EFFECTS OF RADIATION EXPOSURES
E. MUSCULOSKELETAL SYSTEM ........................ 888
............................................. 8%
CARDIOVASCULAR SYSTEM ......................... 892
H. LUNG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .892
I . BREAST .......................................... 893
J . DIGESTIVE SYSTEM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .894
K KIDNEY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .895
L BONE MARROW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8%
F. EYE
G
.
.
CONCLUSIONS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 897
Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 899
Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 904
References ............................................... 909
870
U N S C M R 1993 RI~I'OI~T
INTRODUCTION
1.
Dctcr~ninistic rffccLs of ionizing radiation in
humans arc t l ~ crcsult of whole-body or local cxposures tl~atcausc sufficicnt ccll da~nagcor ccll killing
to impair function in the irradiated tissuc or organ.
Thc damagc is thc rcsult of collcctivc injury to substantial nunlbcfs or l)roportio~~s
ofcclls. For any givcn
dctcrministic cflcct, a givcn nu~nbcror proportion of
cclls must bc affcctcd, so that thcrc will be a thrcshold
dose bclow which thc nurnbcr or proportion of cclls
affcctcd is insufficient for tile dcfincd injury or clinical
manifestation of thc cffcct to occur [ F l , 11 1. With
incrcasing radiation dose fcwer cclls survive inlact,
and therefore the dctcr~ninistic crfccts incrcasc in
scverity and frcqucncy with the dosc [U3]. If the
radiation cxposurc is scvcrc cnough, dcath may result
as a conscqucncc of the exposure. Dcath is gcncrally
the rcsult of scvcre ccll depletion in one or morc
critical organ systems of thc body.
3.
Radiation-i~~duccddctcrr~~inisticdanlagc in a
~ ~ oftcn l~avca lllorc scvcrc impact
tissuc or o r g i ~will
on t l ~ cindividual during childl~ood,when tissues are
activcly growing, h n n during adulthood. Examples of
dctcr~l~ir~istic
scquclac aftcr radiation cxposurc in
cl~ildl~ood
includc cffccls on growlh and dcvclopn~cnt,
hor~nonnldcricic~lcics,organ dysfunctions and caccts
on i~~tellcctual
and cognitive functions. In this Anncx,
a rcvicw is rnadc of latc, dctcnninistic d a m a g to
nor~naltissucs in cl~ildrcncauscd by ionizing radiation.
Life sbortcning is not discussed due to the paucity of
data. Othcr cffccts of radiation exposurc, such as
canccr illduction, l~crcditarycffccts and early radiation
cffccts, arc not considered. One objcctivc of this
review is to try to dctcrminc thc critical dosc lcvcls
for thc appearaacc of c l i ~ ~ i c adctcnninistic
l
effccts.
Such dosc lcvcls will dcpcnd on the end-points
considcrcd and on the sensitivity of the techniques for
measuring Lhc cffccLs. Pcrn~ancnlrather than transient
biocl~cniicalchaagcs are cn~phasizcdin thc attc~nptsto
dcfinc the threshold doscs.
Ionizing radiation can irnpair function i l l all
2.
tissucs and organs in the body because of cell killing;
howcvcr, tissucs vary in thcir sensitivity to ionizing
4.
Thc Comnlittcc rcvicwcd the detcrministic
radiation [Fl,11). Thc ovary, tcstis, bone marrow,
cffccts of radiation in Anncx J of the UNSCEAR 1982
lymphatic tissuc and the lcns of the eye belong to the
Rcport [U3]. T l ~ cbasic conccpts of ccll survival wcrc
most radioscnsitive tissucs. In general, thc doscrcvicwcd, including the factors influencing tissue rercsponsc function for thcsc tissucs, i.c. thc plot on
sponsc to fractionated or continuous exposures to
linear axes of the probability of harm against dosc, is
radiation. That rcvicw of effccts was bascd n~ainlyon
sigmoid in shape. Above thc appropriate thrcshold, thc
results of animal cxpcrimcnts and clinical obscn~ations
effect becon~esmore scvcrc as thc radiation dosc
of adulb who had rcccivcd radiotherapy. Its main obincrcascs, reflecting thc numbcr of cclls damagcd. Thc
jcctivc was to idcntify the naturc of cffeck in various
effect will usually also increase with dosc rate,
tissucs and thc doscs and modalities of irradiation that
because a morc prolractcd dosc causcs thc cell damage
causc tl~ceffects. I t was the Commitlee's opinion that
to be sprcad out in timc, allowing for more effcctivc
bcttcr quantitative results io man would bc rcquircd,
repair or rcpopulation [12]. This typc of cffcct, which
although it was rccognizcd that such dala wcrc diffiis charactcrizcd by a severity that incrcascs with dosc
cult to obtain. For cffcck in children, the nccd for data
above sonlc clinical thrcshold, was pr~\~iously
callcd
and thc difficulties wcre considcrcd to be cvcn grcater.
"non-stochastic". The initial changes on thc ccllular
lcvcl occur csscntially at random, but thc large nunlhcr
5.
of cclls rcquired to rcsult in a clinically obscnlahlc,
The i~~for~ni~liorl
in tliis Anncx on thc possiblc
non-stochastic cffcct givcs the cffcct a dctcrmi~~istic dctcr~ninisticcffccb specific to the cxposurc of childrcn conlcs from t l ~ capplicatior~of new methods to decharactcr. For this rcason such cffccts are now callcd
rive data and Ltic continued monitoring of p a t i c ~ ~who
k
"detcrministic" cffeck. The dosc lcvcls that rcsult in
rcrcivcd radiot11cral)y and othcr individuals cxl)oscd to
the clinical appearancc of pathological effects arc
doscs high cnougll to causc dctcnninistic damage to
generally of the ordcr of a few gray to some tens
spccilic tissucs or to the wholc body. For practical
of gray. This clinical thrcshold or critical dose is
applications it is important that attcmpts should be
bascd on clinical cxaniination and laboratory tcsts. Thc
m;~dcto quantify this damage in tcrrns of tlic degree
timc of appearance of tissue damagc ranges lroln a
~t.
to t l ~ cpaucity of datii, it is not
few hours to marly ycars aftcr the cxposurc, d c p c ~ ~ d i r ~ g ol' d c t r i ~ n c ~0wi11g
really possiblc to quantify cffec~sby agc in most
on the typc of eflcct and thc charactcristicr of tllc
situirtions.
particular tissuc.
ANNEX 1: U T l i DiTERMINISTIC RADIATION EWECIS IN ClllLDREN
I.
DETERMINISTIC EFFECTS OF RADIATION EXPOSURES
6. Although thc pathobiology of radiation-induced
latc deterministic effects is poorly understood, it is
reasonable to believe that latc damage can result from
a conibination of loss of parc~~clrymel
cclls, injury to
the fine vasculaturc and/or dysfunction of the fibrocytes and other cclls [CI]. Radiation-induced latc
tissue injury of a deterministic nature appears to havc
its origin in h e sterilization of a large proportion of
the stem-like cclls of the tissue or organ in question,
although thcse cells may be only a small proportion of
the total number of cells in that tissue/organ. The
consequent injury results from the natural loss of postmitotic cells that :ire not replaced or from the loss of
cclls that arc stimulated into mitosis. The timing of
tissuc injury depends on the natural proliferation
characteristics of cells and also on kinetic changes
resulting from the radiation exposure that are characteristic of the tissuc p 3 ] . In addition to the loss of
functional cclls, supporting blood vessels may be
damagcd, resulting in secondary tissue damage.
Damage to the capillary network has been implicated
in the degenerative changes that are accompanied by
a progressive reduction of functional capacity [Fl 1.
Other mechanisms for latc effects include increased
vascular permeability. which causes plasma proteins to
lcak into interstitial spaces, resulting in the deposition
of collagen and leading to atrophy of parenchymal
cells. There may also be some replacement of functional cells by fibrous tissue, reducing organ function.
The clinical effect that ensues depends on the specific
function of the tissue in question.
Various processes of repair and repopulation will
7.
increase the threshold level of dose when radiation is
given over a long period or when a second period of
irradiation is encountered sometime after an earlier
exposure. The exact role of repopulation, recruitment
and intracellular repair of radiation injury over long
periods is not clear [Cl]. Another aspect that is not
wcll understood is the effect of prior radiation therapy
on late injuries following a second course of radiotherapy. There is repair of sublethal damage related to
fraction sizc and fractioti number, as wcll as to dose
rate. There appears to be a wide rangc in the amount
of repair that can occur betwccn radiation doses or at
decreasing dose rates, which seems to be a tissuespecific phenomenon [CI ]. Increasing tolerance occurs
as a function of time (days to weeks between fractions) in organs expressing late damage and is thought
to be based on slow cell renewal.
Late radiation effects often occur in tissucs with
l i n k or very little prolifcration. The radiation effects
have been attributed to parenchymal depletion secondary to endothclial changes in small blood vessels or to
the direct depletion of parcnchynial or stromal cells
8.
871
[ R l , R2, R3, T I , W1 1. The dose-survival relationship
for latc effects differs fro111 Illat of acute responses.
Injury to slowly responding tissucs is more dependent
on fraction sizc. When conventional radiotherapy Gactionatio~ischedules have been altered to fewer Gactions of larger doscs, an increase in late complications
has ensued, with little or no difference in the severity
of acute effects [T2]. Studies in animals indicate that
the dose-survival characteristics of target cclls for late
injuries are different from those of target cclls of
acutely responding tissucs. The slopes of the isocffect
curves as a function of dose per fraction are greater
for latc effects, indicating a greater irifluence on
sparing from dose fractionation for late effects [T2,
W2]. The data for low-LET radiation in adults show
a wide range of sensitivities of diffcrent tissucs P I ,
RI]. Few tissues show clinically significant effects
after acute exposures of less than a few gray, with the
exception of the gonads, lens and the bone marrow,
which show higher sensitivities.
9. Thcrc is little direct correlation between acute
reactions and late effects of radiation [Bl, R2, N ] . It
is, therefore, the latc radiation effccts [hat are the doselimiting factors in curative radiotherapy. Interactions
with other treatment modalities may also limit the
radiation dose. For example, chemotherapy administered
during, before or after irradiation may reduce the
tolerance of the tissues exposed to ionizing radiation
IN, Wl]. In radiotherapy, normal tissues are unavoidably included in the target volume, and it is the effects
in thcse tissues that limit the dose that can be tolerated.
There is still poor understanding of the exact tolerance
of a given organ or tissue and of changes in tolerance
caused by variations in fraction size, target volume,
duration of treatment, dose rate and Lhc presence of
various chemical compounds. For a variety of tissues or
organs, a critical radiation dose for a limited volume of
this tissue has been established empirically, mainly in
adults. This dose is usually defined as the dose that will
produce a small but detectable incidence of serious
complications resulting from the radiation effect on the
normal tissue, and often 5% of serious con~plicationsis
considered rcasonablc in radiotherapy [Cl, Rl]. This
critical dose or dose rangc is different from the tern1
"tolerance dose", historically used in radiation
protection. Most clinical practice involves daily
fractionation with approxiniatcly 1.5-2 Gy four or five
days per week. I n Ibc following paragraphs this will be
rcferred to as conventionally Gactionatcd radiod~crapy.
Rubin et al. [ R l ] and Molls and Stuschkc [h441] havc
published d a b on acceptable doscs in rirdiothcrapy and
have presented estimates of radiation doses for
deterministic effects ill organs and tissucs of adults and
children. There are wide variations in the critical dose
lrom one tissue to another (Tablcs 1-2).
UNSCMR 1993 WI'OHT
872
have also bccn treated with other modalities, e.g.
surgcry, cytostatic drugs al~d/or honnoacs. Most
clinical cvaluatio~~s
arc, moreover, based on small
nurnbers of paticnts, and often appropriate control
groups are lacking. Furthernlorc, the long duration of
che illness, tile need for hospitalization. tbc lack of
school iittc~ida~~cc
and olher social factors rnay have
had a n irnpact on certain effects nleasured, such as
neuropsychologic fu~~ctioning.
The fact that most data
are obtained fro111 studies of patients with pacdiatric
tumours makcs i t even niorc difficult to draw
conclusior~sthat can be generalized to the general
pacdiatric population. One reason for this is that
groups of children ueated for malignant disease may
11. Only a few large epiden~iological studies of
deterministic effects in cl~ildrenexposed to io~iizir~g include individuals with a genetic predisposition to
cancer, some of whom can perhaps have a higher
radiation have bccn published. Most data are obtained
sensitivity to other radiation-induced effects as well. In
from clinical follow-up of small groups of patients
general, there is a great variability in the ages of the
successfully treated for paediatric turnours. In the
patients studied, and many studies have also assessed
1950s and early 1960s the prognosis for a child with
patients at widely different ages. A sizeable portion of
a malignant turnour disease was grave, and for riiany
eligible
patients arc often riot assessed: the children
types of turnours death would follow in a matter of
may not be available for evaluation, owing to, for
months. With the introduction of modem surgery,
exaniple, their refusal or that of their parents, the
high-voltage radiotherapy and chen~otherapy,the prodisease itself or geographical factors. These selection
gnosis has improved considerably, and today a large
criteria obviously also affect the interpretation of data.
proportion of children with paediatric tumours are
cured. The proportion of two-year survivors, which
13. Radiation therapy has been claimed to account
implies the cured fraction, in 1980 ranged from
for
about 80% of the long-tcnn sequeiae in surviving
approximately 40% for patients with neuroblastoma or
children
with neoplasms [MI]. Severe disabilities were
brain tumours to 80%90% for patients with Wilrns'
noted
in
41% of 200 children treated for cancer who
tumour or Hodgkin's disease [Sl]. Consequenlly,
had
no
sign
of disease for at least five ycars after
many children are now surviving into adulthood,
therapy [M2]. The disabilities included severe
making it possible to study the late effects of their
cosmetic changes (16%), severe growth retardation
treatment. Increasing reports of late effects have Icd to
(lo%), the need for special cducation (8%), gonadal
systematic investigations by groups of paediatric
failure (7%) and other apparent organ dysfunctions
cancer treatment inctitutions, such as the Childrens
(12%).
Hypothyroidisni (3%), minimal scoliosis and
Cancer Study Group in the United States and Canada
bypoplasia
(22%) were some of the mild to moderate
and the International Late Effects Study Group.
disabilities. Li and Slonc [ L l ] studicd late effects in
142 patients trcatcd for childhood cancer and observed
12. In this review of deterministic effects in children,
major defects in treated organs in 52% of the patients.
the various observed effects have been grouped
Dcspite this, a large proportion of the patients had
according to the organ or tissue affected. It is
fully active lives, 61 % had attended collcgc, 53% were
generally difficult to single out thc specific effect of
married arid 32% had progeny.
radiation in children with paediatric tumours, as most
10. There is great variability in the latent intervals
between radiation exposure and the clinical nlanifcstation of late deterministic eKccts, which niay develop
at times varying from ~ i ~ o n t htos 10 or more ycars
after treatment. The latent interval depends on the
tissue or organ affcctcd and is, for example, up to 2
years for myelitis, one to several years for nephritis,
1-5years for eye effects and 6 months to many ycars
for fibrosis in subcutar~cousand connective tissues
[T2]. The rate at which radiation injury becomes
manifest in a tissue rellects the rate of turnover of
target cells and their progeny [Fl].
11. RADIATION EFFECTS IN TISSUES AND ORGANS
A.
BRAIN
'
1. Organic elTects
14. The developing human brain is especially
sensitive to ionizing radiation. Previous UNSCEAR
Reports have considered the general developnien~al
effecls of prenatal irradiation [U2, U4]. A review of
the results of the study of survivors of the atomic
bombings in Japan, as well as reviews of other epidemiological investigations relating to prenatal
exposure to ionizing radiation and effects on the brain,
arc presented in Annex H, "Radiation effccts on the
developil~g hurn;tn brain". The mechanisms of observed effects from exposure in fetal life are different
from the mecl~anisn~sin a nearly fully developed
brain. This S e c t i o ~reviews
~
d a b on late effccLs following exposure of the brain of i~~fatits
and children.
15. The rcsponsc of thc nornial brain to radiation
dcpcnds on the total and fractional doses of radiation,
the duration of exposure, tile cxposcd tissue volume
and the age of the exposed subject. The outcomc of
iatrogenic radiation da~nagc to the normal brain
depends on the nlagnirudc of the darnage and the
brain's lack of cellular repopulation. Although partial
recovery takes place bctwecn fractionated cxposurcs,
the brain has very little repair function [KI. M3j. Aftcr
birth, the pcriod of greatest radiosensitivity of thc
human brain is during the first two yean of life, before
maturation is completed. Treatment involving the whole
brain is more likely to have an adverse effect on
younger children by interfering wilh ncural devclopnient before maturation of the brain is complete.
16. There is a large body of evidence indicating that
radiotherapy to the central nervous systeni is associated with adverse late effects [B2, B3, D l , D26, F2,
K2, K3, 0 1 , P3]. This delayed type of damage is
believed to be the effect of injury to the fine vasculalure andlor loss of parenchymal cclls, resulting in
ischaeniic necrosis and loss of parenchynlal function
[ A l , C1, C2, S2]. Vascular changes may occur aftcr
relatively low radiation doses. Glial cells proliferate
during the first yean after birth and are therefore
sensitive to ionizing radiation. A decrcase in the
replacement of glial cells and the associated interfcrence with myclination have also been postulated as
causes of delayed radiation injury [M4].
17. Treatment-related sequelae of the central nervous
system have been documcntcd in children with brain
tumours and acute leukaemia, as well as in children
having other tumours h a t require treatnient of the
central nervous system. The concept of treating the
central nervous system of children with acute lymphoblastic leukaemia was developed in the 1960s in order
to avoid leukaemic relapse of the central nervous
system [A2, MI. Most patients with leukaemia or
solid tumours other than of the brain do not have
primary disease of the central ncrvous system, and the
effects of treatment can therefore be better distinguished from the effects of disease. In addition, the
radiotherapy in these patients generally involves
relatively low radiation doses in the brain. Analysis of
radiation effects in brain tunlour patients is more
difficult because of the much highcr radiation doses
and the possible effect of the tumour on brain function. In a follow-up study of 102 subjects treated for
brain tumour in childhood [L2], 40% of the subjects
had mild to moderate disabilities but were living
independently, 9% were capable of self-care and 4%
required ir~stitutior~alization.Moderate or severe
disabilities were reported in 13 of 30 (43%) irradiated
patients and in 11 of 72 (15%) who did not receive
radiotherapy. Functional deficits were more cornmon
anlong those treated before two years of age.
18. Five distinctive forms of late effects in the
central ~lcrvoussystem have bccn dcscribcd: necrotizing Icukomyelopathy, Ieukoencephalopathy, mineralizing microangiopathy, cortical atrophy and necrosis.
Necrotiziag leukomyelopathy is a spinal cord lesion
that does not appear to be related to radiotherapy,
since the majority of cases have bcen observcd in nonirradiated patients [P2]. Lcukocncephalopathy is a
syndromc caused by dcmyclination; it develops in
patients who have rcceivcd cranial irradiation with
intrathecal andlor systc~nicniethotrexate treatment [ P I ,
P2, R4]. I-listopathologically, leukoencephalopathy is
charactcrizcd by dcmyclination, beginning with axonal
swelling and fragmentation and progressing to necrosis
and gliosis [MI. Leukocncepl~alopathypresents as
multifocal coalescing areas of necrosis in the deep
white mattcr, and in the late stage white matter is
rcduccd to a relatively thin gliotic calcified laycr.
Cortical grey mattcr and basal ganglia are not affected.
Clinical findings range from poor school performance
and mild confusion to lethargy, dysarthria, ataxia,
spasticity, progressive dementia and even death.
19. Both intrathecal methotrexate and cranial
radiotherapy affcct endothelial pinocytosis, and
damage to the endothelial barrier could be involved in
late effects following such treatments [L3]. The
interactions between nletholrexate and radiation within
the central nervous system may be due to the overlapping neurocytotoxicity of the two treatment modalities or to mcthotrcxate acting as a radiosensitizer.
Irradiation of the central nervous system niay also
increase the pernleability of the blood-brain barrier or
may slow the turnover of cerebrospinal fluid and
clearance of methotrexate from the central nervous
system. This would alter the distribution of methotrexate in the cel~tralnervous system so that some
areas accumulate higher amounts of the agent [B4].
Significant levels of methotrexate can also bc found in
the spinal fluid aftcr it has been administcrcd
systea~ically.The risk and severity of Ieukoencephalopathy are dircclly proportional to the total radiation
dose, the cumulative dose of systemic methotrexate
and tt~enumber of therapeutic modalities used (Figure
1) [B2, B4].The highest incidence of Ieukoencephalopathy is found ill patients receiving radiothcrapy and
methotrexate administered both intravenously and
intrathecally. The least neurotoxic combination appears
to be intrathecal plus intravenous mclhotrcxate. If
radiotherapy to the central nervous system must be
e
neurocombined with methotrexate thcrapy, d ~ least
toxic approach appears to be to administer these
modalities in sequence [B2].
20. Leukocncephalopathy has been reported after
20 Gy or riiore ill cornbinatio~~
wit11 intrathecal methotrexate [M6, P3, R4j. No evidence of leukocncephalopathy has bcen found in children for whom intra-
vcnous or i~~trathccal
~l~ctllotrcxatc
was discontinued
beforc radiothcrapy. Lc~~kocnccpl~i~lol~atl~y
has not
been rcportcd aftcr fractionated radiothcrapy of the
central ncrvous systcrli with 18-24 Gy alone and rarcly
with intrathccal mcthotrcxatc alo~lc184, K4].Leukocnccphalopathy can illso occur aftcr a single dnsc of
10 Gy whole-body irradiation prior to bo~lcmarrow
transplanlation [A4, D2, Jl]. Almost all such rcportcd
cascs havc occurrcd in childrcn, suggesting that the
maturing brain is nlorc susccptihlc. Thcse paticnts
wcrc usually givcn intensive chcmotl~crapyand cranial
radiothcrapy with 20-24 Gy ovcr a fcw wccks prior to
the whole-body irradiation. Lcukocnccphalopathy
occurrcd within a fcw ycars of whole-body irradiation
in thcsc paticnts and has usually rcsultcd in scvcrc
neurologic deterioration.
21. Mineralizing niicroangiopathy affects prcdominantly ccrcbral grcy nlattcr and somctimcs ccrebcllar grcy mattcr and is charactcrizcd by focal calcifications in the central ncrvous system. This dcgcncrativc and mineralizing disorder is believed to rcsult
from radiation-induccd damage to thc sn~allvcsscls
[B4,P2, P4]. Histopathologically, calcifications arc
found in small blood vesscls occluding the lunlcn with
mineralized necrotic brain tissue around the vcsscls.
Neurological abnormalities, such as poor muscular
control, ataxia, hcadachcs and scizurcs, havc bccn
obscrvcd in patients with this complication. Mincralizing microaryiopathy is not fatal, and its cffcct on
ncuropsychologic functioning may bc minimal, although permanent destruction of specific regions of
the brain may occur. Mirlcralizi~~g
microangiopathy
has not bccn found in childrcn who did not rcccive
cranial radiothcrapy [P4]. It occurs predominantly in
childrcn who rcccivcd 20 Gy or morc. Bctwccn 25%
and 30% of p a t i c n ~who survivc more than nine
months alter intraU~ccal mcthotrcxatc and cranial
irradiation with 24 Gy havc evidcncc of mincralizing
microangiopalhy. The lesion occurs more oftcn in
young childrcn [B4,DS].Whcn mineralizing microangiopalhy arid lcukocnccphalopathy coexist, the
clinical manifcstatioris oftllc Icukocnccphalopathy will
prcdon~inatc.
22. Cortical atrophy is perhaps the niost conimon
manifestation after lrcat~ncntof thc ccntral ncrvous
system. It is thc rcsult of multiplc arcas of radiationinduced focal necrosis causing loss of cortical tissue
and production of ventricular and subarachnoid space
dilatation [C3, D3, D4, D5]. The cortcx of atrophic
brains is microscopically charactcrizcd by an irrcgular.
neuronal loss from a l l six layers. Astrogl ial proliferation is son~ctimesprcscnt, usually confined to the marginal layer. Ccrcbral atrophy occurs alter fractionated
cranial radiotherapy in nearly half of the patients
receiving >30 Gy to UIC entire brain. The latcnt pcriod
between radiothcrapy and thc onset of atrophic than-
gcs dclcclablc wit11 roa~putcdto~nographyis 1-4 ycars
or CVCII lol~gcrID31.
with 25-65 Gy to thc
23. Aftcr cranial rirdiod~cral~y
wl~olcbrain (dclivcrcd at s 2 Gy pcr day) to trcat brain
tuniours, cortical alrol)hy has bccn found in half of the
cllildrr~~
ID.51, abnornlalilics of the whitc niatter in
26% and calcifications in 8% of the patients. Cortical
atropl~yhas also bccn dcmo~lstratedin one third of
childrc~~
with acutc lyn~phoblasticlcukacmia rcccivir~g
24 Gy ~)rophylacticcranial irradiation and iatrathccal
mcdiotrcxatc IU].Crosley ct al. [C3] found cvidcnce
of abnormality of thc central ncrvous systcnl at autopsy ill 93% of 91 cl~ildrcntrcatcd for acute Icukacmia.
Modcralc to scvcrc atrophy was observed in 13% of
paticnLs rccciving no prophylactic treatment of thc
central ncrvous systcm, in 19% of patients receiving
radiothcrapy given in 1-2 Gy fractions over 2-15 days
(the total brain dose was not stated), in 43% of
patic~~Ls
givcn intrall~ccalmethotrcxate and in 47% of
paticnts who reccivcd both chc~notherapyand radiotherapy. Atrophy did not conelatc with lcukacmic
infiltrations or vascular or i~~fcctiousprocesscs.
Childrcn with thc most scvcrc atrophy wcre thc ones
who wcrc youngcst at onset (mcan age: 2.5 ycars).
24. Ccrcbral necrosis is a serious sequclac and is
usually diagnosed 1-5 ycars after treatment but may
dcvclop morc than a decade Iatcr. It is characterized
by all insidious onset of clinical features [ U ] . Postirradiation myclopathy occurs with rapidly increasing
incidence at doses above 45-50 Gy with conventional
fractionation. Tllc dose per fraction is critical, and
almost a11 cascs of llccrosis following total doscs of
c60 Gy had fractions of >2.5-3.0 Gy [ K l , M7, S 2 ] .
An interaction betwccn chcrnotherapy and radiothcrapy
has bccn obscrvcd for methotrcxate in childrcn but has
bccu difficult to show for othcr agents. A total dose o f
50 Gy with 2 Gy pcr fraction or 55 Gy in 1.8 Gy fractions over six wccks, five daily fractions per wcck, is
considered to bc tolcrablc in adults [As, 1(2,S561. A
morc rcccnt cstimatc has been givcn by Bloom [B35],
who assu~ncdth;~t thc maxiniu~n tolcrahlc radiation
~ to 3 yciirs old is 33% lowcr thari
dosc for c h i l d r c ~up
in adults, and for childrcn 3-5 ycars old the dose has
to hc reduced by 20%.
25. Vcry few data arc available on the cffccts of
hypcrliactionatcd radiothcrapy. Frecman et al. [F3]
studicd 34 paticnk 3-18 years old (mean: 7 ycars) who
wcrc irradiiitcd for brain SICIII turnours with 1.1 Gy
twicc daily with a minimum intcrval o f 4 - 6 hours, to
a total dosc of 66 Gy given in 60 frac~ionsover 6
wccks. In thc 16 patients who were alive at one year
(only 7 wcrc free o f progressive disease), d~crcwas no
of radiation-relatcd injury. Microclinical suspicio~~
scopical examination of thc I1rai11in 8 patic~lLsfailed
to show any injury altributal~lclo the radiothcrapy.
ANNEX I: MIX DETERMlNlSTlC RADIATION IiITECIS IN CllllDREN
26. Abnormalities are frequently obscrvcd by
computcd tonlographic scannir~gin long-term survivors
of cl~ildhood acute leukacmia treated with cranial
radiothcrapy and intrathccal ~ncthotrcxate (B5, B6,
C14, D24, El, M5, 02, 03, 013, 014, PS, P7,
R5,
S55]. Abriornial brain scan Iiridings rliay not hccomc
apparerlt until many ycars have elapsed since thcrapy.
The type of brain abnormalities dctcctcd include
intraccrcbral calcifications, white matter hypodensity
and cortical atrophy (Table 3). Patients who received
24 Gy in 2 Gy fractions with ietrathecal chemotherapy
appear to have a higher incidence of each of the
various abnormalities detected by computcd tomography than those who did not receive radiotherapy.
On average, there is a 40% incidence of brain
abnormalities after 24 Gy in 12 fractions over 2.5
weeks combined with intrathccal methotrexate,
although the incidence varies from study to study,
depending on the number of patients arid length of
follow-up. At brain doses of 18-20 Gy combined with
intrathecal methotrexate or after intrathecal plus
il~travenousmethotrexate, the average prevalence of
brain abnormalities detected is 10%-15%.
27. Magnetic resonance imaging appears to be more
sensitive than computcd tomography in demonstratilig
treatment-related neurologic damage in irradiated
children. The types of changes observed by magnetic
rcsonance correlate well with the type and severity of
the neurologic dysfunctions [A6, C4, K5, P6). Constine et al. [C4] observed radiation-induced changes in
the white matter in 90% of the patients by magnetic
resonance imaging, and 68% of these changes were
not visible by computcd tomography. Enlargement of
the sulci was demonstrated in 76% by magnetic resonance imaging and in 52% by computed tomography.
Patients treated on a hypcrfractionatcd schedule
(1.2 Gy per fraction) had less severe changes, despite
the fact that some received over 70 Gy.
28. Summary. The available clinical data on
deterministic radiation effects on the brain in children
are based on small and often heterogenous groups of
patients with varying age at exposure and varying
lengths of follow-up. Well-designed epidemiological
studies of late effects are lacking, and it is therefore
not possible to draw any firni conclusions about the
radiation effects on the brain and the exact critical
dose levels for the appearance of various clinical
pathological entities. There is evidence that the
incidence of late brain effects will increase as the
number of fractions is decreased and the fraction size
is increased. l'he most important effects in the brain
following radiotherapy to the central nervous system
are leukoencephalopathy, miricralizing microangiopathy, cortical atrophy and cerebral necrosis. Radiolherapy involving the whole brain is more likely to
have more severe adverse effects in young children by
875
iritcrferir~gwith ~icuraldeveloprncnt bcforc maturation
of the brain is complete. Brairi changes have been
dcmo~istratcdwith coniputed tomography and magnetic resonance iniaging after 18 Gy of fractionated
radiothcrapy to the brain. Leukoenccphalopathy has
been observed after >20 Gy in 1.8-2 Gy daily fractions to the whole brain together with systemic
mcthotrexate and has rarely becn reported after 1&
24 Gy without niethotrcxatc (Table 4). Leukoencephalopathy has been found in children who were given
a single dose of 9-10 Gy whole-body irradiation, but
they bad generally received cranial radiotherapy prior
to the whole-body treatment. Mineralizing microangiopathy has rarely been reported following radiation
doses below 20 Gy in 1.8-2 Gy fractions in combination with methotrexatc. Cortical atrophy has been
observed after 18 Gy in 1.8-2 Gy daily fractions combined with intrachecal methotrexate. A whole-brain
dose of 50 Gy in 2 Gy fractions over 6 weeks is
generally considered to be a critical dose in adults for
radiation-induced necrosis. For children up to 3 years
old, the dose should be reduced by 33% and for children 3-5 ycars old the dose has to be reduced by 20%.
2.
Neumpsychologic effects
29. Individuals vary in personality characteristics and
mental abilities, and tests have becn designed to
measure such differences. Ability tests are among the
most widely used tools in psychology. They can be
divided into achievement tests (designed to measure
accomplished skills and indicate what the person can
do at present) and aptitude tests (designed to predict
what the person can accomplish with training),
although the distinction between these two types of
tests is not clear-cut. The intelligence quotient (IQ)is
an index of mental development and expresses
intelligence as a ratio of mental age to chronological
age. Heredity plays a role in intelligence, and cnvironmental factors such as nutrition, intellectual stimulation and the eniotional climate of the home will
influence where within the reaction range determined
by heredity a person's IQ will fall. Ability tests are,
despite their limitations, still the most objective method
available for assessing individual capabilities [A7].
30. Intelligence and academic achievement testings
of long-tcrm survivors of childhood cancer reveal a
high incidence of memory deficits, visual-spatial skill
impairment and attentional deficit disorders. Available
data identify radiothcrapy to the central nervous
system and the synergism with intrathccal chemotherapy as primary etiologic factors in the ncuropsychologic sequelae of survivors o r childhood cancer
[ G l , Ma]. The brain is particularly sensitive to biologic insults during periods of rapid growth and development, which after birth comprise tbe first four years
876
UNSCFAR 1993 REPORT
when glial cells proliferate and myelination occurs.
Therefore the age at which the child receives cranial
irradiation is of importance, and the younger the age
of the child at the time of exposure the more serious
the intellectual dcficit will be. The effect of age a t
which brain damage occurs depends heavily on the
type of psychological ability n~casuredand the instruments for that measurement as on well as tbe location,
extcnt and pcrmancnce of the damage. Multiple factors
may be involved in the causation of intellectual
deterioration, and the interpretation of IQ may be
confounded by the type, location, extcnt and permanence of lesion, hydrocephalus, age of the child at
the time of diagnosis, the aggressiveness of the surgery, radiotherapy and chemotherapy, lack of school
attendance, and by anxieties and fears experienced by
h e child at the time P I , E3, M8]. Parental social
class or parental education level havc in some studis
been found to be strong predictors of IQ in the survivors of acute childhood lcukaemia In, W3]. This
emphasizes the importance of controlling for social
class differences.
31. Neuropsychologic dysfunction with behaviourial
or intellectual impairment may occur in up to 50% of
children with brain tumours IB6,B7, B8,D6, D7, D8,
D9, D10, D11, E2,H2, K6, L2,M9, M10, R6, S3,
S4]. These children have received high radiation doses
to the brain, and the direct cffects of tumour andlor
increased intracranial pressure may havc contributed to
the development of the intellectual problems. Radiotherapy is the most important factor for cognitive
sequelac in long-term survivors of pacdiatric brain
tumours who rcceived brain doses of 40 Gy or more
in 1.8-2 Gy daily fractions [D8, D9, E2, J2. K6, LA,
S3]. In some studies a strong correlation has been
observed between IQ and radiotherapy, and young
childrcn have generally shown the greatest IQ losses.
32
Radiotherapy to the central nervous system in
acute childhood leukaemia (usually 24 Gy fractionated
over 2 5 weeks) has been associated with subsequent
adverse neuropsychologic effects [C4, C5, C7, E3,E4,
E5, H3, 13, K5,L22, M2, M5, M6, M I 1, M12, 0 3 ,
017, P5, R7, R8, R9, S5, T4, T14]. The most
common finding is decrements in general intelligence.
Otbcr documented cffects include general memory
impairment, difficulties with short-term memory,
distractibility, deficits in abstract reasoning,
quantitative skills, visual-motor and visual-spatial
skills [C6, D9, E3, E4, J3, M4, M6, M11, M131.
Neuropsychological dysfuriction has been reported in
up to 30% in children with acute leukaemia, although
the deficiencies have been mild, and the children have
usually functioned well within the wide normal range.
Some studies suggest that adverse effects on intellect
are not noted until 2-5 years after treatment. Prophylactic radiotherapy with 24 Gy is associated with
poorer intellectual function than is intrathccal
chemotherapy (Figure II), Mean overall intelligence
scores in irradiated children are, in general, 10-15
points lower than niean scores in non-irradiated childrcn. Perfomlance skills arc usually more affected than
verbal skills, irradiated patients scori~iga n average of
15-25 points lower than the mean performance IQ of
non-irradiated children [B2, B7]. The younger the
child is at the time of irradiation, the greater the
ncuropsychologic dcficit [C7, H4,J3]. Children treated
with 24 Gy plus cytotoxic agents for acute leukaemia
generally display greater neuropsychological disabilities in a variety of ncuropsychologic tests [B9,
C5, E3, E5, L5, M11, M12, R8, R9], although some
studies have failed to detect such deficits [H4, M8, S6,
V2]. Overall, data show that radiolherapy in conjunctior~with n~cthotrexatchas a deleterious effect on
later cognitive dcvelopment. Intrathccal methotrexate
as the only prophylactic therapy does not appear to be
associated with any global or specific neuropsychologic impairment [PS,T5]. There is some evidence
that chemotherapy combined with radiotherapy impairs
intellectual functions to a greater extent in children
with acute leukaemia who are less than 5 years of age
than in older ones (E3, E4, E5, J3, M12].
33. Neuropsychologic late effects can also be seen
after doses to the brain of 18 Gy from fractionated
radiotherapy [M13, 0 1 , 0 4 , 0 1 7 , R7, T4, T6]. Studies
by Tamaroff et al. [T4, T6] suggest that a dose to the
brain of 18 Gy or 24 Gy in children with acute leukacmia in combination with intrathecal methotrcxate
may have similar delcterious sequelae for neuropsychologic functions. Patients receiving radiotherapy
had significantly lower mean full-scale IQ scorcs and
performance IQ scores than non-irradiated children.
Ochs ct al. [Ol, 0 4 , 0171, on the other hand, did not
observe any significant difference in initial or final
full-scale IQ scores between long-term survivors of
acute leukaemia having rcceived 18 Gy cranial fractionated radiotherapy plus intrathecal methotrexate and
those having received methotrexate only. However,
statistically significant decreases in overall and verbal
IQ and arithmetic achievement were found in both
groups. Thus, 18 Gy of cranial radiotherapy and intrathccal methotrcxate may be associated with comparable decreases in neuropsychologic function.
34. A clear dose-response relationship for impaired
neuropsychologic functions has, however, not yet been
established. Ron et al. [RlO, R30) studied a cohort of
10,842 Israeli children who were irradiated for tinea
capitis a t a mean age of 7 years, receiving a mean
brain dose of 1.5 Gy (range: 1-0-6.0 Gy), a control
group of ethsicity-, sex- and age-matched subjects
from the generiil population and another control group
of siblings. For a subgroup taking scholastic aptitude
tests between 1%6 and 1970, the irradiated children
ANNEX I: L4nl DETERMlNlSTlC RADIATION EFFECTS IN Cl+tLDREN
achieved lower examination scores. For males born
between 1949 and 1955, irradiatcd subjects achieved
lower examination scores on 1Q and psychologic tests,
completed fewer scl~oolgrades and had ;I sligl~tcxcess
of mental hospital admissions. Malcs with multiple
irradiations had twice the ~ncr~tal
hospital admission
rate of males with a single irradiation (34.0 versus
17.4 per 1,000); there was no such difference among
females. The standardized risk ratio for mental
hospital admissiorls was 1.0 for non-irradiated males,
1.1 for rrialcs having one treatment, 2.4 for two
treatments and 4.8 for 23 treatments (test for linear
trend, p c 0.01). Therc were also cliangcs in tlie
electroencephalogram anlong the irradiated subjccts
and significant diffcrenccs betwccn the irradiated and
control subjccts in visual-evoke-respo~~sc
averages,
providing further evidence of inipaircd brain function
following the radiotlierapy. Children irradiated at less
than six years had a relative risk of 1.7 (95% CI: 1.12.8) for mental hospital admissions, whereas for older
children that relative risk did 1101differ significantly
from 1 [RlO].
35.
An indication of an cxcess of admissions to
mental institutions was also obsewed in a survey of
American children with tinea capitis after similar
radiation doses ( 0 5 , S7]. Shore et al. IS71 studied
2,215 patients givcn radiotherapy for tinea capitis in
childhood. The brain received 1.5-1.8 Gy at the
surface and 0.7 Gy at the base. Therc was a 30%
excess of psychiatric disorders in the irradiatcd group
overall when controlling for race, sex, socio-economic
status, age at therapy and interval from treatment to
disease. Oniran el al. [ 0 5 ] made a psychometric and
psychiatric evaluation of 177 subjects treated 10-29
years earlier for ringworm of the scalp. Radiotherapy
was given to 109 subjects, and 6 8 received topical
medications. Average age at treatment was eight years
in both groups. The irradiated group manifested more
psychiatric problems and were judged more maladjusted in the testings when controllil~gfor educational level and family psychiatric disorders. However,
the psychiatrist's overall rating of current psychiatric
status showed only a borderline difference between the
two groups.
36. The Israeli and America11 studies of children
irradiatcd for tinea capitis suggest that doses to the
brain of 1-2 Gy would be associated with late neuropsychologic effects. The dose givcn to these patienls
is the lowest that has becn reported to lead to functional ncuropsychologic disturbances after radiotherapy
in childhood. However, it is difficult to identify
mechanisn~s that could explain these functional
changes after such relatively low radiation doses.
Furthermore, the observations are not supported by
clinical follow-up of patients treated for childhood
tumours, and the possibility that confoundi~lgfactors
8-77
are responsible for this observed association cannot be
ruled out. The trauma of baldness and of having had
trcatnicllt for tinea capitis may have caused sorne of
the psychological problenis. Also, at least in the Israeli
cohort, parts of the brain received higher doscs than
the meall doscs of 1-2 Gy.
37. Summary. The incidence and extent of ncuropsychologic dysfunction anlong children given radiotherapy to the central nervous system arc difficult to
define. A variety of factors complicate the study of a
possible association between effect and dose, including
the underlying disease and associatcd clinical findings,
other treatment modalities, the impact of illness on
body image and school attendance, and perhaps also
parental social class. Most studies contain a small
number of patients of varying ages, who received a
variety of treatment modalides and had varying
follow-ups. Several studies, however, indicate that
radiotherapy increases the risk of adverse neuropsychologic effects. Younger children, particularly
those less than five years of age at time of treatment,
are more severely affected. Clinical follow-ups of
sunlivors of paediatric cancers have demonstrated a
decline in IQ after doses to the brain of 18 Gy with
conventional fractionation. In general, performance
skills are more affected than verbal skills. It is
difficult to distinguish the impact of radiotherapy from
that of metliotrexate. It is possible that intrathccal
methotrexatc administered prior to radiotherapy in
children with acute lcukaemia may be associatcd with
less intellectual in~pairmentthan its administration
during and after radiotherapy. TWOepidemiological
studies of children irradiated for tinca capitis of the
scalp suggest adverse ncuropsychologic effects after
1-2 Gy to the brain, with parts of the brain having
received more than the mean doses in at least one of
the studies. It is likely that these observations can be
at least partially explained by confounding factors. The
available data on neuropsychologic effects after radiotherapy in childhood do not allow an analysis of the
possible effect of the fraction size on neuropsycbologic functions, s i ~ ~ cmost
e
studies deal with conventional fractionation schedules.
3.
Neumendocrine effects
38. Growth depends on a delicate interplay of endomine and nictabolic factors, and secretior~of growth
hormone from the pituiury gland is necessary for
riornial growth [S31, W4]. Growth horlnol~cdeficiency
is usually defined as an impaired response of serum
growth honnone to various provocative tcsts. The
cornmonly used tcsts include slimulation with arginine,
omithine, insulin-induced hypoglycemia, Ldopa,
growth-homioae-relcasir~g hormone or exercise.
Neuroe~~docrinc
ab~lormalitieshave becn observed in
A N N I X I: ] A T E L)ITL~UVIINIS~ICRADIATION EI:I:ECTS
Shalct ct al. [Sl I ] foul~d normal growth hormone
rcsponsc to hypoglycacmia in 14 childrcn with brain
tunlours prior to trcatnlcnt, and growth hormonc
dcficicncy occurrcd ancr a br;iin.dosc of 25-29 Gy in
7 paticnts within two ycars of radiothcrapy. Of 13
childrcn in whom growtli could be asscsscd, 12 had
poor growth.
4 2 Cranial irradiation with 24 Gy in 12-16 fractions
ovcr 2-2.5 weeks for acutc Icukacmia has also bccn
associatcd with a measurable reduction in growth
hormonc responsc, although growth remains rclativcly
unaffected at this dose [M14, M15, M16, M17, 0 9 ,
P2, S19, S201. OLhcrs havc claimcd wholc-brain irradiation to be an important cause of short stature in
survivors of childhood acute lcukaemia [D15, K 7 , 0 7 ,
P8, WS]. Some data suggcst that a significant numbcr
of childrcn less than 4 ycars of agc with acute
lyniphoblastic leukacmia are short before the onsct of
thcrapy [Bll]. Some data suggcst that thc effect of
radiation on growth hormone secretion can be reduced
by decreasing the dose per fraction. Shalct ct al. [S19,
S21] studicd growth hormone levels and growth in 17
leukaemic children who rcccivcd 25 Gy in 10 fractions
ovcr 2.5 weeks and in 9 childrcn who rcccived 24 Gy
in 20 fractions ovcr 4 weeks. Of the 17 children who
rcceivcd 25 Gy in 10 fractions, 1 4 had subnormal
growth hormone rcsponse to insulin, compared to 1 of
9 patients who rcccivcd 24 Gy in 20 rractions (p <
0.002). Arginine stimulation tcst was carricd out in 16
children givcn 25 Gy and in 7 childrcn receiving
24 Gy, and impaired rcsponsc was seen in 6 and 1
patients, respcctivcly. The grcatcr impairment of
growth hormone rcsponse to insulin hypoglycaemia
followil~girradiation with 25 Gy in 10 Gactions to thc
hypothalamic-pituitary axis suggests that the hypothalamus rathcr than UIC pituit;iry gland was the site of
damage. 'Iberc was no differcncc in mcan standing
hcight standard dcviation score bctwccn the two
irradiated groups, but thcy bob differed significantly
in this respect from nonnal childrc~~.
43. Griffin and Wadswortl~ [G2] colnparcd UIC
growth of 66 children with acute lcukacmia to thc
growth of nonnal childrcn matchcd for agc and scx by
calculation of the standard dcviation scorc. All paticnts
had cranial radiotherapy with 24-25 Gy in 15-20
fractions ovcr 21-28 days, and 24 of thcrn also had
spinal radiothcrapy with 10-24 Gy in 5-20 fractions
ovcr 7-28 days. The standard deviation scorc for
height [calculated as (x-x)/SD whcrc x = mean of the
normal population: x = [tic mcasurcrnent; SD = standard dcviation] of the paticnts fell significantly in the
first ycar of treatment (Figurc IV), This was spccifia l l y related to craniospinal radiotherapy but not to
agc or chemotherapy. Robison ct al. [R13] studicd I87
children (mean age: 5 ycars) with acutc lcukaemia
who reccived cithcr cranial irradiation with a median
IN CIIII-DRIIN
879
of 24 Gy (range: 14-28 Gy) in 1.2-2 Gy fractions five
tinlcs a wcck plus intratliccal ~ncthotrcxatc;c r a ~ ~ i o spinal irradiation alonc (24 Gy); or craniospinal
irradiation plus a b d o ~ ~ ~ i nirradiation
al
(12 Gy). At
diagnosis no sig~rificantdiffcrcncc was obscwcd in the
hciglit distribution comparcd to cxpcctcd population
standards. Aftcr trcatnlcnt, an cxccss was obscrvcd in
Ihc proportion of paticnts ir dtc lowcr pcrcc~~tilcs
in
conjunction wit11 a dccreasc in the proportion of
patict~ts in thc l~igtlcstpcrccntilcs. The o111y factor
found to have a significa~~t
impact on attaincd height
pcrccntilc was radiothcrapy.
44. Childrcn with acutc lcukacmia havc a high
Gcqucncy of biochemically abnormal growth hormonc
response to stimuli, but growth liormone deficiency is
unconlnlon. Impaired rcsponse to stimuli, suggesting
abnormality in thc hypothalamic-pituiey axis, does
not necessarily indicatc absolutc growth honnone
deficiency. Thc prcscncc of growlh hormone abnormalities is not ncccssarily corrclatcd with clinical
findings of short stature [07, S19]. Most of the
adverse ccntral nervous system sequclac in paticnts
with acutc lcukacmia have been observcd among those
who rcceivcd 24 Gy of cranial radiation and intrathccal chcniothcrapy.
45. The dose rcquircd to prevent lcukaen~ic
infiltration into the central ncwous systcnl can now be
safely lowered from 24 Gy to 18 Gy [Nl]. Few data
cxist on UIC cffcct on growth of radiation doses bclow
24 Gy. In some studies, growth impairment has been
similar aftcr 24 Gy and after 18 Gy [R13, S22, W5].
Others havc observed that growth impairment in childrcn wilh acutc lcukacmia has bcen less frequent and
gencrally ~nildcrbelow 24 Gy [B12, C11, C23, G2,
S19, V1, V2]. Cicognani ct al. [C23] found that
children who had reccived I 8 Gy in 10 fractions had
complete growth recovery and normal growth homione
responses to pharmacological tesL5. Childrcn who had
rcccived 24 Gy in 1 2 fractions showcd significantly
lowcr standard deviation scorcs for height than at
diagnosis and had irnpaircd growth honnonc rcsponse.
46. Aftcr a single whole-body dose of 10 Gy, scvcrc
growth retardation appear ia most childrcn ID2, S23].
Many if not most of thcse children also rcccivcd
cranial radiotherapy prior to thc wholc-body irradiation. The majority of paedialric patients trcated with
have dccrcascd growth ratcs on
whole-body irradiatio~~
longitudinal growth velocity curves, and growth
hormonc lcvcls havc bcen subnormal in ahout OIIC
third of thc paticnL~ID14. S24. S25). Sandcrs IS241
rcportcd suhnoni~allcvcls of growth h o r ~ n o ~in~87%
c
of children who rcccivcd both cranial radiothcrapy a ~ i d
wholc-body irradiation, c o ~ ~ ~ p a rtoc d42% of those
who received wholc-body irradiation only. Dceg ct al.
velocily curves in
ID21 obscrvcd ~ ~ o r l n agrowth
l
transplant-treated children who did not receive wholebody irradiation, whereas irradiated childre11 had
impaired growth and dccreascd growtl~ velocity.
Growth hornlone levels wcre sub~~ornlal
in about one
third of the irradiated patients.
47. Some data suggest that fractionation will reduce
the adverse effects of whole-body irradiation. Barrett
et al. (B13j rcported growth lior~nonedeficie~~cy
in 6
of 8 children after a single whole-body dose of 10 Gy
and in 3 of 8 children who had a fractionated wholebody dose of 12-14 Gy in 6 fractions given twice
daily for 3 days. Sanders et al. IS231 evaluated growth
in 144 patients following marrow transplantation for
childhood leukaemia at a median age of 10 years. All
children had received nlultiagcnt chemotherapy, and
55 had received a median of 24 Gy (range: 18-29 Gy)
to the central nervous system, 5 of whoni had also
received a median of 12 Gy to the spine. A wholebody dose of 9.2-10 Gy in a single exposure was
given to 79 patients, and 63 patients had a fractionated
regimen of 2.0-2.3 Gy per day for 6-7 days for cumulative doses of 12-16 Gy. Growth hormone levels were
measured in 43 patients 1-8 years afier transplant. and
growth hormone deficiency was present in 27 subjects
(63%). Of these, 21 patients had received pre-transplant cranial irradiation. By three or more years after
transplant, boys who received single whole-body
exposure were 8.0 i: 2.3 cm shorter than boys who
received fractionated whole-body exposure (p c 0.03).
Among boys who had not received cranial irradiation,
those given single whole-body exposure were 15.2 i:
3.2 cm shorter than thosc given fractionated wholebody exposure (p c 0.04). Girls showed similar trends
that were not statistically significant
48. Hiroshima survivors exposed to >I Gy at ages
0-19 years were shorter and weighed less than the
overall population. Those who were less than 6 years
old and who also received >1 Gy [B14] at the tinle of
the bombings were shorter still, on average. The
analyses were based on the T65 dosimetry. Exposure
to high radiation doses markedly reduced mean height
for those who were very young at the time of the
bombings, but this e f i c t diminished with increasing
age. Average height for those agcd 0-5 years at the
time of the bombings was significantly smaller for the
>1.0 Gy dose group than for the groups 0 Gy (not in
city), 0-0.09 Gy and 0.10-0.99 Gy for both males and
females: smaller by 4.4 cm or more for males and by
2.5 cm or more for females (Table 5). For those aged
6-11 years at the time of the bombings, sn~aller
heights were again found for the >1 Gy dose group,
allhough to a lesser degree. For subjects aged 12-17
years at the tirile of the bombings, no apparent differences between the four dose groups were found. When
the high dose group was further divided into 1.002.49 Gy and 22.50 Gy groups, the mean heights were
less for hot11 n~alesand fe'crtialcs aged 0-5 years at the
tinlc of the bombings ill d ~ 22.50
e
Gy group. The diffcrcnce froni tlrc 1.00-2.49 Gy group was statistically
significant for ~nalcs.Average hcigbls of fen~alesaged
6-1 1 years at t l ~ etime of the bonibings and for malcs
a l ~ dfernales agcd 12-17 years at the time of the b o n ~ h
ings were al~proxin~atcly
the siime for UIC two dose
groups (Table 6). 111 Nagasaki, the effect of dose on
height was not statistically significant, although the
nlcan heigl~tof Nagasaki fcmalcs aged 0-5 years at the
time of the bombings was least for those who were
exposed to >I Gy (Table 5). Among males, those exposed to 0-0.09 Gy at agcs 0-5 years at the time of the
bombings showed the smallcst mean height. For both
the 6-11 year and 12-17 year groups, however, the
mean height for boys in the high dose exposure group
was the smallest. A reanalysis based on the same T65
dosimetry was undertaken of the relationship between
attained adult height and radiation dose of 628 survivors of the atomic bombings in Hiroshima and
Nagasaki aged less than 10 years at the time of the
bombings [14]. Average height tended to be lower as
exposure increased, except among Nagasaki males
(Table 7). Two-way analysis of variance of height in
relation to sex and dose by city showed that height
was significantly different by sex and total kerma in
Hiroshima. In Nagasaki, however, it was significantly
different by sex but not kernla total dose. Growth and
dcvclopnle~~t
of stature depends on nutrition, socioeco~~oniic
conditions, the quality and quantity of
radiation received and, possibly, other factors.
Contrary to the report by Bclsky and Blot [Bl4], the
results of Ishimaru el a]. [I41 suggested that diminished stature was not significantly related to age at
the time of the bombings for individuals exposed
before the adolescent growth spurt, something which
was probably due to the small sample size. The observed difference between the two cities may change
with new aa;~lysesbased on the new DS86 dosirnctry.
49. Children on the Marshall Islands exposed to
radioactive fallout in 1954 wcre also found to have a
significant reduction in height, which was probably
mainly due to radiation-induced hypothyroidism [R14,
S261 (see Section 1I.B).
50. Children with radiation-induced growth hormone
deficiency can now be treated with growth hormone,
although thcre are as yet no long-term studies of the
effccts of such a therapy in a large number of children.
Some data suggest a significant growlb response to
therijpy in children who receivcd cranial irradiation
alone, wl~ercasthe response in patients rcceivirig cranie
has beer1 less satisfactory IG3, S20].
s p i ~ ~ irradiation
al
51. Sunlrrrary. Irradiation of the central nervous
system nlay produce damage to the hypothalarnicpituitary axis, resulting most c o ~ n ~ n o ~in~impaired
ly
growth hormone secretion. The hypothalaniic cells
producing the powth-hor~nonc-relcasitlghormone are
the most sensitive endocrinological target. Growth
hormone deficiency can be expected in approximately
75% of children treated for brain tumours, and a
growth velocity or height below the 10111 percentile
can bc expected in 70%. The growth hannone deficiency is permanent. Patients with acute leukaemia
have in general received lower doses to the central
nervous system but growth hormone secretion is still
affectcd. After 25-30 Gy, the growth l~ormoneresponse to insulin-induced hypoglycaen~ia is impaired
within two years of irradiation. After 24 Gy in 12-16
fractions, there is also a rueasurable reduction in
growth hormone response to stimuli. Growth has been
less affected after 24 Gy than afier higher radiation
doses in the brain, suggesting that the normal physiologic requirements of growth hormone secretion have
becn m e t No effect on growth hormone secretion has
been observed below 18 Gy. A 1 0 Gy whole-body
dose in a single fraction results in severe growth
retardation in the majority of children, who generally
have been pretreated with chemotherapy and cranial
radiotherapy. Fractionation appears to be of importance for the effect on growth hormone secretion and
growth, and increasing fiaction size will result in a
higher proportion of patients with subnormal growth
hormone response. Growth impairment is seen more
often after a single-dose whole-body irradiation with
10 Gy than after a fractio~~ated
regimen of 12-16 Gy
in 2 Gy fractions over a weck. It is not possible to
define the lowest dose capable of impairing growth
hormone secretion, since available data are obtained
from small studies with varying ages at exposure and
lengths of follow-up, as well as different methods for
assessing the growth hormone level. Such a dose
appears to be lower than 18 Gy from fractionated
exposure. G~owthhas been affected in the survivors of
the atomic bombings in Japan at acute doses of >1
Gy, especially among children less than 6 years of
age. This effect may be due to a combination of brain
damage, damage to the spine, nutritional factors etc.
13.
THYROID GLAND
52 Hypothyroidism is the most common late detcrministic effect of the thyroid gland following exposure
to ionizing radiation. Thyroid nodularity is considered
to be a stochastic phenomenon and is therefore not
discussed in this Section. Clinical damage to the pituitary and thyroid glands is usually manifested several
years after exposure and is preceded by a subclinical
phase [F4]. Direct damage to the thyroid gland by
radiation can cause primary hypothyroidism, whereas
damage to the hypothalamic-pituitary axis may produce secondary hypothyroidism. Primary hypothyroidism has been demonstrated in 4094~90%of
patients with pacdiatric tunlours given 15-70 Gy to the
thyroid gland and followed for up to six years [BlO,
C5, C13, D16, F4, G4, K8, 08. P9, S9, S23, S27,
S281. The onset of hypothyroidism may be several
months to years following the radiotherapy. Administration of oral thyroxine during radiotherapy does not
appear to prevent later thyroid hypofunction IBIS].
Radiotherapy alone and with chernothcrapy have becn
associated with similar high incidences of hypothyroidism. Paticntq treated with chemotherapy only
have generally not had any significant thyroid hypofunction, although transient thyroid dysfunction has
been reported IG4, G5, H7, L7, S27, S28, S29].
53. The incidence of overt [low serum T 4 and
elevated thyroid-stimulating hormone (TSH)] and compensated (norn~alserum T4 and elevated TSH) hypothyroidism varies with the radiation dose in the thyroid
gland, the length of follow-up and the way in which
the thyroid function was determined. Thyroid surgery,
iodine-containing contrast material and age of the
patient at the time of radiotherapy may contribute to
the development of hypothyroidism. The effect of age
at the time of radiotherapy on the development of
hypothyroidism is a matter of controversy. In one
study, 48% of patients with Hodgkin's disease who
were younger than 20 years of age at the time of
treatment had elevated TSH levels compared to 33%
of older patients [G4]. Green et al. [GS], observed that
7 of 15 children with Hodgkin's disease and irradiated
at the age of less than 13 years developed hypothyroidism, compared to 3 of 12 among those who had
been older than 1 3 years. In a study by Tarbell et al.
IT91 of patients irradiated for Hodgkin's disease, the
15-year actuarial risk for hypothyroidism was 64%
among patients aged 16 years or less, as comparcd to
29% among those older than 16 years. Others have not
identified age as a contributory factor [D16, K8, N2,
S28, S29]. The possibility that the thyroid is more
sensitive in childhood is also supported by the high
incidence of increased TSH levels in children irradiated for Hodgkin's disease [D16, S27].
54. Elevated TSH levels have been observed in
children who received radiotherapy for brain tumours
after 25-30 Gy to the hypothalamic-pituitary axis or
24 Gy to the thyroid gland [C26, D6, H6, 0 6 , SlS].
Various studies show that hypothyroidism is dosedependent. In a study by Glatstein et al. [G4], no
patient had an elevated TSH level afier 15 Gy to the
thyroid, as compared to 44% of the paticnts receiving
40 Gy or Inore. Kaplal~ct al. [KS] round elevated
TSH levels in 15% of patients who received <30 Gy
and in 68% of those who received higher doses. Logistic regression analysis showed &at both higher
radiation dose (230 Gy) and lymphangiography increased the risk of having an elevated serum TSH
level. Constine el al. [ClS] measured thyroid function
in 119 childrc~r irradialcd for Hodgkin's discasc.
Radiotherapy was dclivcrcd ovcr 4-5 wceks: 24 childrcn rcceivcd a neck dosc of 26 Gy or less (rncan:
22 Gy) and 95 rcccivcd >26 Gy (nlcan: 44 Gy). Morc
rccciving >26 Gy had clcUran 75% of tl~ccl~ildrc~r
coml)i~rcrlto 17% of ~ ~ O StreilIcd
C
vatcd TSH ICVCIS,
with lower doscs. A weak correlation wit11 age (p c
0.05) was found, and thc doubling dosc for thc nrcan
peak TSH valuc was 11 Gy (Figure V).
55. Most of the cxpericr~ccin radiation-rclatcd late
effects in the thyroid has bccn gained from the trcatmen1 of Hodgkin's discasc. Cornpc~rsatcdhypotl~yroidism occurs in up to 75% of thc trcatcd clrildrc~r,and
uncompcnsatcd bypothyroidisrn has been obscrvcd in
less than 30% of the children [C14, D16, D17, F4, F5,
G4, G5, M18, S17, S27, S28, S29, T8). Paticnts irradiated for lymphonias or head and neck carlccrs have
generally rcceivcd 24-60 Gy fractionated ovcr sevcral
wceks. In some studics lymphangiography prior to
radiotherapy has bccn shown to increase thc risk of
hypothyroidism [G4, G5, K8, S27, S28, S291; in
others, it has not [C14. G5, N2, T8]. Lymphangiography may incrcasc thyroid damage from subscqucnt
irradiation for the following reason: the iodine released
from the contrast material could inhibit thyroid
hormone synthesis and secretion within a fcw days,
thcrcby causing increased tbyrotropin sccrction and
consequent stimulation of thyroid cells at the time of
irradiation [Kg]. An expanded extrathyroidal pool of
iodine may increase susccptibility to hypothyroidism
in irradiated subjects.
56. Lower radiation doses may also incrcasc the risk
of hypothyroidism. In children with acute lcukacmia
receiving cranial irradiation with 1 8 Gy, the thyroid
dose is 3%8% of the cranial dose IRIS]. Hypothyroidism has bccn observed in up to 20% of longterm survivors of childhood acute leukacmia aftcr 1825 Gy of cranial or craniospinal radiotherapy with
conventional fractionation [N3, R16. R18. S12j; others
have failcd to observe such an effect aftcr cranial
doses of 8.5-24 Gy in 2 Gy fractions ( 0 7 , V1 1. Mcan
thyroid doses of 4 1 0 Gy in infancy or childhood from
fractionated radiollrcrapy for bcnign discasc has not
bccn associated with clinical hypothyroidism, although
fo1lou~-uplasted as long as 25 years IH8, R19]. In
conlrast, hypothyroidisrn has been reported in 7 of 9
'loma
Russian children after radiolberapy for skin an&.
with thyroid doses of >l.l Gy [T15].
57. Thyroid hypolunctio~~
can occur aftcr wholcbody irradiation. Children w11o rcccivcd a rcgi~iicnof
chc~nolherapyin preparation for a transpla~~t
have an
incidence of Uryroid dysfunction that is not greater
than normally observed among non-transplant childrcn
[S24, S2.51. Radio~hcrapyappears to be thc major, if
no1 the sole, causc ofsubscqucnt thyroid hypofuection
in thcsc ~)aticnts.111 1cr111sof its cffccts OII Ulyroid
hypofr~~~clioa
IT1 71, single-dosc radiotherapy has bcc~r
clai~rlcdto be cquivalcnt to a total radiation dose 4-5
tinrcs Iargcr w l ~ c ~it ris dclivcrcd ill convc~~tional
kactions. Si~ndcrsct ill. IS23, S24I studicd 142 palic~rls
1-17 ycilrs old i~ftcr~ O I I CIrliirrow transpla~~tatio~r
to
trca t hi~c~ni~lological
nii~ligr~;~rrcics.
All patie~rtshad
rcccivcd ~r~ultiagcnt
chc~nothcrapy.55 had been prctrcatcd witlr 24 Gy fractionated cranial radiotherapy
and 12 hiid rcccivcd 1 2 Gy spinal inadialion. Wholcbody irradiation was dclivcrcd as a single dose of 9.210 Gy (n = 79) or 2-2.2 Gy daily for 6-7 days to 12.015.8 Gy (11 = 63). A ~ n o ~ rclrildrcri
g
who rcccived 10
Gy si~rglcwlrolc-body exposure, 56% had conipcnsatcd I~ypo~hyroidism
and 13% had ovcrt hypothyroidism, a~rdthe figurcs for c h i l d r c ~who
~ rcceivcd fractionatcd whole-body irradiation were 21% and 3%. respectively. These diffcrcnccs most likely reflect the
shorter observation tinles after fractionated exposure
(mcdian nine years versus five years). Longer followd dctcrmine whether there is any rcal
up is ~ ~ c e d cto
diffccrcncc bctwecn the two typcs of whole-body exposure. Ka~sanisct at. [K9] evaluated thyroid function in
80 patients aftcr bone rnarrow transplantation for
aplas~icanacmia or acute Icukacniia. Median age at
the tinre of trar~splanlalionwas 10 years (range: 2-21
years). Patients with aplastic anaemia received hi@dose chcmothcrapy and total lymphoid irradiation with
a si~rgle dose of 7.5 Gy, and leukacrnia patients
rcccivcd cidicr whole-body irradiation as a single
fraction of 7.5-8.5 Gy (n = 33) or fractionated wholebody irradiation with 13.2 Gy (n = 20) in 1.7 Gy
frac~ionstwice daily for four days. 0 1 2 7 patienls with
l
irradiation, 11
aplastic anaemia plus t o ~ lymphoid
showcd thyroid hypofunction, as compared with 9 of
5 3 patients with acute lcukacmia plus whole-body
irradiiition. The five-year actuarial risk estimate of
hypothyroidism aftcr total lymphoid irradiation was
42% (95% Cl: 23%-61%), wl~icllwas significantly different from 10% after fractionated whole-body irradiation (95% C1: 0%-23%) (p c 0.05), but not dirfcrent
fro111 21 % after singlc-dosc whole-body irradiation
(95% CI: 7%-35%).
58. Thc tllyroid gland 11as t l ~ ccapacity to i~ctivcly
corrccnlratc iodinc, and ri~dioiodinc can U~crcforc
dclivcr co~rsidcrablcradiation doses to the gland, a fact
that has bcerr and is still uscd in diagnostic and
thcrapcutic medical proccdurcs D18, G6). The most
c o m n ~ o ~ ~used
l y radioiodi~rcis ' I , which has a halflife of ciglrt days. Most d i ~ l i011
~ hypotl~yroidismafter
13'1 cxposurc cn~alratefro111studics on paticnts wid1
hypcrll~yroidisni, and tl~cir cxpcricecc rnay not bc
dircc~lytriit~sferahlcto a r~orn~al
cuthyroid population.
r t s hypcrthyroidis~n,hypothyroidism is
In ~ ~ a t i c ~witlr
common cvcn after surgcry or trcallncnt with antithyroid drugs [B17, HlO]. The thyroid uptake of 13'1
is Irighcr ill Irypcrthyroid patic~rls,but the turnover of
'1
ANNW I: IAlT DEI-ERMINISTIC RADIATION EFFEC7S IN ClllLDREN
chc nuclidc is morc rapid. I t may thcrcforc bc possiblc
to approximalc the cxpcricnce of hyperthyroid paticills
to that of cuthyroid subjects [M19, M20, N4j. In adult
h crthyroid palicnk trcatcd wit11 a sii~glcdosc of
the cun~ulativcprobability of lrypotl~yroidis~~l
is
rclatcd to tl~c l 3 I l activity ad~nioistcrcd pcr ui~it
thyroid weight IB16j. Holm ct al. 11-191 obscntcd an
a~lnualhypothyroidisrn of 3% t l ~ cfirst 24 ycars aftcr
I3'l thcrapy for hypcrthyroidism. Thcrc arc only "cry
limikd data on thc cffccts of thyroid absorbcd doscs
from 1 3 1 ~of c25 Gy and h c cffccts in childrcn.
NCRP Report No. 55 [N4] citcd unpublished data
from Hamilton and Tompkins, who obscrvcd that8 of
443 subjccts (2%) lcss than 16 ycars old and judgcd to
have nonnal thyroids bccame hypothyroid aftcr diagnostic l % tcsts. Thc incidence of hypothyroidism
was 0% pcr ycar in 146 subjects who rcceivcd ~ 0 . 3
Gy in thc thyroid, 0.15% per ycar in 146 subjects who
received 0.3-0.8 Gy and 0.23% per ycar in 151 subjccts aftcr thyroid doscs of >0.8 Gy. A linear modcl
with a thrcshold was postulated for hypothyroidism;
owing to the largc functional capacity of the thyroid
gland, a largc nu~i~bcr
of cells would havc to bc
affectcd lo result i n hypothyroidis~n. I-Iayck ct al.
[ H l l ] obscrvcd hypothyroidism in 8 of 30 (26%)
patients bctwccn the ages of 8 and 18 ycars who
rcccivcd I3l1 therapy for hyperthyroidism. Thc mean
amount of l3'l adniinistcrcd was 240 MBq, and the
mean follow-up was nine years. Frcitas ct al. IF61
found a 92% prevalcncc of hypothyroidism in 51
patients aged 6-18 ycars aftcr 1 3 1 ~therapy for
~
520 MBq).
hypcrthyroidism (~ncan1 3 1 activity,
"6,
59. In 1954, following dctonatiol~of a megatonne
nuclear dcvicc at Bikini, 250 inhabitants of the Rongclap, Ailingnae and Utirik atolls of thc Marshall Islands
were cxposed to radioactive fallout IC16, L8, R14].
This consisted ofwhole-body gamma-irradiation, bctairradiation of the skin from fallout dcpositcd on the
skin, and internal absorption of radionuclides from the
ingestion of contaminated food and watcr. The most
serious internal exposurc was that to the thyroid gland,
from radioiodines in thc fallout. Thc cstiniatcd thyroid
dose varied from 0.3 to 3.4 Gy among those agcd 18
years or more to 0.6-20 Gy among thosc lcss than 10
ycan of age. Many uncertainties wcrc involvcd in the
dose calculations. and particularly in the thyroid
dosimetry. The most widcsprcad late cffccts of fallout
cxposurc arnong thc Marshallcsc havc bccn rclatcd to
radiation injury to Lhc thyroid gland. The growth status
of childrcn cxposcd to fallout radiatio~~has bccn
studied in 67 uncxposcd a ~ 38
~ dexposed childrcn, 4
born to cxposcd
childrcn exposcd in tcfcro,39 childrc~~
parcnts and 53 childrcn born to ur~cxposed parents
[S26]. Retardation in both statural growth and skclctal
maturation has been obscrved among cxposed boys, as
comparcd with uncxposcd childrcn. Thc retardation
was notcd among boys who wcrc undcr 5 years of age
883
w11c11cxposcd to [Ire fallout, being niost prolnincet
alnong tl~oscagcd 12-18 mortl~sa t t l ~ ctime of cxposurc. No sig~~ificai~t
diffcrcnccs wcrc notcd in the
growth pattcnls hutwccn cxposcd and uncxposcd girls
and hctwccn childrcn b o n ~to cxposcd or uncxposcd
p;ircllls.
60. Thc i~~cidcncc
of subclinical hypothyroidis~~l
was
31% among childrcn less than 10 ycars of age at exposurc aftcr an cstimatcd thyroid dosc of >2 Gy. No
casc of hypothyroidis~noccurrcd in this agc group at
lowcr doscs (Tablc 8). Amoi~gsubjects 10 ycars or
oldcr, OIIC case (1 %) of hypothyroidisn~was obscnlcd
at all cstimatcd thyroid dosc of c l Gy, one casc (8%)
at 1-2 Gy and four cascs (9%) a t doscs highcr than
2 Gy. Only two of the subjccts cxposcd a1 lcss than 10
ycars of age had clinical hypothyroidism. The incidcnce of hypothyroidism began to increase approximately onc decade aftcr cxposurc. A thorough rc-evaluation of the absorbcd dosc in thc thyroid was done
by Lessard et al. [L9]. The rccalculated cumulative
external doscs of gamma rays wcrc close to the initial
estimates, but doscs from intcrnally deposited radionuclidcs wcrc niucl~highcr. Most of the thyroid dose
rcsultcd from short-livcd radioltuclides. Thc rc-cvaluation of thc thyroid absorbcd dose makes thc obscrved
results conipatiblc with those of olher studies with
similar doscs [R20].
61. Rallison ct al. [R21, R22) observcd two cases of
hypothyroidisni in 1,378 childrcn exposed to 13'1 fallout from r~uclcar weapons tcsts, comparcd to four
cases in 3,801 non-imadiatcd control subjccts. The
follow-up tirnc was, on avcragc, 16 years, and the
Incan thyroid dose was estimated to be c0.5 Gy. The
diffcrcnce in the incidcncc of hypothyroidism between
chc two groups was not statistically significant.
Clinical cxaminatiolis wcrc pcrformcd it1 1990, and
lcvcls of Srcc T4 and thyroid stimulating h o r m o ~ ~ c
wcrc mcasurcd in childrcn living in Russia, Belarus
and Ukrainc at thc time of thc nuclear plant accident
in Chcrnobyl in 1986 and in children born in 1989
[HI. Thcrc was no cvidcncc Ulat thyroid function had
hecn affccted in a way that could be dctectcd cithcr
clinically or by laboratory tcsting at that timc.
62. Thyroid disorders wcrc studicd 30 ycars aftcr
urldcr 20 ycars of agc a t
cxposurc in 978 i~~dividuals
thc tirlie of thc bo~nhingsin Hiroshima and Nagasaki
[M21. M22]. Thc cstimatcd doscs from thc atoniic
bornb fallout radiation wcrc based on T65 dosi~~ictry.
Thcrc wcre 200 n~iilcsand 277 fcmalcs in thc >1.0 Gy
cxposed group and 219 ~iialesand 282 fc~nalcsin the
urlcxposcd (0 Gy) group. Of thcsc, 128 wcrc aged 0-9
years and 349 wrcrc 10-19 ycars at the tirrlc of the
bombings in the >1.0 Gy group; and 139 suhjccls were
agcd 0-9 ycars and 362 wcrc 10-19 ycars a t thc time
of the bonlbings ill the unexposcd group. Tlrcrc wcrc
no significant dilfcrcnccs in mean serum TSH lcvcls
or nican seruni thyroglobulin levels between thc 0 Gy
(unexposed) group and Ihe >1 Gy (exposed) group. In
a recent analysis IN71 of 2,774 subjects of the Nagasaki Adult Health Study cohort, the prcvalcrice of
hypothyroidism was 5% in exposed subjects arid 2%
in controls. 111oue ct al. 1171 studicd nearly 2,600
individuals from the same cohort and obscrvcd hypothyroidism in 3% of the subjects. The fitted relative
risk increased fiom 1 for those less than 5 ycars at the
lime of the bombings to 3 for those 30 ycars at the
tinle of the bombings.
63. Summary. Thyroid dysfunction may result from
irradiation of the thyroid gland or the hypothalamicpituitary axis. A substantial proportion of patients
receiving radiotherapy for various paediatric turnours
have impaired thyroid function. The incidence of
hypothyroidism varies with the definition used and is
highest when elevated TSH levels are used to define
the impairment. Young children seem to be more sensitive to radiation-induced hypothyroidism. Various
studies show that hypothyroidism is dose-dependent.
The prevalence of hypothyroidism is increased in
leukaemic children who have received cranial radiotherapy of 18-24 Gy over 2-2.5 weeks. The thyroid
doses in these cases have been calculated to be 3%
8 % of the brain dose, i.e. 1-2 Gy. However, the children also received associated chemotherapy, which niay
affect the risk for hypothyroidism. No epidemiologic
study has demonstrated hypothyroidism in children
after a thyroid dose from external irradiation el Gy.
There is limited evidence that dose rate nlay be of
importance and that the risk of hypothyroidism is
rcduccd when fraction size is reduced. There arc insufficient data on the effects of l3'l to detcrniine a
possible threshold dose for the induction of hypothyroidism.
C. OVARY
64. The ovary is a highly radiosensitive organ, and
single doses of 0.6-4 Gy have caused temporary sterility in adults, with higher doscs required to produce the
same effect when fractionated. Permanent sterility
results from 25-10 Gy in a single dose and from 6 Gy
with protracted exposure [ F l , 11, U3]. The radiosensilivity of the ovary depends on the degree of maturity,
and the thrcshold for permanent sterility decreases
with age, although the age-related differences are hard
to estimate IA12, Fl]. The fact that the ovary of a
young woman is more resistant is explained by the
reduction, ovcr time, in the fixed pool of oocytes,
since these cells are not replaced. The radiation dose
required to destroy all the oocytes is herefore larger
in younger than in older women. Ovarian dysfunction
has been observed in more than 50% of adolescer~ts
and yo~111g
womc~iafter doscs of 25-4.0 Gy. Rccovery
has bccn age-rclatcd. After 4 Gy, p c r ~ ~ i a ~ ~
amenent
orrhca alid i~ifcrtilityhavc occurred ill approximately
one d~irdof youngcr wolncn and in all worilen older
than 40 ycars of iigc IA12, H121.
c ovarian dysfunction
65. The niost comeion ~ i u s of
in patients trcatcd for pacdiatric tumours is direct
damage to the gonads by radiation and/or cytotoxic
agents. The ohscrvcd ovarian effects have basically
heen fibrosis arid follicle dcstructio~i with elevated
lcvcls of lutciriizing l~ormoncand follicle stimulating
hormone. Irradiation oftlie I~ypothalamic-pituitaryarea
can also result in goriadotropin deficiency or hypcrprolactinaemia, which may impair subsequent reproductive function [A13, R23]. Quiescent ovaries have
been found in childrcn after radiotherapy with 2030 Gy to the abdo~nenovcr 21-30 days, either alone
or combined with chemotherapy [H13]. Chemotherapy
used for a short time has been reported to be without
effect on the small follicles, whereas prolonged
treatment destroys tlicm [M23].
66. Pelvic or abdominal irradiation has been
associated with ovarian failure, resulting in elevated
levels of follicle-stinlulating hormone, amenorrhea and
failure to develop secondary sexual characteristics [G7,
0 9 , S32, S33, W6]. In a study by Wallace et al. [W6],
ovarian failure occurred before 16 ycars of age in 19
paticnts irradiated ill childhood for abdominal tumours
with 30 Gy in 16-26 fractions over 21-38 days. An
upper limit for the LD50 of the human oocyte was
estimated at 4 Gy. Stillnian el al. [S33] observed signs
of ovarian failurc in 12% of 182 long-term survivors
of childhood cancer. Of 25 patients (68%) with both
ovaries within the treatment fields (nican ovarian dose:
32 Gy), 17 showed ovarian failure, as compared with
5 of 35 patients (14%) whose ovaries were on the
border of the treatment ficld (mean: 2.9 Gy), none of
34 patients with one or both ovaries oulside h e treatment ficld (mean: 0.5 Gy) and none of 88 patients
receiving no radiation to the ovaries. The likelihood of
ovarian failure in patients with both ovaries in the
ficld was 19.7 (95% CI: 5.3-728), higher than those
for other irradiated paticnts. Subseque~itfertility has
heen obscrvcd in prcpubcrlal girls aftcr pclvic doses of
10-30 Gy, despite follicular depletion and elevated
~ i c (H13, L11, S32).
follicle-stimulating h o r ~ ~ i o levels
67. Horning ct al. [HI21 studied 103 women aged
13-38 years (median agc: 19 years) with Hodgkin's
discasc trcatcd by c l ~ c ~ ~ ~ o l l ~aclroa ~p ~(a
y e = 34), totallyniphoid irradiation alone (n = 19) or irradiation plus
cheniothcrapy (n = 50). The pelvic dose was 3040 Gy, delivered with conventior~al fractionation.
Menses werc present in 94% after total-lymphoid irradiation alone, 85% aftcr chemotherapy alone and in
48% after total-lynil)hoid irradiation plus chemo-
ANNEX I: LATE DETERMlNlSllC RADIATION EITECTS IN CIIILDWN
therapy, of which 47%, 56% and 20%, respectively.
were regular. Chemotherapy was associated with the
liighcst and combiliation therapy with the lowest probability of regular Iiienses. Tlic probability of regular
menses decreased with a p at treatnicnt (Figure VI).
When age at treatment, interval after conipletion of
treatment, stage of diseasc, number of cyclcs of
chemotherapy and pelvic radiation dose were included
in a multivariate analysis to detemiine factors predicting regular menses, o~ilyage was significant for
any of the three treatment modalities.
68. Irradiation of the central nervous system and
chemotherapy can destroy gonadal function by causing
darnage to the hypothalamus or direct damage to the
gonads themselves [B18].Various hormonal effects
have been observed after cranial or craniospinal radiotherapy with 25-50Gy fractionated over 3-4weeks,
e.g. elevated, normal or reduced levels of gonadotropins, secondary amenorrhea arid lack of pubertal
progression [A13,B10, C17, L10,R23, SlS].Leipcr
et al. [L12]observed early puberty in 10% of 233
children given cranial radiotherapy with 18-24Gy in
10-15fractions over 2-3weeks for acute lcukaemia at
a mean age of 4 years. Three girls had precocious
puberty, i.e. signs of sexual maturation occurring
before 8 years. Early onset of menarche after cranial
radiotherapy has also been observed by others [B19,
M15, 01,R23, S15]. Othcrs have reported normal
levels of gonadotropins and oestrogens after 24 Gy
cranial radiotherapy in 2 Gy fractions over 2.5 weeks
[DS,0 7 , Vl].
69. Hamre et al. [HI41assessed gonadal function in
163 children treated for acute lcukaemia at an average
age of 6 years and who were randoniized to receive 18
or 24 Gy to one of three fields: cranial, craniospinal or
craniospinal plus 12 Gy abdominal, including the
ovaries or testes. Gonadal evaluation 4 years later
showed elevated levels of follicle-stimulating hormone
and/or luteinizing hormone in 36% of the patients.
There was an association between elevated gonadotropins and the radiotherapy field: 9% of patients who
had cranial fields had elevated Ievcls, as compared to
49% for craniospinal fields and 93% for craniospinal
plus abdominal fields (p < 0.001). Girls receiving
24 Gy had a relative risk of 14 for elevated folliclestimulating hormone and 8.7 for elevated luteinizing
hormone compared with girls rcccivi~~g
18 Gy. Craniospinal plus abdominal radiotherapy was significantly
associated with abnormal gonadotropin levels and lack
of pubertal development.
70. Patients who receive only cheniotherapy prior to
bone marrow transplantation have nonnal pubcrtal development and normal levels of gonadotropins and sex
hormones. The majority of children receiving 10 Gy
single whole-body exposure cxpcrie~~ce
a delayed onset
885
of puberty, and their gonadotropin levels reflect primary
gonadal failure. Nearly half of children receiving
fractioriated whole-body irradiation have nonnal
puberbl developnie~~t
and nonnal gonadotropin levels
IB13,D2,S24,S341.Ovarian failure appears to develop
in almost all fenialcs of postpubertal agc after wholebody irradiation with 10-12Gy. Normal gonadotropin
levels have been observed in the majority of girls who
were prel)ubertal at UIC time of transplantation.
71. Sanders el al. [S23]studied ovarian function in
142 children (52 girls) treated with bone marrow
transplantation at the median age of 10 years. ,411
patients had received chemotherapy, and one third of
the patients also had received radiotherapy to the
central nervous system. Patients were given chemotherapy and whole-body irradiation, as a single dose of
9.2-10Gy (11 = 79) or as fractionated doses of 22.3 Gy daily for 6-7days to a cumulative dose of 1215.8 Gy (11 = 63). Of 35 girls who were prepubertal at
transplant, 10 had delayed development of secondary
sexual characteristics at evaluation 4 years later.
Gonadotropin arid oestradiol levels were determined
for 1 1 of 16 girls older than 12 years of age, and 7
had elevated levels of follicle-stimulating hormone,
low levels of oestradiol and delayed onset of puberty.
Gonadal failure occurred in nearly all who were postpubertal at transplant, with amenorrhea and elevated
levels of luteinizing hormone and follicle-stiniulating
hormone. I t was not possible to determine how many
of these endocrine abnormalities occurred as a result
of treatment administered prior to transplantation. No
information was provided on the effect of fractionation
on gonadal functio~~.
72 Sarkar et al. IS351 studied fertility in 33 subjects
after l3'l therapy for thyroid cancer in childhood or
adolescence. They received a mean 1 3 1 ~amount of
7,250MBq, with a range of 2,960-25,560MBq, and
the estimated cumulative gonadal dose ranged from
0.08 to 0.69 Gy. The incidence of infertility and miscarriage did not differ significantly from that in the
general population.
73. Summary. The effects of radiation on the ovary
are age- and dose-dependent. The ovary of young
women is less sensitive to radiation-induced deterministic effects because of their higher number of
oocytes, although it is difficult to define the magnitude
of these differences. A variety of factors complicate
the study of a possible association between radiation
dose and the effects on the ovary, including the underlying disease for wllich treatment was given. Unfortunately, most studies have been performed on a limited
number of patients of varying ages at exposure, who
received a variety of treatment modalilies and had
varying lengths of follow-up. The available data thercfore do riot allow an a ~ ~ a l y s iof
s the dose-cffect
ANNM I: IATE DETiiKhtlNIS71C RADIATION III-FECIS IN CIIILDRIN
887
of cl~ildl~ood
in UIC postpubertal male, plns~na tcstosteronc and
canccr lrcatcd during prcl)ubcrty and
lcvcls wcrc normal. O~rlyone boy had an
gonadokopi~~
puberty wit11 a rlicall tcsticular dose of 1.9 Gy (range:
elevated follicle-sti~nulati~~g
hornionc Icvcl. The
0-25Gy). Spcrm sarnplcs wcrc obtained from 23 subradiation-induced damage to tlic gem~inirlc p i t l ~ c l i u ~ ~ ~jects, and thc 4 who rcfuscd had fathered healthy
thus resulted in raised lcvcls of follicle-stimulating
childrc~~.
Four paticnts were oligospcrmic and 14 werc
The four sterile mcn had reccivcd at
:~zoospcr~nic.
hormone aftcr pubcrty but not bcforc. In rcspcct of
lcast 1.4 Gy to thc tcstcs without chemothcrapy and as
pelvic radiothcrapy and/or chcmothcrapy for Hodgkin's
low as 0.08 Gy in co~nbinationwith alkylating zigcnts.
disease in childhood, G T ~ CctI Iill. IG71 did not observc
Sterility was niainly associated with alkyli~tingagents.
any diffcrcncc in gor~adalft~nctionb c t w c c ~nine
~ boys
and n~alcadolcscc~itswho received a gonadal dosc of
1 Gy and scvcn p;~ticntswho rcccived o ~ d ychemo79. Alicr chemothcrapy and whole-body irradiation
with a single exposure of 10 Gy, dclaycd pubertal
therapy. Six and live men, rcspcctivcly, had clcvatcd
lcvcls of follicle-stirnulatin& hormone up to cigl~tyears
dcvelopn~cnt occurred in one of 12 boys (hc also
rcccivcd testicular irradiation); four werc still
aftcr completion of trcalrncnt.
prcpubcrtal at cvaluation and scvcn boys had ~ ~ o r n l a l
78. Abnornial pubcrty and gonadotropin deficiency
pubertal devclopmcr~t [B13].Four of the boys with
normal pubcrtal dcvclopmcr~thad clcvatcd lcvcls of
have been observcd in about 10% of children irrafollicle-stimulating hormone with normal luteinizing
diated to the hypothala~nic-pituitary rcgion with 25hormone and testosterone. Anolher seven boys reccived
50 Gy over 3-4wccks [LlO,R23]. After cranial radioliactionatcd whole-body irradiation with 12-14Gy in 6
therapy for lcukacmia in childhood, varying results
fractions over three days, and five of them were still
have bcen observcd. Quigley ct al. [Ql]found eviprepubcrlal and two had achieved pubcrty, one after
dence of germ-cell damage in 25 boys who received
tcstoslcrone adminiskation. Dccg el al. [D2]observed
chemotherapy and 24 Gy in 15 fractions ovcr three
that 5 of 16 boys subjected to whole-body irradiation
weeks. Germ-cell damagc was confirmed by the abdeveloped secondary sex characteristics appropriate for
sence of genn cells in testicular biopsy specimens and
their age and 11 had delayed onset of puberty. Fortyby the small size of the tcstcs in all boys. Boys
one malc patients who were past puberty at the tinie of
rcachcd puberty at a mean age of 12 years. Plasma sex
transplantation developed primary gonadal failure and
steroids were nornlal. but the level of luteinizing
azoospcrmia. Two had rccovery of sperr~latogcncsis
hormone aftcr stimulation with gonadotropin-releasing
approximately
six ycars after transplantation, and one
hormone was elevated in pubertal children, suggesting
of
then1
had
two
normal children. Gonadal failure
compcnsation for decreased gonadal function. Sklar ct
be nearly universal after wholctherefore
appeared
to
al. IS411 evaluated testicular function in 60 long-term
body
irradiation
with
10-12Gy in patients of postsurvivors of childhood acute leukacniia who had been
pubertal
age.
Sandcrs
et al. IS231 studied gonadal
randomized to cranial radiotherapy with 18 or 24 Gy
function
in
90
boys
1-17
years old who had bone
(n = 26), 18 or 24 Gy plus intrathecal mcthokexate (n
Illarrow
transplantation
aftcr
prior chemotherapy and
= 23) or 24 Gy aar~iospinalradiotherapy plus 12 Gy
radiotherapy
to
the
central
nervous
system (n = 55).
to the abdomen including gonads (n = 11). T r e a t m c ~ ~ t
Whole-body
irradiation
was
given
as
a single dose of
was dclivercd in 1.2-2Gy daily fractions, and the
9.2-10
Gy
or
fractionated
doses
of
2-2.3
Gy daily for
scattered dose in the tcstcs was 0.4-3.6 Gy after
6-7
days
to
a
cunlulative
dose
of
12-15.8
Gy. At
aaniospinal radiothcrapy. Primary germ-cell dysevaluation on average four years later, 21 of the 63
function on average five ycars after cessation of
boys who werc prepubertal at transplant had dclaycd
therapy was significantly associated with type of
dcveloprnent of secondary sexual characteristics.
radiotherapy field: 55% aftcr craniospinal plus
Gonadal failure occurred in nearly all who were
abdominal field, 17% ahcr craniospinal and 0% ahcr
postpubertal at transplant.
cranial radiotherapy (p c 0.01). Leydig cell function
was unaffected in UIC majority of patients regardless of
80. Summury. The efrccki of radiation on the testis
type of radiolfierapy. Lciper et al. [LIZ]observed
arc agc- and dosc-dcpcndcnt. Radiation appears to
early puberty in five boys treated with 18-24Gy in
have its greatest effect on the germ cells rather than
10-15 fractions ovcr 2-3 weeks. The mcan age for
on Leydig cells. It is difficult to draw any certain
onset of pubcrty in these children was 9 years, which
conclusions regarding the elfcct of ionizing radiation
was greater than two standard dcvia~ionsfrom the
on the gonadal function in boys and malc adoiesccnts.
mean. Precocious puberty, i.e. signs of scxual maturaThe data have been obtained from studies based on
tion occurring before 9 ycars, has also bcen reported
l~eterogcneousmaterials, with grcat variation in agc at
[B19, L12]. Von Muchlcndal~l et al. [Vl] noted
and treatment n~odalities. Furthcrn~ore,
exposure
~ ~ o r n ~lcvcls
a l of lutcinizing hormone and folliclegonadal
function
has been assessed in many different
stimulating hormonc in 17 boys after 8-18Gy of
ways. The threshold radiation dosc that will damagc
cranial radiothcrapy. Jaffc et al. [J4] evaluated
Ihe germinal epithelium in childhood cannot thtrcfore
reproductive function in 27 male long-term survivors
be clearly defined at present. Tcsticular function rnay
be comprorniscd at doscs as low as 0 5 Gy. Lcydig
cell function appears more rcsisbnt to ionizing
radiation, and impaired function occurs after 10 Gy or
more. Testicular function is also impaired by chemotherapy and may also be abnonnal prior to therapy for
malignancy h a t docs not involve the testis. Irradiation
to the prepubertal gonads may not always result in
irreversible damage. Whole-body irradiation has been
shown to produce primary gonadal failure of various
degrees in Lhe majority of boys receiving 10 Gy,
regardless of pubertal status. In most of these patients,
Leydig cell function appeared adequate.
E. hlUSCULOSKELETAL SYSTEM
81. Two processes of bone formation occur within
the human skeleton: membranous bone fornlation and
enchondral bone formation [PlO]. Flat bones and the
cortices of long bones are formed by membranous
bone formation, in which there is no pre-existing
cartilage template, and osteoid tissue is laid down
adjacent to existing collagen, cartilage or bone. In
enchondral bone formation, which is responsible for
longitudinal bone growth, new bone is formed at the
epiphyseal growth plate. Chondroblast proliferation is
responsible for widening of the epiphyseal growth
plate and lengthening of the bone, and osteoid is
formed by osteoblasts. External irradiation affects, in
particular, dividing chondroblasts and small blood
vessels. Membraneous bone formation is disturbed to
a lesser extent than enchondral bone growth. Epiphyseal irradiation causes arrest of chondrosis due to
direct effects on the cholidrocytes and secondary
vascular effects. Radiotherapy also disrupts the normal
processes of resorption of bone at the cpiphysis.
Actinomycin D and adriamycin enhance the effects of
radiotherapy (€61. Bone absorbs less radiation in the
megavoltage range than in the orthovoltage range, and
it has been believed that there is less growth disturbance in bone after megavoltage therapy. However,
the major radiation changes occur in the chondroblasts
and the fine blood vessels of the physis. Since both
are materials of unit density, it is reasonable to expect
growth disturbances to be largely indepcl~derit of
radiation voltage quality.
82 The first evidence of growth disturbances
following x-ray treatment in patients under 20 years of
age was reported in 1929 by Hueck et al. [H15]. In
adults, cartilage tolerates 40 Gy over 4 weeks or >70
Gy over 10-12 weeks, and bone tolerates 65 Gy over
6-8 weeks. Higher doses cause necrosis [C24]. These
tissues are more sensitive in children, and some
growth retardation may occur after 1 Gy, depending
on the age a t irradiation and the conditions of exposure 111, TlO]. The maximum growth depression has
been obscrvcd in cl~ildrcl~
treated up to the age of 6
years I I I I ~ i n y o ~ ~ np~lberty
g
[G9, P10, R25, R26).
Rocatgenographic changcs of the bone in children less
than 1 year of age occur aftcr conventionally fractionated radiotherapy of >4 Gy, while a dose of >18 Gy
with si~llili~rfractioni~tio~lis required to produce
significant changes in children 1-2 years of age and
>26 Gy is required in older children [N5, TlO]. Other
skclctal changes occur in children at doses >20 Gy,
including scoliosis, kyphosis and slippcd capital
femoriil epipllysis.
83. Growth in children can be adversely affected by
direct radiation damage to long bones and spine, malnutrition, steroid therapy, cytotoxic drugs, thc presence
of residual tumour and endocrine complications [B3,
B23, B24, B25, D17, G8, P11, P12, S20, S42, T10,
W7j. The effects of ri~diotherapyon the skeleton are
related to the anatomical site, the target volume, the
radiation dose, the source and pattern of the radiation
used, the age of the patient and chemo~berapy.These
effects may be seen in any bone but are most often
observed in the spine after fractionated radiotherapy
with cumulative doscs of 20 Gy or more [P13]. The
severity increases with increasing radiation dose and
with decreasing age at'tirne of treatment. Mature bone
and cartilage may also be devitalized by ionizing
radiation without showing clinical consequences until
stressed by, for example, iufection or trauma. Prednisorle and doxorubicin depress cartilage responsiveness
to soniatolnedin and also growth-hormone-stimulated
sonlatomedin productiol~ [P12]. 11 is difficult to
quantify the cffects of ionizing radiation on growing
bones for several reasons:
(a)
@)
(c)
(d)
there is a lack of large groups of patients of
various ages in whom the same epiphyseal cartilage has been irradiated with a range of doscs;
the turnour itself and other heatmcnt modalities
can contribute to the growth disturbance;
patients must be followed until growth is completed;
often patients with growth disturbances have
deformities corrected surgically, making it
impossible to qual~tifythe dalnage [G8].
84. Children lcss than 6 years old and at the time of
the adolescent growth spurt, i.e. duriug periods of
rapid bone growth, are especially sensitive to irradiation of the vertebral colu~nn. Impaired growth has
been observed after total doses of 25 Gy, and higher
doses to the entire spi~reresult in suppression of spinal
growtl~and decreased sitting height ID17, P10, P11,
S Z ] . Probcrt et al. [PlO] observed changes in both the
sitting and stalidil~gheights o f 4 4 children heated with
megavoltage radiation, particularly among those
receiving >35 Gy in 2-2.5 Gy fractions, whereas only
s
observed among tllose receiving
slight c h a ~ ~ g ewere
c25 Gy with sirrlilar fractionation (Figure VII). Shalet
el al. IS431 measurcd growth after radiotherapy for
brain tuniour in 37 childrcn who had reccivcd craniospinal irradiation will1 27-35 Gy to tile vertcbrac in
17-20 fractions ovcr 3-4 wccks and in 42 children who
rcccivcd cranial radiotherapy. Tllc cranial dose was not
stc~tcd.All had cornplctcd thcir growth ;it the tilnc of
evaluation, and at U~at timc thcre wcrc significa~~t
diffcrcnces between the two groups on standard dcvialion scores for standing heigl~tand sittil~gheight, but
1101 for leg length. The youngcr the child was at tllc
time of treatment the greater the subsequent skelctal
disproportion; the estimated cvcntual loss in hciglit
was 9 cm when spinal irradiation was givcn at 1 year,
7 cm whcn given at 5 years, and 6 cm whcn givcn a:
10 years.
85. Growth retardation has also been observed in
a intendcd treatment of
childrcn injccted with 2 2 4 ~ for
tuberculosis of bone and soft tissue [M24, S44]. Spicss
el al. [S44] obtaincd the adult heights of 133 patients
injected as juveniles. Radium-224-induced growth
retardation was greatcst in young childrcn, who had
the greatest amount of potential growth aftcr exposure.
The growth rctardation increascd with radiation dose,
arid thcre was a 2% decrease in potcntial growth postirradiation pcr gray for averagc skelctal doses up to
20-25 Gy.
86. Functional and cosmetic disabilities involving
bone, teeth, muscle and othcr soft tissucs havc bcen
reported to occur aftcr radiothcrapy in up to 38% of
survivors of paediatric canccrs, in particular aftcr
treatment for solid tumours (D19, L16, M2, M25,
S43]. The clinically significant problems often involve
bone abnornlalitics, such as scoliosis, atrophy or
hypoplasia, avascular necrosis and osteoporosis. Scoliosis may occur following radiotherapy to scgmcnts of
the spinal column in patients with solid turnours [H16,
J5, S42, S45, W8]. Scoliosis has been most apparent
in children treated with orthovoltage radiation to fields
cxtending to the midline, resulting in asymmetric
radiation of the vertebrae. The dcgree of scoliosis has
increascd with dose and has been mild aftcr 20-32 Gy
and significant after higher doses [ 0 1 0 , P10, R27].
Vcrtcbral abnormalities havc bcen less pronou~~ccd
with high voltage radiotherapy and with radiation
fields encompassing the entire vertebrae, and significant scoliosis below 35 Gy is uncommon [H16, P10,
T l l ] . The cases of scoliosis that occur at prcsent are
usually not s o severe that orthopaedic intervention is
required.
87. Slipped epiphyscs can dcvelop in paticnts who
have received radiotherapy to the proxinial femoral
epiphysis, combined with chcn~othcrapy,in childhood
[B26, L17, R1, S46, W9, WlO]. S i l v e n n a ~et~ al. IS461
studied 50 patients undcr 15 years of age who had
radiotherapy that included the non-fused capital
fcmoral epiphyscal plate in the treatment ficld. Mcan
dose to thc cpiphyscal plates was 23 Gy (range: 1.55 3 Gy), and 10% of the 8 3 plates at risk showed cpipl~yscalslippage or othcr severe radiographical abnormalities. Cl~ildrenundcr the age of 4 years at the timc
of irradiation wcre at higher risk (47%) than older
ct~ildrcn(5%). No complications occurrcd below 25
Gy and no dose-response curvc was obtained. A mcan
diffcrcnce of up to 12 crn in clinical length bctwccn
unirradiatcd and irradiated extremities has been
observed after 26 Gy to the cpiphyscal plates [G8].
Figure V1lI shows the relationship bctwecn age at
irradiation, dose and shortening for 20 patients who
had epiphyseal plate irradiation. Damage increased
dramatically at doses up to 40 Gy but levelled off
beyond that. Shortcning was strongly age-dependent,
amounting to 9-12 cm in several patients who were
less than 1 year old. When growth expected to remain
after irradiation was taken into account, age at irradiation did not influence h e final effect, and the radiation
dose was the most important factor. Radiation-induced
aseptic necrosis of the fcmoral heads have been
observed in childrcn aftcr doses of 30-40 Gy [L17].
Chemotherapy may be a contributing factor, since
aseptic ostconecrosis has bcen reported in children
after chemotherapy alone [P14]. Slipped proximal
humera] cpiphysis has also been reported aftcr slightly
higher radiation doses than those received by childrcn
with slippcd capital femoral cpiphysis [E6]. That the
shoulder is not as stresscd as the hip may be the
rcason why slipped proximal humeral cpiphysis is less
frequent than slippcd femoral epiphysis.
88. Bony hypoplasia of the orbit with facial asymmetry was reported in half of 50 children with orbital
rhabdomyosarcoma aftcr 50-60 Gy in 5-6 weeks
[H17]. Thc dcgree of hypoplasia appeared to be higher
the younger the child was at the time of trcatmcnt.
Other conilnon findings werc asymmetry of thc face
and/or ncck and the presence of dental problems, both
of which occurrcd in 58% of the patients. Evidence of
muscle atrophy or fibrosis of thc subcutaneous tissues
was evidcnt in 40% of the patients in the head or face
and 33% in the ncck. Hypoplasia of bones in treated
sites was documented in one dird of the patients and
judged to bc largely due to radiotherapy. Similar late
effects have been observed by others [E7, GlO].
89. Radiotherapy niay also have advcrse effects on
developing dentition, including root abnormalities,
iricomplctc calcification, delayed or arrested tooth
dcveloprncnt and caries [B27. D19. H18, J6, M261.
These and other maxillofacial abnormalities, such as
kismus, abnormal occlusal relationships and facial
dcformitics are more severe in patients irradiatcd at an
earlier age and at higher doses. Jaffc et al. [J6]
observed dental arid maxillofacial abnormalities in
82% of 45 long-tern survivors of childhood cancer
after iiiaxillofacial radiotl~crapy.Younger patients and
those treated with higher doscs, i.c. rhabdornyosarcoma patients (median dosc: 55 Gy) as opposed to
l-iodgkin's diseasc and Icukacniia patients (median
dosc: 35 Gy, p < 0.001) h:~d more severe abnonnalilies. In a study by Sonis ct al. [S47], abnor~naldental
dcvelopnicnt occurred five or niore years later in 94%
of 97 children with acute lcukacrnia treated bcforc 10
alone (n =
ycars of age with intrathccal ~ncU~otrcxatc
19) or in combination with 18-24 Gy c r a ~ ~ i aradiol
Ulcrapy (n = 78). All c h i l d r c ~who
~ received lrcatnicnt
before 5 ycars of age and those who received radiohcrapy had Uic most scvcrc abnornialitics. Tooth
brcakagc due to tooth resorption has been comrnon
among patients injected with 2 2 4 ~ aespecially
,
those
injected iiS teenagers [S48]. The incidence of tooh
brcakagc increased significantly with dosc. The tooth
fractures rcscrnblcd those observed in radium dial
painters in the Uriited Statcs lR25). Children given a
single whole-body exposure of 10 Gy for marrow
transplantation have developed similar disturbances in
dental development and facial growth similar to those
seen after 18-65 Gy fractionatcd radiotherapy to the
maxillofacial region for Icukacniia or solid tumours
[D20,
S2.51. The most scvcrc effects have bcen seen in
children irradiated when they were less than 6 ycars of
age.
90. Anthropomctric analyses were performed in 1990
on children living in Russia, Belarus and Ukraine at
the time of the nuclear plant accident in Chcrnobyl in
1986, and in children born in 1989 [HI. The main
conclusion horn these studies was that there were no
significant differences in height or weight between the
control and contaminated regions.
91. Summary. Growth in children can be adversely
affected by direct radiation damage and by malnutrition, other treatment modalities, the presence of
residual tumour, and endocrine late radiation effects.
Most clinical data arc based on small and hctcrogeneous groups of patients treated in different ways at
varying ages. The skeletal eflccts have also been
assessed in a variety of ways, and i t is not possible to
give any estimates of latc deterministic effects based
on large-scale epidcniiologic data. Skeletal changes in
children generally occur at doses exceeding 20 Gy and
include scoliosis, kyphosis, slipped femoral cpiphyses,
hypoplasia, growth retardation, dcntal problems etc.
Absolute shortening of the long hone depends on the
absorbed radiation dose and the age at the tinie of
irradiation. Exposure at ages less than 6 ycars and
during puberty appears to have h e greatest effect on
growth retardation. However, other studies have
observed that whcn growth expected to occur after
irradiation was taken into account, Lhe age at irradiation did not ir~fluencethe final effect, and h e radiation
dose was then the most important factor. Scoliosis and
kypllosis arc conimon alter spinal or flank irradiation
followi~lgdoscs of >20 Gy. Slipped fcn~oralcapital
epipl~ysisdocs not occur bclow 20 Gy, and this latc
effect is more c o n ~ n ~ oillt ~cl~ildrenunder 4 ycars of
age a1 dlc ti~ncof irradi:~tion.A dose exceeding 20 Gy
is rcquircd to arrest cncondral bonc lormation, and
doscs ol' 10-20 Gy cause t l ~ cpartial arrest of bone
growth. Tllcrc is little altcr;~lionin bonc growth below
10 Gy of fractionated exposure directly to the bone.
No radiation-related effect on height has bcen
obscrvcd in cl~ildren living in Russia, Belarus or
Ukraine at the time of tllc Cllcn~obylaccideat.
F.
EYE
~g
chcn~othcrapy and cortico92. l o ~ ~ i z i rradiation,
stcroids have all bcen found lo increase the risk of
cataract formation [C20, H19, 11, 011, P15,S49, U3].
Different cornporlents of the eye have different sensitivity to ionizing radiation, ilnd the lens is especially
sensitive whcn uniformly irradiated. There are difrercnt forms of cataract, and radiation-induced cataract is
in its early stages a characteristic lesion, which is
defined as a posterior subcapsular opacity. The threshold dose for cataract in adults is about 2 Gy of x rays
from a single exposure and 4-6 Gy when fractionated
over 3-13 wecks [ F l , M271. Minimal stationary opacities have been obscrvcd after single doscs of 1-2 Gy,
and with 5 Gy more serious progressive calaracts
occur [U3]. The threshold dosc for cataract formation
is increased by non-uniform irradiation [B28]. Higher
radiation doses yield more progressive cataracts with
a greater loss of vision. The average latent period is
2 ycars but lnay be up to 35 years. The combination
of radiotherapy and chemotherapy enhances the risk
for cataract for~iiation[F7]. Other late radiation cffects
in the eye include retinopathy, optic neuropal~yand
lacrimal gland atrophy. These types of injuries rarely
occur below 45 Gy.
93. Dccrcased vision due to cataract formation in the
ircated eye is commolr ia children treated for orbital
rhabdomyosarcoma after doses to thc tuniour of 5060 Gy in 2 Gy fractiol~sover 5-6 weeks [H17]. The
time to first reported evidence of cataract varied from
one to four years after radiotllcrapy. Otber reported
structural late eKects include changes in the cornea or
r c t i ~ ~cnophthalmos,
a,
and stenosis of the lacrimal duct.
[Q2] estimated
94. Qvist and Zacllau-Christia~~sc~~
Ihe ~niainiu~n
lenticular dosc to produce cataract in
childrer~to be 13.8 Gy from radium moulds; the maximum non-cataract dose for infants was 9.9 Gy and for
school-aged children, 11.4 Gy. Notter ct al. [N8]
observed cataracts after considerably lower doses in
234 patienLs who had been irradiated will1 2 2 6 ~ a containing applicators for skin hacmangioma between
1920 and the mid-1950s. An ol)l~thal~~~ologic
examination was conducted in 1961-1965. Of 468 cycs
examined, cataract was observed in 5 1 (1 1 Ti). No
cataract was obscrvcd i n Ihc 246 cycs rcccivi~~g
c2.5 Gy in the Icns. The prrvalencc of cataract was
8% (100 eycs) aftcr ;I Icnticular dosc of 2.5-3.5 Gy
and 54% (122 eycs) aftcr higher doscs.
95. Stcfani et al. [S37, C25] rcportcd on the devclol)mcnt of cataract in 899 patients rccciving multiple
injcctions of 2 2 4 ~ afor the intcndcd trcat~ncnt of
tuberculosis or ankylosing spoadylitis. Cataracts were
found in 6% of the 218 juver~ilcpatic~~ts
and in 5 % of
the 681 adult patients. In those with known injected
activities, juveniles recciving >1 MBq kg-' of 2 2 4 ~ a
had a cataract incidence of 14% (11 of 80) compared
to 0.8% (1 of 131) rccciving lcss than that amount.
The cataract incidence increased significantly with
dosage in both juveniles and adults.
96. The dose received by the lens in cranial radiotherapy for acutc lcukacmia is of importance for the
induction of cataract [KIO]. The dose to the lens is
approximately 15%-30% of the midline dosc, depending on the type of treatment fields. Ncsbit ct al. IN31
found one case of posterior subcapsular cataracts in 50
survivors of childhood acute Icukaernia. In contrast,
lnati ct al. (131 observed a 50% incidcncc of cataract
formation in 69 children with acutc Icukaemia given
24 Gy cranial radiotherapy in 13 fractions over 2.5
weeks, intrathccal nicthotrcxilte and high doscs of
steroids. All cataracts wcre sn~alland did not impair
vision. In another study of 34 long-term survivors of
acute Icukaemia, all 18 patients in the non-irradiated
group had normal results in eye examinations, while
4 of 16 of those receiving 24 Gy to the whole braill in
1 2 fractions over 2.5 weeks had ocular abnonnalitics
[ W l l ] . None of the ocular findings could, however, be
definitely attributed to radiation, and all patients had
normal visual acuity.
97. Posterior subcapsular cataracts occur in the great
majority of patients aftcr 10 Gy of single whole-body
exposure but in only about 20% after 12-15.8 Gy of
fractionated exposure [A14, B13, CEI, D21, L23, S24,
V7]. Among 105 paticnts givcn 10 Gy single-dose
whole-body irradiation, 80% developed cataracts by
six years compared to 19% of 76 patients givcn fractionated whole-body irradiation (12-15 Gy in 2-5 Gy
fractions over 6-7 days) and 18% in patients who did
not receive radiotherapy [D2]. This last figure indic.g. steroids or
cates that factors other than irradiatio~~,
previous treatments may have contributed to the
development of cataracts. Nearly all cataracts
developed after a singlc exposure need to be removcd,
whereas a smaller fraction of those dcvcloped aftcr
fractionated exposure require removal.
98. 111 ii study conducted among subjccts of the
Adult Hcalth Study of Hiroshi~naand Nagasaki, a significant excess risk for postcrior subcapsular changcs
was obscrvcd for all ages in the group receiving >3 Sv
ia conip;iriso~~
with tl~osein the control group amorlg
rcsidcats in Hirosl~inl;~
but 1101in Nagasaki [C21 1. The
study w ; ~ sbased on Ihe T65 dosimetry and the cxaniination was conducted 011 2,385 persons. The relative
risk of cataract for pcrsons in Hiroshima exposed to
>3 Sv was 4.8 in persons under age 15 years at the
time of the bombings, 2.3 in pcrsons 15-24 years at
the time of the bombings and 1.4 in pcrsons more than
25 years at the time of the bombings. The relative risk
for postcrior subcapsular changcs in Hiroshima for
pcrsons under age 15 ycars at the time of the bombings was 2.8 in the 1-1.9 SV group, 4.3 in the group
rccciving 2-2.9 Sv and 5.3 in the group recciving >3
Sv. A con~parisonof relative risks in the different age
groups suggested a stronger effect in Hiroshima for
persons under age 15 years at the time of the bombings. These results support h e hypothesis that younger
individuals are more sensitive to radiation-induced
cataract than oldcr individuals. A more recent assessment of the dose-effect relationship for cataract
induction has been made using the DS86 dosimetry
systcni 1015, 016). This new study confirms the previous findings of a higher sensitivity in young persons.
The magnitude of log relative risks for cataracts in
pcrsons aged 40, 50, 60 and 70 years at the time of
examination was 8.2, 6.4, 4.6 and 2.8-fold highcr,
respectively, than in pcrsons aged 80 ycars at the time
of examination. The bcst-fitting rclationship for
posterior postcapsular changes suggested a linearquadratic dose-response.
99. Summary. The available data on radiationinduced cataract formation in adults suggest a sigmoid
dose-response relationship with an apparent threshold.
This threshold varies from 2 to 5 Gy aftcr x rays and
gamma rays given as single exposure and is about
10 Gy for doscs fractionatcd over a period of months.
Data on radiation-induced cataracts in children are
scarce and are based on small groups of patients
rccciving different treatment niodalities. Cataracts have
been reported aftcr 24 Gy cranial radiotherapy for
childhood leukac~niaresulting in 5-7 Gy in the lens.
Cataracts have been obscnred after 2.5 Gy or more in
h e lens, and in one study the prevalence of cataract
was 8% (100 eyes) aftcr a lenticular dose of 2.53.5 Gy. Whole-body exposure of I 0 Gy in childhood
has also been associated with cataract formation in the
niajority of cases, wlicreas fractionatcd wholc-body
irradiation with 12-15.8 Gy is associatcd with cataract
in about 20% of the patie~lls.Cataracts wcre observed
in the survivors of the atomic bombings in Japan
exposed to >3 Gy, and the risk for cataract was higher
in persons lcss than age 15 years at the tin~cof tile
bombings than in persons oldcr than that.
H92
UNSCFAR 1993 REPOI1'T
100. Ionizing radiation affec~ssmall and large vcssels
within the treatment field, and changes may develop
within months and up to two decades after radiotherapy [K2]. The main chitngcs tbat occur consist of
premature athcrosclerosis with vascular occlusion. The
heart was formerly thought to be relatively resistant to
ionizing radiation. The increasing use of radiotherapy
to the mediastinum, however, has been associated with
well-documented instances of cardiac abnormalities.
Late effects following radiotherapy have been reported
in both adults and children and usually occur as
cardiomyopathy, coronary artery disease, pericardial
effusions or constrictive pericarditis [A15, B29, 830,
D17, G11, G12, K11, L1, P9, R28, T9].Interstitial
myocardial fibrosis and coronary artery changes have
been reported after 30 Gy, and pericarditis has been
reported after 15 Gy [B29, G12, K12, M28, M29). In
children as well as in adulb, a dose of 40 Gy to the
heart appears to be the critical dose for clinical
cardiomyopa thy.
101. The incidence of post-irradiation pericarditis
increases with dose and fraction size [SO]. In patients
irradiated for Hodgkin's disease, the frequency of
radiation-related pericarditis correlates with the
pericardial dose [C22]. C a m e l and Kaplan [C22]
found a 7% incidcnce of pericarditis after doses
<6 Gy, 12% after 6-15 Gy, 19% after 15-30 Gy and
50% after >30 Gy. Symptomatic pericarditis may first
appear as late as 45 years after therapy [B29, G13,
H20, K12, S.511. Kadota et al. [K12] evaluated cardiopulmonary function in 11 children who received radiotherapy for Hodgkin's disease with a mean dose of
36 Gy (range: 20-55 Gy) with conventional fractionation. Mean age at radiotherapy was 11 years, and
evaluation was performed, on average, nine years
later. Ten patients had no clinical evidence of
cardiopulmonary dysfunction, and one had constrictive
pericarditis. Four had thickened cardiac valves on
echocardiography, without significant stenosis or
insufficiency. Only three had normal cardiopulmonary
function, and the others had one or more abnormal
tests.
102. Makinen et al. [M30] evaluated cardiac sequelae
in 41 individuals who had received chest radiotherapy
or doxorubicin for childhood cancer at a median of 17
years earlier. Radiotherapy had been used in 21
patients, and in 13 of them irradiation was directed at
the heart witb doses of 12-60 Gy in 8-30 fractions
over 12-47 days. Of the 41 patients, 20 (49%) showed
some abnormality in cardiac tests (e.g. abnormal ECG
or echocardiogram, reduced exercise capacity), and
each additional year of follow-up was associated with
a 1.3-fold increase in pathologic cardiac findings. The
risk of an abnomlal cardiac test result in the 13
patients who had received radiotherapy to the hcart
was 12.8 tiales the risk for other patients (95% CI:
1.8-90.8). No dclailcd analysis of the effect of radiotherapy wils presented.
103. T l ~ eii~~tl~riicyclincs
doxorubici~iand daunoniycin
are cardiotoxic and may cause electrocardiographic
cl~arlgcsand congestive heart failure. There is a doseresponse rclatio~ishipbetween the total dose of anthracyclincs and cardiomyopathy, and children appear to
be more susccptiblc to drug-induced cardiomyopathy
[P16, P17, S52, V3, V4]. Several studies have shown
that mcdiastinal irradiation enhances the myocardial
toxicity of antbn~cyclines[B31, G14, M31, P16, P181.
Gilladoga et al. [GI41 observed severe cardiomyopatl~y
with congestive heart failure in 16% of 50 children
receiving adriamycin and in 3 % of 60 children recciving daunomycin. Four of 8 children who also had incidental cardiac irradiation prior to or during adriamycin
administration had severe cardiomyopathy. In contrast,
Von Hoff ct al. [VS] observed a lower risk of cardiomyopathy for children than for adults at any given
cumulative doxorubicin dosage.
104. S ~ t n m a r y .Radiation exposures cause occlusion
of both sniall and large blood vessels. Cardiac abnormalities have been observed particularly following
irradiation of the mediastinum. Patients may have
abnormal cardiac function without clinical evidence of
such dysfunction. Myocardial fibrosis has occurred
after 30 Gy. The few data available suggest that 40 Gy
with converitiorial fractionation can be considered as
a a i ~ i c a ldose for clinical cardiomyopathy in both
children and adults. The anthracyclines are cardiotoxic
arid enhance the effects of mediastinal irradiation.
105. The lung is the most radiosensitive organ in Lhe
thorax. The mechanism for respiratory damage in
young children may be different from tbat in adults or
in adolcsccnts. Specific radiation effects in children can
include the impaired forn~ation of new alveoli or
failures in tlie development of the thoracic skeleton arid
thus a reduced size of the lung (B32, R17]. Interstitial
fibrosis of the lung, resulting in decreased total lung
capacity, vital capacity and diffusion, is a late effect
that has been observed in adults after d a e s of >30 Gy
and above [D22, H21, L l , L18, M18, M32, S54]. The
effect i n children appears to be similar for the same
dose and fractionation schedules [D17, S53, T9,W121.
Children younger U~an3 years a1 Ule time of treatment
may be at higl~errisk for lung dysfunction (M32j. The
effects depend on the target volume and on the concurrent use of chemotherapy [W13]. Interstitial pneumonitis and pulmonary fibrosis have also been reported
after chemotherapy in children and adults (A16).
106. Restrictive lung volun~cwith total lung capacity
bctwccn 62% and 80% of normal capi~cilywas rccordcd aftcr trcatlncnt for Hodgkin's discasc in 5 of
11 paticnts (nlca~rage: 1 1 years) who rcccivcd 111al1tlc
licld radiothcrapy with 20-55 Gy [K12]. Six childrcn
had rcduccd cxcrcisc tolcraucc, n~anifcstcdby rcduccd
rnaximum oxygcn uptakc (<65% of prcdictcd) arid
cxcrcisc duration (<75% of prcdictcd). Millcr ct al.
[M32] observed reduced forccd vital capacity and/or
total lung capacity in half of 29 childrcn with childhood canccr. Thc incidcncc of pulmonary dysfunction
was high in both irradiated childrcn and in individuals
who did not rcceivc radiotherapy to thc thorax.
107. After fractionated pulmonary radiothcrapy for
Wilms' tumour at age 2-4 ycars with a lung dosc of
20 Gy, children may dcvclop dyspnoca and cvidencc
of interstitial and pleural thickening on chcst x-ray
examination up to 14 years after treatment [W14].
Mcan total lung volumcs may bc reduced by approximatcly 40% after such radiothcrapy owing to effects
on lung growth and on chest wall growth. Restrictive
lung changes aftcr fractionated radiothcrapy with 1114 Gy to thc wholc lung have bccn rcported in othcr
studies of children with paediatric tumours [B32, L191.
Benoist et a]. [B32] studied the effects of whole-lung
irradiation on lung function in 48 childrcn treated for
Wilms' tumour with pulmonary metastases. The mean
age was 3 years, and all paticnts reccivcd fractionated
radiotherapy with 20 Gy bilateral pulmonary irradiation over three weeks plus actinomycin D. Greatly
reduced sagittal and frontal thoracic diamctcrs were
observed in nearly all of the cases 3-4 years aftcr
radiotherapy. Lung volun~esand dynamic lung compliance and functional residual capacity decreased with
time. Static pressure volurt~ccurves, blood gases and
carbon monoxide transfer were normal, making it unlikely that post-radiation pulmonary fibrosis was
involved.
108. Littman ct al. [L19] cvaluatcd pulmonary
function in 33 paticnts trcated for Wilms' tumour and
followed for up to 20 years aftcr diagnosis. All but
five childrcn received at least one course of actinomycin D. Eightecn childrcn who did not receive lung
irradiation had normal pulmol~ary function. Radiotherapy was givcn to 10 children for pulmonary
metastases and to 5 childrcn as prophylaxis with a
lung dose of 12-14 Gy and varying fractionations.
Patients trcated for lnetastases Iliid findings suggeslivc
of moderately reduced lung volumes, whereas patie~~ts
recciving prophylactic trcatmcr~lhiid esscl~tiallynonn;~l
lung volumes. Vital capacity and functional residual
capacity were significandy lower i n the irradiated
group of patients than in the non-irradiated patiellts.
Residual volume was lower in the irradiated group as
was forced expiratory volume. The fact that patierlts
who were treated for metastatic disease had greater
ab~~orlnalities
ill pullnonary funclio~~
than those irradiated for prophylaxis suggests that the prcscllce of
mctas~atic~ ~ o d u land
e s additional lung t r c a t n ~ c ~
could
~t
have aggravatcd the cffccts.
109. Two studics did not obscrvc any i ~ i ~ p a i n ~ lof
cl~t
lung fu~~ction
in paticnts 15 ycars old or lcss after
wholc lullg irradiation with 20 Gy in 1.5-2 Gy Gactions livc tin~cspcr week [B39, Zl]. According to
Margolis ct al. [M34], the n~aximurnsafc dosc to thc
wholc lung for paticnts receiving aclinonlycin D is
15 Gy in 1.5 Gy fractions. Howcvcr, doses lower &an
that may affcct pulmonary function. Wohl ct al. [W14]
reported that total lung capacity averaged 71% of the
cxpcctcd valuc in six childrcn treated with fractionated
and bilateral pulmonary irradiation for Wilrns' tumour
and evaluated more than scven ycars later. Thc exposures at the midplane of the cl~estranged from &
1 2 Gy dclivercd ovcr an average of 11 days. The total
lung capacity for cight children receiving no radiotherapy was 94% of the expected value. Springmeyer
ct al. [S53] found rcstrictivc ventilatory changes in 79
patients with haen~atologicmalignancies or aplastic
anaemia one year or more after bone marrow transplantation. There was a mean loss in total lung
capacity of 0.8 and in vital capacity of 0.5, but thcse
changes were not significantly associated with wholebody irradiation.
110. Surnmary. The lung is a radiosensitive organ,
and radiotherapy during a period of lung growth and
chest wall growth primarily results in a reduction of
the subsequent size of both lungs and chest wall.
Respiratory damage in young children is rnorc scvcre
than in adults at the same doses. The effects depend
on the targct volume and concurrcnt usc of chemotherapy. Interstitial fibrosis may occur 6-12 rno~iths
after absorbed doscs to the lung of 30 Gy or more. A
lung dose of 15 Gy in 1.5 Gy fractions is generally
considered as the rnaxi~nurn safe dose in childrcn
rcccivi~~g
radiothcrapy to the whole lung and simultaneous treatment with actinornycin D. Howevcr, rcslrictivc lung changes have b c c ~reportcd after doscs of
11 Gy or more in childrcr~ trcatcd for paediatric
tumours, arid rcduccd total lung capacity has been
found after 8 Gy or more to the wholc lung with
similar fractionation.
I.
BREAST
1 1 1. Breast dcvelol)~nc~~t
is rcadily i~ihibitcdhy radiotherapy in infancy, and scvcre hypoplasia of brcast
tissue has bccn rcportcd i n women having a history of
breast irradiation in childhood [D19, F8, F9, G15,
H22, K13, U l l ] . Breast hypoplasia or aplasia have
also bccn notcd as sequclae after radiothcrapy for
pacdia~rictumours i n childhood [F8]. The knowledge
894
UNSCEAR 1933 Rli1'011'1'
of dose-cffrct pattcnls is scarcc 111, 151. Moss [M35]
statcd Illat an cxposurc giving a ski11 dosc of 15-20 Gy
ovcr cigl~ldays would ilnpair hrcast dcvcloptnclrl.
Accordiag to Rubill ct ;!I. [R2], a dosc cxcccding
10 Gy to thr prrpubcrtal fcln;rlc brcast of cot~vcntior~ally Sractiol~:~tcd
x-ray tltcriipy 111:ry rcsult i l l t l ~ c
abscl~cc of brcast dcvclopnrclrt i l r 1963% of tllc
paticl~~s.
112. Fiirst ct al. IF91 studicd thc l)rcvalcr~ccand
dcgrce of brcast hypoplasia ill 129 womcn irradiatcd
in infalrcy or childhood for hacniangioma in the brcast
rcgion. The patients wcre trcatcd in 1934-1943 at an
agc of 4 ycars or lcss. Radiotherapy was n~aitrlygiven
with applicators containing 2 2 6 ~ awith
, flat applicalors
or ncedlcs and/or tubcs having hccn uscd. Mcan absorbed dosc to Urc brcast anlagc for t11c wholc cohort
was 2 3 Gy (rangc: 0.01-18.3 Gy). Brcast asynimctry
was estimated by rcsponscs to a mail questionnaire to
all paticnts and by the clinical cxaniinatiorr of 53
paticnts living in Stockholm county. Brcast hypoplasia
on the trcatcd sidc was reported by 57% of the
patients and on the contralatcral side by 8%. Among
wonicn reporting a smallcr brcast on thc untrcatcd
side, the nican dosc to thc trcatcd brcast was 0.5 Gy
(range: 0.01-1.0Gy). In 28 of thc 5 3 clinically
cxamined patients, breast hypoplasia excccdir~g10%
was found on the trcatcd sidc, and five paticnls had
hypoplasia of more than 10% on tlrc contralatcral sidc
(Figurc IX). The Iicqucncy and t l ~ escvcrity of impaired brcast dcvclopmcnt itrcrcascd with tllc radiatio~r
dose. In this study, the possibility of a tl~rcsholddosc
for radiation-induccd breast hypoplasia could rrcithcr
be established nor rulcd out, and thc rcsults suggcstcd
h a t the available risk cstiniatcs for brcast hypoplasia
underestimate Lhc cffcct 111, R21. At lowcr doscs, the
dosc-cffcct relationship nlay bc c o ~ r f o u ~ ~ dbyc dnormal
variations in brcast size. At highcr doscs and with
largcr fields than wcrc uscd in thc Swcdish study,
Lhcrc may also bc a radiation cffcct OII tllc chcst wall
with subscqucrrl growth impairrnenL
113. Summary. Tllc scnsitivi~yof brcast tissue in the
irradiatcd child is rccognizcd, with low Urrcshold doscs
for thc occurrcrtcc of clilrical cffccb. Onc study has
rcportcd that hypoplasia occurs in niorc than 50% of
childrct~trcatcd with radiothcrapy at lcss that1 4 ycars
of agc with doscs to thc brcast of thc ordcr of 2 Gy.
Highcr doscs cause inocascd incidcncc ; I I I ~scvcrity of
impaired brcast dcvclopnic~~t.
114. Late radiation effects ol'thc gas~ro-intestinal tract
dcvclop n~onthsor ycars aftcr cxposurc alrd include
fibrosis, stricture, intestinal pcrforatiolr and fistula
formation [RI]. The liver appears to h a w a low thres-
hold for 1;itc injury, and ill adults vcno-occlusivc
discasc has I)cct~obscrvcd aStcr sitlglc doscs of 10 Gy
or 18-30 Gy wit11 co~rvc~rlionirlfraclionatiolr [FlO].
T l ~ cd i ~ ~ u ; ~isg cduc to cl~;~ngcs
that il~tcrfcrcwith
~uitosisill t l ~ cirr;~diatcd l i ~ l ) i ~ t ~ and
c y tto
~ ~vascul;~r
clr;~ngcs I l l ] . R:~dialio~r-iliduccd livcr disci~se is
clrs l.:~ctcrizcdstructur;llly Ily progrcssivc fibrosis and
obliteration of ccntral vcins, possibly by injuring
prcCcrcnti;llly tllc cndotl~clial cells of ccntral vci~is
[FIO, L20j. Vcno-occlusive discasc nlay also bc
caused by ;~l~tincopl;istic
drugs, and hepatic fibrosis
has b c c ~obscrvcd in childrcl~receiving cl~cmotherapy
[M36, N6j.
115. Tllc risk for radiatiolr-ioduccd livcr datrragc incrcascs wlrel~I;lrgc volui~icsof the liver arc irradiatcd
or w11c11t l ~ clivcr is irradiatcd aficr rcscction. A largcr
dose caa bc tolcri~tedif ot~lypart of thc livcr is cxposcd [FI, 16, K14]. In children, Tcfft ct al. IT131
aftcr radiothcrapy to the livcr
notcd livcr abeor~n;~lilics
with doscs of 12-30 Gy. This could be rclated to the
grcatcr sensitivity of thc younger child, who gcrrerally
also rcccivcd the lowcr doscs. Tbomas ct al. [ T l l ] observed livcr fibrosis i t ~3 of 26 long-term survivors of
Wil~ns'tunlour wlio had rcccivcd at lcast 30 Gy to the
livcr in 1.5-2 Gy fractions. Hcpatic discasc, ranging
froni abnormal livcr cnzylnes and thrornbocytopcnia to
death, has ;ilso bccn rcported by othcrs [S45, T12].
116. Hepatitis followi~~g
irradiation and chcniolhcrapy
at doscs and volurncs of irradiation ordinarily considercd within tllc tolerance of hepatic function has
bcen rcporlcd [K15]. Fatal livcr damage occurrcd in a
13-year-old boy who had received adriamycin bcforc
and during radiothcrapy of 24 Gy ie 17 fractions ovcr
28 days to thc uppcr abdon~crri~rcluditrgthc entire
livcr. A 13-year-old girl had modcratc clil~icallivcr
changcs Sollowing 25 Gy in 23 fractio~lsovcr 3 2 days
witlr adri;~t~~ycilr
;itl~ninistcrcdbeforc and during irradiation. 111 this cast niuch of the rig111 lobc was
shicldcd during r;rdic~tlrcrapy.Aboul 20 patients havc
bccn rcportcd to havc dcvclopcd liver discasc aftcr
fractiollatcd radiotl~crapywith 12-40 Gy to t l ~ clivcr in
childlrood togcll~cr with chc~nothcrapy [J7j. Most
paticnts wcrc asylnptomatic, and U~circo~rditionwas
discovcrcd bcc;tusc of hepatomegaly or abnor~iialitics
shown ia a routil~clivcr scil~~igrain.
When hepatitis is
obscrvcd following radiation cxposurc, cspcially if
exposure is rcccived i n conjunctio~r with clrclnoIhcr;lpy, it is ilnportanl to ~loteLhat not o111y 1)ostirr;.diatioe cffcck but illso toxic and il~fcctious
colnplicirliolrs rcquirit~g approprialc tlrcra1)cutic
prol)l~ylarticIrlc;lstlrcs will occur.
117. n r c stnil11 il~tcstirrehas a high radiosc~rsitivity
but is Sorrrcwl~atsparcd by its mobility. Thus, rcpcated
cxposurc of' a particular scglncnt is avoidcd. This is
1101 t l ~ c
c;isr for t l ~ crcctuln, which is fixcd to adjaccl~t
tissucs ilnd conscquc~~tly
c x l ~ c r i c ~ ~ ctbc
c s cffcc~$of
to scvcri~lyc;lrs after cxposllrc [ F l , K16, L21, M38,
[I-111. 111adult.., t l ~ crisk 01'
radiation niorc frcquc~~tly
M39. U l ] . Thc critical dose for thc kidncys ill adults
snlall l)ou.cl con~plicatio~~s
dcl>cnds(III radi:~tiondosc,
is usually sct at about 23 Gy ovcr l'ivc wccks. Rubill
volunnc of bowcl irradi;~tcdand fractionatio~~
scl~cdulc.
IR3] s~~ggcstcdthc critic:~l dose for 5% chronic
Surgcry incrcascs thc risk of dcvcloping radiation
~~rphrosclcrosis
to be 20 Gy with convc~~tional
fraccntcropatby. The ~nanifestations of latc rl1di.t'
$1 1011
results frorn lcsionis of
tio~latior~.
Radiatio~l~~cl)liritis
cntcropathy arc considcrcd to bc duc m a i ~ ~ ltoy vastllc tubulcs and ~nlicrovasculaturcof thc kidney. Radiacular and conncctivc tissue damagc. Magc ct al. [M37]
tion injury to largc and mcdium-sizcd artcrics can also
rcportcd late gastro-i~~testin;~l
cffects i l l 17 c h i l d r c ~ ~ rcsult i l l stenosis or occlusior~[h138]. The scvcrity of
rccciving abdominal fractionatcd radiothcrapy with 30radiation injury sccms to be a function o f t h c radiation
dosc and thc sizc of tllc vcsscl. L ~ r g c rdoscs and
55 Gy. Stcnosis, subn~ucousi~lfiltrationsand nlcscntcrs~nalicrvcsscls arc rnorc likcly to end in total occluitis wcrc obscnrcd 2-13 nio~ltllsaftcr radiothcrapy. No
sion, wl~crcaslargcr vcsscls or sniallcr doses result in
dctails of thc radiothcrapcutic rcgi~ncnswcrc b'
.IVCII.
Thc combincd cffects of r:~diation dainagc to t l ~ c
stcnosis or hypopl;~siaof thc vcsscl. Children arc morc
susccptiblc to vascular injury, bccausc of thcir small,
niucous mcnibranc and cxaccrbation of alrcady cxistgrowing arteries and rclativc scnsitivity to a givcn
ing gastro-intestinal infcctio~~s
can cause pcrforation
dose of radiation. Radiation injury to the rcnal artcry
and ulceration.
niay produce a rcnovascular hypcrtcnsior~,which can
bc distinguished from the more common radiation
118. Donaldson ct al. [D23] rcvicwcd latc r;~diation
nephritis.
cffects in the gastro-intcstinal tract of 44 children
receiving whole abdominal radiothcrapy for lym121. Rcnal injury is rtiore sevcrc in childrcn, and thcy
phoma, Wilms' tumour or tcratoma. Of 14 long-lcrm
have limited tolerance for combined chcmothcrapy and
survivors, 5 dcvclopcd scvcrc radiation injury with
radiothcrapy. A nor~nsl crc;~tinine clearance and
small bowcl obstruction wiUli11two ~nonthsaftcr comglomcrular filtration ratc may be anticipated bclow a
pletion of radiotherapy. Their mean agc at the lime of
fractionatcd dosc of I 5 Gy whcn actinomycin D is
therapy was 6 ycars, and the abdominal dosc was 31
uscd c o ~ ~ c u r r c ~ but
~ t l yprogrcssivc
,
renal insufficicncy
Gy (rangc: 10-40 Gy) dclivercd in 7-20 fractions ovcr
occurs after doscs of 20 Gy and morc [JS]. However,
11-39 days. Surgery contributed to the prcscncc of
radiation nephritis has been rcportcd 20 ycars after
abdominal adhesions and fibrosis.
14 Gy to the kidney in childhood 10121. Reduced
crcati~iirlcclearance has been found in 18% of 108
119. Summary. The risk of radiation-induced liver
childrcn who undcnvcnt nephrccloniy for nlaligna~~t
damage increases with increasing volume of the livcr
disease and rcccivcd < I 2 Gy to the remailling kidncy
inadiatcd and after liver resection with regencrating
and in 33% among those rccciving 12-24 Gy [M33].
livcr tissue. Some data suggcst that cl~ildrcnarc nlorc
In anothcr study, Lcvitt et al. [L24] obscrvcd that
sensitive to such late effects than arc adults. Livcr
childrcn with Wilms' tumour and less than 2 ycars old
abnormalities have bccn obscrved aftcr 12 Gy with
convcr~tional fractionation and oftcn in c o ~ ~ i b i n a t i o ~ ~who rcccivcd chcmothcrapy with > I 2 Gy to the rcmaining kidney had a worse rcnal prog~~osis
than othcr
ri~diation-induccdhepatitis
with chcmothcrapy. Cli~~ical
childrcn. In children cxposed in itrero in Hiroshinia
has rarcly bccn rcportcd at doscs bclow 30 Gy in 0.9and Nagasaki. urinary cxami~~ation
rcvealcd transient
1.0 Gy fractions fivc times per wcck. Casc-reports
proteinuria, which was not found in adults [Fll].
have presented data on livcr damage in cl~ildrcnaflcr
24-25 Gy in 1.1-1.4 Gy fractio~~swith
concomitant usc
122. Radiotherapy for Wilms' tumour has also bccn
of anthracyclines. Radiation cffccts in the gastro-intcassociated with latc cffccls in the kidllcy [A17, K16,
stinal tract include fibrosis, stricture, pcrforation and
M40, V61. McGill ct al. [M40] rcportcd post-irradiaformation of fistulac. Thcrc arc hardly any data availtion rc~~ovascular
hypcrtcruion in a boy who received
able on such cffects in childrcn.
chcmothcrapy and fractio~~atcdradiothcrapy with
30 Gy to the abdo~ncnat Lhc agc of 9 lnol~thsand ia
anothcr boy 14 montl~sof agc who reccivcd 51 Gy to
K. KIDNEY
tllc abdonlc~~.
Scvcrc l~ypcrtc~~siorl
dcvclopcd 6-8 ycars
later. Koskimics [K16] rcportcd lhrcc p a t i c ~ ~agcd
b
120. The urinary system shows a wide rangc in radiosensitivity, with ihc kidney bcing thc most s c ~ ~ s i t i v c 1-2 ycars with Wil111s' tumour who dcvrlopcd I~ypcrtcnsion more than 10 ycars after rccciving >36 Gy
organ, the bladder htiving an intcni~cdiatesensitivity
postopcrativcly to rhc tumour area. Thc hypcrtcnsion
and the ureter bcing niorc resistant, although the full
was
co~~sidcrcd
to be of rc11;11origin for d ~ r c crcasons:
Icngtl~ is scldom irrediatcd [Ul]. Late radiation
the
likelil~ood
of
renal damage was supported by gross
sequclac of thc kidney are directly rclatcd to the total
macroscopic
changcs
in the nearby organs: two
dose to the tissuc and are charactcrizcd by tissue
patienb
had
protcirll~ria
i~ldicatingrc11:11dami~gc;and
r~ccrosisand librosis, which rnay occur a few months
other causes known to cause secondary hypertension
had bee11 excluded. In another study of 14 patients
with Wilms' tumour evaluated at a median of 17 years
later, four had elevated diastolic blood pressure and
two had mild proteinuria [B33]. That study provided
no data on the radiothcrapy. Arncil et al. \A171
reporled ncphritis four months aftcr surgery in two
children aged 2 and 5 years who received actinomycin
D and vincristine followed by 15-20 Gy to the
remaining kidney fractionated over 2-3 weeks.
123. Radiation nephropathy is common after wholebody irradiation for bonc marrow transplantation [T3,
V8]. After 12-14 Gy in 6-8 fractions over 3-4 days,
the child may develop anaemia, haematuria and
elevated creatinine. This renal insufficiency is due
both to the radiotherapy and to the chemotherapeutic
regimens employed.
124. Summary. Late effects following irradiation of
the kidncy include nephritis, tissue necrosis and
fibrosis, renal dysfunction and hypertension.
Available
-data do not indicate that children are more susceptible
to radiation-induced renal injury than adults. Radiation
nephritis has been reported after fractionated doses of
1 4 Gy, and decreased aeatine clearance has occurred
after doses around 1 2 Gy. The seemingly higher
sensitivity among children can probably be explained
by the combination of radiotherapy and chemotherapy,
which can enhance the side-effects in the kidncy [R3].
L. BONE MARROW
125. Few studies have bccn performed to determine
tbe long-term deterministic effects on bone marrow
function after exposure to ionizing radiation in childhood, and most available data refer to exposure in
adulthood. Rubin et al. [R29] studied the repopulation
and redistribution of bone marrow in 27 adults irradiated for Hodgkin's disease wilh 40-45 Gy of fractionated radiotherapy to large segments of their bone
marrow (mantle and inverted fields). Bone marrow
scanning techni ues using w m ~ c - s u l p h u rcolloid,
which parallels Fe activity and can be used to reflect
haematopoietic activity, indicated that prolonged
suppression of bone marrow occurs immediately following completion of radiotherapy and persists for 2-3
yean. Partial to complete bone marrow regeneration
after fractionated radiothcrapy with 40 Gy occurs in
85% of the exposed bonc marrow sites at two years.
Mechanisms of this recovery may include increased
hacmatopoietic production in shielded marrow sites,
expansion ofbone marrow space and infield regcneration of bone marrow. The study suggested that the
dose-response data for bone marrow suppression
following localized and sebmental exposun: need to be
revised upwards for fractionated radiotherapy. At the
9
40 Gy level thcre was evidence of prolonged suppression of bone marrow activity starting in the immediate
post-irradiation period and continuing for one year.
Regeneration of bonc marrow activity and expansion
of ~ O I I Cmarrow occurred aftcr one year following the
40 Gy treatment and continued to improve with time
from the first to the third post-irradiation year.
Baisogolov and Shiskin [B36, B37, B381 observed
bone marrow hypoplasia in 8% of examined bone
marrow from exposed parts in 200 patients irradiated
for I-lodgkin's disease, and in 89% the marrow was
aplastic.
126. Magnetic resonance imaging can detect radiationinduced marrow changcs. There are at least two
distinct types of late marrow patterns [S57]: homogeneous fatty replacement and another pattern possibly
representing hacmatopoietic marrow surrounding tbe
central marrow fat. These changes have been observed
in the lumbar vertebral bone niarrow of adults after
15-50 Gy delivered over 3-6 weeks. No similar studies
have been performed in pacdiatric patients.
127. No evidence exists of a late radiation effect of
primary disturbance of haematopoiesis in the absence
of malignant disease in the populations of Hiroshima
and Nagasaki [F12]. There is no evidence for radiation-induced disturbance of granulocyte function, but
the age-related accelerated decline in the immunological functions of T-lymphocytes and age-related alteration in the number of certain subsets of circulating Tand B-lymphocytes appear to be radiation-related
128. The Cheniobyl accident does not appear to have
caused statistically significant effects on the major
haematological parameters of children living in Russia,
Belarus or Ukraine at the time of the accident, or who
were born later [A18, 18, K17, Kl8, L25,L29, V9].
There were no differences between control and contaminated settlcmcnls. From the calculated and measured radiation dose levels, no changes should have
bccn expected as a direct result of radiation exposure.
129. In childrcr~ having an intact thymus, immune
function recovers more rapidly and does not necessarily have permanent effects. Blomgren et al. [B34] analysed peripheral lymphocyte populations and serum
immunoglobuli~~
levels in 10 long-term survivors of
Wilms' tumour (age: 0.5-6 years). and 6 long-term
survivors of non-Hodgkin lymphoma (age: 3-13
years). All received chemotherapy, and the tumour
dose was 7-32 Gy and 2-21 Gy, respectively. Lymphocyte counts, as well as frequencies of E,EA and EAC
rosette-forming cells, did not differ Goni those of
healthy controls. Serum levels of immunoglobin E
were somewhat lower in patients treated for lymphoma, but for other immunoglobulins h e r e was no
difl'ercnce between patients and controls. The treatment did not have any long-lasting effects on the lym-
phatic systcni. In comparison, adults rcceiving radiotherapy for breast cancer dcvclopcd T-cell lymphopcnia that persisted for a decade. Studies on niore than
900 childrcn from contami~~atcd
areas in Russia and
Ukraine havc not demonstrated any radiation-related
effect on T-cells [L26, L27, L28j.
130. Summary. Studies of bone niarrow suppression,
recovery, latc marrow changes and effects on the
immunc system pertain only to adults. Too few data
exist on the effects of ionizing radiation on bone
marrow and on imniune function to determine or even
suggest critical levels for clinical effects to appear.
CONCLUSIONS
131. Deterministic effects of ionizing radiation in
humans depend on the dosc and can be expected to
havc thresholds below which the radiation effccts are
too small to impair function of the irradiated tissue or
organ. In children, tissues are actively growing, and a
radiation-induced deterministic damage in a tissue or
organ will often be more severe than in adults. Examples of such deterministic scquclae include effccts
on growth and development, hormonal deficiencies,
organ dysfunctions and cffects on intellectual and
cognitive functions.
fractions or after 10 Gy givcn as a single whole-body
exposure. Necrosis occurs after considerably higher
doses, and a whole-brain dose o f 5 4 Gy in 2 Gy fractions over six weeks is generally considered to be a
critical dose for radiation-induced necrosis in children
older than 5 years. For children 3-5 years old the dosc
should be reduced by about 20%, and for children less
than 3 years old the dose should be reduced by about
30%. Brain doses of 1 8 Gy or more of fractionated
radiotherapy have been associated with neuropsychologic effects and decline in IQ.
132. Well-designed epideniiological studies of latc
deterministic effects are generally lacking, and it is
therefore not possible to draw any firm conclusions
about the exact critical dose levels at which various
late deterministic effects appear. Most data concerning
such cffects are obtained from the clinical follow-up
of groups of patients treated for paediatric tumours.
These groups generally comprise small numbers of
patients of differcnt ages and who were followed for
different lengths of time. The treatment modalities
have usually included surgery, radiotherapy and
chemotherapy, and it is not always possible to single
out the effect of radiation alone. A variety of factors
complicate the study of a possible association between
effect and dose, including the underlying disease and
associated clinical findings, other treatment modalities,
the impact of illness on body iniage and lack of school
attendance.
135. Endocrine syslern. The most important endocrine effects of radiation exposure are impaired
secretions of growth hormone, thyroid-stimulating
hormone, gonadotropins, thyroid hormones and oestrogcns/testosterone. Impaired growth has bcen observed
after fractionated radiotherapy to the brain with
cumulative doses of more than 24 Gy and aiter >1 Gy
in a single exposure among the survivors of the atomic
bombings in Japan, whereas impaired growth hormone
secretion has been observed in patients after 1 8 Gy of
fractionated radiotherapy. Hypothyroidism has been
reported in leukaemic children receiving thyroid doses
of 1-2 Gy over 2 - 2 5 weeks from cranial radiotherapy
and chemotherapy. In subjects under 20 years at the
time of the bombings in Hiroshima and Nagasaki,
those exposed to greater than 1 Gy had a significantly
higher incidence of thyroid disorders than those in the
unexposed control group. No study has so far dcmonstrated hypothyroidism in children after a thyroid dose
<1 Gy. There are insufficient data on the effects of
1 3 1 ~to determine a possible threshold dose for the
induction of hypothyroidism.
133. The methods for assessing a given deterministic
effect vary greatly, and this makes conlparisons between different studies difficult. Based on the available
findings, some general conclusions can be drawn.
Children appcar to be more sensitive to radiation than
adults, and, in general, younger children arc more sensitive than older children. Radiation doses indicated in
this Annex are usually given with fractionation over a
period of several weeks. The deterministic cffecls
following radiation exposures ill childhood arc summarized in Table 9.
134. Brain. Leukocncephalopathy, microangiopathy
and cortical acrophy have been reported after cumulative brain doses of 18 Gy or more givcn in 1.8-2 Gy
136. Gomds. The cffects of radiation on the testis
and ovary are age- and dose-dependent. Tbc radiation
dosc required to ablate ovarian function seems to be
around 20 Gy for girls: because of the greater number
of oocytcs in young girls, higher doses arc tolerated
before castration. Infcrtilily occurs in approximately
one third of girls receiving 4 Gy and in almost all
women over 40 years of age. Ovarian failure has bcen
documented in prepubertal girls following 1 0 Gy of
whole-body irradiation and occurs in all pubertal girls.
Amenorrhea has been observed in two thirds of girls
ANNFX
I: LATE D I X R M I N I S T I C E I T E C I S IN C l l l L D l l l i N
899
T ~ i t ) l e1
or doses Tor 3 964% a n d 258-508 i n c i d c n c - c s or c l i n l c ~ ~ l ldyc t r i n ~ c n b ~c lle l e n ~ i i n i s l i cc r r c c l c I n n d u l L c
Eslin1111n
a1 f i v e years t ~ n c m
r dinlion cxlxlsurc a
[11. K21
Approximc darc (Gy)
O~KM
Bone narrow
licornunr
JirU
Whdc
Whdc
Whdc
Whde
Whde
Whdc
lobc
Whdc
Whdc
Whdc
Whd c
Ovary
Testis
Lens
Kidney
Iibw
Hean
Thyroid
Piluilary
Brain
Spinal cord
Bras1
Skin
5 m'
Whdc
100 cm2
Whd c
Eye
k p h a ys
Bladdu
Bonc
Uraer
Mudc
75 cm'
Whdc
10 m?
5-10an
Whde
Injury
UI
jilr !cars
of
doses
i n c h i l d r e n 111 f i v e
[[I.
f o r 190-5% u n d 25%-50% i n c i d e n c e s
years c i R e r r l ~ d i u l i o ne x p o s u r e a
Effcrt in 2S%-50%
ofpaim
5
2
l lypopiaria
Pcrmancnl slcril~ty
Pcrmancnl slcrihly
G~araa
h'rphraclcrosir
L ~ r rfailurc
Pncummi~is,fitrcsis
Puiwditis, pancarditis
llypothyrtidism
I lypopituitarism
h'enosir
Senoris
I\lrcphy. neaosis
Ulccr, severe fihoris
Panoph~halmitis
Lflar. scr~aure
Uccr, cantraawc
Nccroris, fraclurc
Striaurc
Atrcphy
' Ikrcd m ruponrcr d paticats convmlimally trcald uith franimalcd lhcrapculic
Table 2
Estimnh
Eflcrr in J%J%
ofpuirn~
2-3
60
6-12
20
12
2s
45
60
>lo0
150
200-300
>60
A0
>I00
70
100
75
60
60
75
150
1W
5-15
5
3
35
50
40
45
45
50
50
>50
55
55
SO
>I00
x- a gmma-irra&al~m.
o f clinically dclrirnentul dctcrnlinislic
cff~cLs
R21
Approximnrc dart (Gy)
Ordm
fild
Brcas~
Cartilage
5 cm2
Booc
10 cm2
Mlpclc
'
Trcormcnl
Injun a file years
No dercloprncnt
Arres~cdg o u t h
h t c s ~ c dgos*zh
Ilypoflasia
Effcrr in 1%5R
ojpn/;cnu
Efirr in 2SQ-5w
of pnrirne
10
10
20
I5
30
-33
9-30
50-50
Bard m rcsponra of palicnts convcn~~onally
lrcarcd uirh fradlmated thciapcut~cx- a girmn~airrr&al~on
Tat>lc 3
E~CCLS
on UIC hraln In childrcn treated for acute leukaemia delcclcd hy con~pulcdlonioyri~physcnns
Trcornunr
Raiiothcrapy
dasc ro r k t r a i n
Nu&
of
parunrr
Ahamoliria
ppc nf bruh ubnnrmnlirirr dcrccred
Ch~haa"y
~umha
~ocmr
56
40
40
fw
(GY)
IT
24
24
24
24
24
24
24
24
24
24
24
20
18
0
0
0
23
19
24
32
72
lT
14
13
1I
13
17
35
6
lT
IT
25
10
30
45
19
12
11
3
5
1
5
3
IT
TT
IT
IT
lT
IT
IT
IT
IT
N+lT
N+IT
N+IT
44
27
55
12
43
9
8
1
56
54
53
49
43
24
16
11
4
9
Z
19
4
lntracncbral calilicatiau. c o n i d auophy
lntraccrebral ulilicatimr, cortical atrophy
lntrncerebral calificatimc, cortical atrophy
ln~rnccrcbralwlilicatims, cortical auophy
lntrrccrebral colilicutims, cortical atrophy
ln~rncercbralcalificatims, conical atrophy
lntrncerebral calificatimr
Conical atrophy
lntraccrcbral caliliutimr, conical atrophy
Conical atrophy
lntracerebral cslilicatims
Cortical atrophy
White mollcr hypodencity, cortical atrophy
Cortical atrophy
Cortical atrophy
Cortical atrophy
[B6l
IPS]
IRS)
11'7
ICl41
[Ell
Iwsl
PSI
ISSs]
I031
I0131
[Dal
I021
[Ell
[OlJI
Ips]
IT = i n t n t h m l rnethotrexatc and IT + I V = inaathcul and intravcncur rncthoucxatc.
Table 4
EKccts on Ulc hraln of n~dlolhcrapyLo Ule ccntrnl nervous syslcni In ct~lldrcn
Eficr
Lcukocnccphalopa~hy
CNS therapy
>20 Gy i n 15-2.0 Gy franionr
Comments
Rrf.
Y m n g children m a c sensitive
W6. P3.
R41
p ~ r vsystemic r n c t h c ~ u a t c
10 Gy whdc-body irraQatiw
Mineralizing mincangiopnthy
>IS Gy i n 1.5-2.0 Gy fracl~onr
Y w n g children more sensitive
[B4. D5]
Mid atrophy
>I8 Gy i n 1.5-2.0 Gy h s n i m
Sevciat atrophy in young children
IC3. D3,
and i n t n t h m l rncthotrcxate
G r e b n l nmcsir
>54 Gy i n 1.8 Gy hadions
DS,U]
lB35, K2j
ANNM 1: U T E DEIEKMlNlSnC EFTECTS IN CliILDR1.N
901
TIIhl e 5
Avcrt~ge~ d u l hclyhlc
t
of Individu~llscxposcd In the lowcr dose groups In Hiroshln~trt ~ n dN I I R I U I~I ~n~ d
under I S ycrm old ~ t the
t LInlc of boml~lng
113141
Abaage dvl~
heighr (cmj in dare group
Age a time
Sa
o/-int
iycorsj
0 GY
sO.09 Gy
0.10-0.99 Gy
> 1.00 Gy
Ilimabimr
Male
0-5
6-1 1
12-17
166.4
1623
164.3
166.1 "
164.2
163.6
165.9 "
166.3
164.3
161.5
1622
163.4
Female
0-5
6-1 1
12-17
153.3
1325
1521
153.6 "
153.6
1523
IS29
153.6
152.2
150.4
150.5
151.9
Nqsrnki
*
Male
0-5
6-1 1
12-17
166.2
164.0
163.2
166.2
164.1
163.9
166.2
1627
161.8
Female
0-5
6-11
12-17
1528
152.4
151.8
1529
151.3
151.6
150.8
151.5
151.2
Sigificandy diffuml (p c 0.01) cornpard wilh the svcragc d group exposed 10 > 1.00 Gy.
Significantly different (p c 0.05) compared uith the average of g o u p exposed l o > 1.00 Gy.
Table 6
Average adult hcighls of children exposcd in the higher dose group in Hiroshima und
undcr 18 yulrs old ut the tinic of bombing
[Dl41
r
Sa
A ~ w o g rd u l l heighr (rmJ "
Age a lime
of bombing
(VCWS)
In dare group 1.0-2.49 Gy
In dare group > 2.5 Gy
Male
0-5
6-1 1
12-17
164.2 (12)
162.7 (13)
163.2 (43)
159.8 (18)
161.5 (lo)
163.5 (45)
Female
0.5
6-11
12-17
151.8 ( 1 1)
150.4 (17)
1521 (58)
149.8 (23)
150.5 (11)
a1.7 (59)
Tr~hle7
Average hcialll of Indivitltrrtls l'ollowed in the Adult Ilcallh S111dyrtntl untlcr r t ~ c1 0 yer~rsnt the tlnlc of homhing
1141
h'umba of inlbrduals in parcnthesu.
tlomopncily I ~ dI ~ r i a n c cf a lour dcxc goups; dl = 3.
Table 8
Thyroid hyporunction in ir~dividui~ls
cxposcd lo Trtllout rndiutiorl in lhc hlitrshttll lslrrrtds
[C161
Incidmcc of thyroid h>po/unctionfur variour r c t h n l d dm-
AXc
lo rhc rhvroid
a!a p w c
(vcars)
0 GY
< 1.W (;?.
1.00-2.00 Gy
CIO
1n2u(0.4%)
a10
1/37] (0.3%)
0164 (0%)
11100 (1%)
1/12 (8%)
2
2.00 (;y
sns (31%)
4/45 ( 9%)
Tnl)le 9
~ ~ l i nofi lowest
~ ~ l m~d i ~ ~ t l odoses
n
~~ssociatcd
wilh 111k
dclcn~~lnictic
cll'crlc I ~ I I Icw~x~surc
II
in cl~lldhoodlo
in thc form or ~rnctlon~~tcd
rntllolliempy
Ionizing mdlr~Uon,~1su111ly
1:flccr
O r x ~
Tatir
Germ cell depletion
lrydig cell dysfunaim
Ovary
Amcnonhca
Infcrtilily
Ablntim
Thyroid gland
tlypothyraidism
Brain
G p ~ ~ i funarms
vc
1Lstopn1hdogic changes
Xcurocdarinc elleas
Durc (Gy)
0.5
10
> 0.5
4
M
> 1
18
18, (10
>
I&(>
Brcan
I lypoplaria
2
Eye
G~araa
2
Lung
Ebrosir
8-11
Liker
Fibrosis
12
Kidney
Reduced acatinine clcanna
I2
Skdc~m
Skdcld changes
10
Cardiovasmlnr system
Cardimyopathy
40
Bone manow
l lypofunctim
Single whdc-body exposure.
1 ")
hruffiacnt data avarlablc
UNSCMR 1993 EPORT
903
Chcmolhcrapy
(inlravcnous
rnclho~rcxalc)
Radioihcrapy
(cranial irradiation)
Figure I.
Approximi~k incidence r a t s of clinical leukocnccph~~lopnlhy
in patients trcnted by
cranial Irradiation, chcmothenpy or cori~binntion thcrupics.
P4I
I
75
I
100
10 SCORE
I
125
Figure 11.
1Q score dislrihution in children t m k d for ~ c u l elymphocytic Ieubcnila
hy cranial radiolhernpy (RT), inlrathecal mclholrcxute (IT) or inln~venousn~clhotrexuk(IV).
Ill21
TIME AFTER RADIOTHERAPY (years)
Figun? 111.
hfaximurn growth hormone response Lo growth-ho~monc-rclcusing hormone
in children lrcntcd Tor brain turnours hy rndiothcrupy.
[W
Cranial
0 Craniospinal
Othcr
None
I
0
I
1
I
I
I
2
YEARS
3
4
Figure IV.
h l u n s h n d a r d devlntion score or hciphl in rhildrcn Lretlkd ror mulipnunt disease by rndiotheri~py
to various siks. HcsulLs tor those receiving crnnlal nnd crnniospinal trealrncnl
were significantly lower ( p < 0.001) a1 1 4 years Ulun tit the t l n ~ eo r lnltial lrenlrncnt.
IG2l
DOSE (Gy)
Figum V.
Ihymid-stimuli~ling hornionc levels In 116 pnlicnls irgcd 16 ycurs or lcss
Lrenkd for Hodgkin's dkcusc by rudiolhcrupy.
IC 151
20
30
AGE AT TSIEATMENT ( y e a s )
Figure V1.
I'mbuhlllty of rcgulnr menses In wonien ln?ll(cd for Hodgkin's disease
Ily lolal lyniph Imrdltrtion 07.1) tind/or chcniolhcnipy.
lHlZl
ANNEX I: IAX: DETERMINISTIC EFFECIS IN Cl IllnREN
907
AGE AT lyIRST IRRADlAnON (ycars)
0 Standinkheight
Silting
ighl
AGE AT 1:IRSI' IRKADlAnON (ycan)
1:igut-e VII.
Ileviution fmnl mean s b n d i n g and silting hcighk in rhildrcn lrei1Lcd by rudiothcri~py
with c25 Gy o r >35 Gy.
[I'lOl
4
1 year old
1-5 years old
11 years old
Figure V111.
I~oscslTccl rclutionship Tor bone shortening in childrcn Lfcutid hy mdiothenpy
that included cpiphysial pllrle irrudiation.
lG8l
-100
1
I
I
I
I
I
1
0
2
4
6
8
10
12
DOSE
(GY)
Figure IX.
1)iIrercncc In t ~ r c u tvolurnc in 53 women treatid in childhood Tor hirerriangioniu
by radiotherapy ot the hrcusl region.
PI
A N N M I: W l E DEERMINISIIIC EFFECTS IN ClIlLDREN
909
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ANNEX I: IAm DEERMINIS
C8
C9
C10
C11
C12
C13
C14
C15
C16
Calissendorff, n., P. I3olmc and M, cl-Azazi. 'lhc
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Dl
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D8 Duffner, P.K.. M.E. Cohcn and P. Thomas. Late
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D9 Danoff, B.F., F.S. Cowchock, C. Marquettc ct al.
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,
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