UNSCEAR 1993 Report - Annex I - United Nations Scientific
Transcription
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. 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