a clinical study of radiation cataracts * by george r
TRANSCRIPT
A CLINICAL STUDY OF RADIATIONCATARACTS *
BY George R. Merriam, Jr., M.D.**
SINCE the original experimental wvork of Clhalupecky (i) in 1897,the possibility of radiation cataracts hias been appreciated. Theearly investigative work has been reviewed by Desjardins (2) andPoppe (3). In recent years, interest in this complication of therapylhas increased considerably, particuilarly wvith the development ofhiiglher energy equipment and the expanding wvork witlh radio-active materials. A great deal of experimental work has been doneon animals in an effort to determine the dose of various qualitiesof radiation that wvill produce a cataract, the manner and rapiditywvith wvhich the opacity develops, the pathologic and metabolicchanges that result, and otlher related problems. The work of suchinvestigators as Poppe (3), Von Sallmann (4-10), Cogan (1 1-13),Kinsey (14-16), Evans (17, i8), Leinfelder (19, 20), Upton (21, 22),Nordmann (23), and others should be consulted regarding theseaspects of the problem.The underlying stimulus for this investigative wvork is the fact
that so little is knowvn about radiation cataracts in humans. Theclinical appearance was originally described by Rohrschneider (24),and more recently by Cogan, Donaldson, and Reese (25), and isnow well established. General times of onset have been given fromthe reported cases, but not in relation to the many variables, suchas the quality of radiation and the dose and duration of treatment.Furthermore, the essential problems of the minimum dose that
* This work was supported in part by a grant from the Snyder Foundation.The author wishes to express his sincere appreciation to Miss Elizabeth F. Focht
of the Physics Department, Memorial Center, New York City, for her invaluableassistance an(l technical advice.
** From the Head and Neck Service and the Department of Physics of theMeemorial Center, New York City, and from the Institute of Ophthalmology, TheColumbia Presbyterian Medical Center, New York City.
George R. Merriam, Jr.will produce a lens opacity, the incidence of cataracts at variousdosage levels with varying methods of treatment, the relativeeffects of single and divided treatments, the effect of dose andduration of treatment on the time of onset of a cataract, the effectof dose on the incidence of stationary or progressive opacities, theeffect of the quality of radiation, and the relative sensitivity ofyoung and adult lenses still remain unsolved.
Approximately 81 cases of radiation cataracts in humans due toX or gamma radiation have been reported in the literature to date(26-33). However, in only 13 of these is the dose given or theradiation factors stated so that the dose can be calculated. Lein-felder and Kerr (3o) reported 2 cataracts in patients whose lensesreceived over 1,4oor (200 KV in 3 weeks). Hunt (3 i) reported atotal of 5 cases-2 from X ray and 3 from radium. In the 2 X-raycases, one lens received a dose of over 4,5oor and the other 775rwith 130 KV X ray. The treatment time was not specified. Hunt'ssmallest calculated dose to the lens in the radium patients was1,35or. In another of his radium cases (Case 4), Hunt stated thatone eye developed a cataract eight years after treatment, and hiscalculated dose to the lens was 2,400r in five days. The patient'sother eye subsequently developed an opacity eight years after treat-ment, but no estimate of the dose was given. Schulz and Heath(32) reported a lens opacity which developed in an eye exposed to1,2oor, but no factors or treatment time were given. Cogan andDreisler (33), in the most recent report, found a radiation cataractin 1 of 3 patients whose lenses received 6oor (200 KV delivered intwo days). They reported 4 other cases-one with a dose at thelens of 8oor at 2oo KV in one month, the second with a dose of1,ooor in three weeks at 200 KV, the third with 2,400r in a singletreatment at 2oo KV, and the fourth with 2,400r in ten days at1,200 KV. Ham (34), in a recent review article, has suggested thatsoor of X or gamma rays be regarded as potentially dangerous tothe human lens, although no mention is made of the duration oftreatment. In respect to the dose that will produce a cataract, thisis the extent of our knowledge at the present time.
At the Second Conference on Radiation Cataracts held by theNational Research Council in 1950, a report was made on a groupof patients who had developed lens opacities following treatment
6i2
A Clinicail Shi'dy oJf Radiation Cataracts
withl X rays of varyinig energ-ies, or radium 05). The minimutm(calctlilated dose to the lens, in the patients studied at that time, wvasgiven as 1,5oor wvith X rays. In this present study, these andadditional patients have been measured by the method to bedescribed. As wvill be seen, many patients hlave since been found inwh1lomn the mininmum dose is considerably lower than that previ-ously reported.
PLAN OF INVESTIGATION
TFle purpose of this sttudy has been to collect as large a series ofradiatioin cataracts as possible, and to actually measure the amountof radiation to the lens and analyze the available data to gaininformation concerning the followving problems:
i. The minimnutm close to the lens that wvill produce a cataract.2. The percent incidence of cataracts at increasing dosage levels.3. The effect of dose on the time of onset of a cataract.4. The effect of dose on the incidence of stationary or progres-
sive opacities.5. The relative effects of single and divided treatments on the
above.6. The relative sensitivity of youLng and adult lenses.
Dturino' the past tlhirty years, a large number of radiation cata-racts have been seen in the Head and Neck Service of theMemiiorial Center, New York City. In 1939, Reese (36) reported ontile operative treatment of stuch cases, but no attempt wvas made toestim-ate the dose that produced them. Some of the cases reportedin hiis series are in this study, but many are not, since the radiationfactors used in the early cases could not be reduplicated.During the past ten years, the files of the Memorial Center, Newv
York City, have been searched back to 1925, as wvell as the recordsof the Radiotherapy Department of the Institute of Ophthal-nology, Coluimbia Presbyterian Medical Center, Newv York City,whliiclh wvas started in 1947. A total of ioo cases of radiation cataractwvere found in which the radiation factors could be reduplicated.In every instance the eyes wvere examined by an ophthalmologist1
I Dr. A. B. Reese, New York City, examined most of the patients, and the authorwvishes to express his appreciation to Dr. Reese for the tuse of this material.
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A Clinical Study of Radiationt Cataracts (i23
anid the diagnosis establislhed by means of the ophtlhalmoscope orthe slit lamp biomicroscope. Approximately one-fourth of the caseswas examined by this last method. Cases wvliichi did not lhave anocular examination, or in whlich the etiology was in question dtueto some complicating factor (previous surgery, trauma, lhemor-rhiage, or uiveitis), or for whliich the dose to the lens could not bedetermiined wvere excluded from this grotup. Also excluded wverecases vith early peripheral dots or vacuoles, wvhich occurred inelderly patients whlere the possibility of early senile changes madean accurate diagnosis of radiation changes uncertain. Such earlycllanges wNThen found in children wvere included if the other lenswere clear and there vere no otlher complicating factors.
In this study, a radiation cataract is any clinically recog-inizable opacity having the clharacteristic appearance, irrespectiveof wvhiether or not vision was affected.
In addition to the cases wvitlh radiation cataracts, 73 cases wverefound all of whiiclh had had irradiation to the head, but which didnot develop lens opacities.2 All of these patients had eye exami-nations from tlhree years and one month to twenty-eight years andsix months after the completion of treatment. Patients with eyeexaminations less than three years after therapy wvere excluded.The averaoe time of the last ocular examination after therapy wvaseight years and 1 1 months. For this study, therefore, there isa total of 173 cases (ioo with radiation cataracts and 73 wvithoutlens opacities).The actual amount of radiation to the lens for each case has
been measured by the method to be described. The cases are listedin Tables 1 and 2, in which are showvn the age and sex of thepatient, the condition for which treatment was given, the treat-ment factors, the dose of radiation to the lens, the duration oftreatment, the time after treatment wvhen the cataract was firstseen, wvhethier the lens opacity was stationary or progressive, andthe length of follow-up. Most of the figures in Tables i and 2 lhavebeen rounded off to the nearest 50 for the highest doses. In Figure
' An additional grooLp of 52 cases which had radiation to the head and which hadnlo symptoins of impaired vision five years or longer after the completion of treat-ment was also measured. These cases have been exclutded since they did not have eyeexaminiations. It is interesting, however, that they did not alter the percent incidence.
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George R. Merriamz, jr.8 they wvere left as measuired in order to slhow the individual casesmore clearly.
MNIETHOD OF MIEASURENIENTS
In radiologic imeasurements, phantoms of various materials areemployed. Their purpose is to simulate different liuman tissues indensity and atomic nutmbers, and thus permit measurements to bemade in various areas of the body. Such measurements are essentialfor all depth dose calcuilations, and are the basis for all standarddepth dose clharts.Phantom measturemients of the partictular type to be described
hlave not, as far as could be determined, been made previously.The only stuidy approxinmating this is the recent one of Cogan andl)reisler (33).
FIGURE 1. PHANTOM SKULL USEI)
FOR MEASURING DOSE OF RADIAT'IONTO THE LENS
Wax eyeli(ls and plastic cye with ioniiza-tion chamiber in position of lens can lbeseen. Apex of orbit filled with wax, asseen on right, to maintain eye iniproper position. BoILtIS used to fill cal-
varium seen above.
A phiantomn (Figuire i) wvas devised employing a skuill of averagesize covered wvith- aIflixture of paraffin and beeswvax (equial partsby wveight) hiaving unit density. The skuill wvas coated in such amanner and thickness as to simulate normal skin and subcutaneoustissue and thus approximate the same amount of scatter to the eyefrom these structures. The cranial cavity was filled wvith bolUS.3
3This is a compositioi of sucrose and magiesiLM carbonate in the form of small,hard spheres with an average diameter of abouit 2.3 mm. The electron denisity and(effective atomic number are well within i percent of the values for water. It hasnbcn
6i3o
A Clinical Stutdy of Radiation Cataracts 631Plastic eyes (FiguLre 2) of approximately unit density wvere con-structed. A hole wvas drilled in one side, so that a small Baldwvin-Farmer condenser ionization chamber (37) wvith a measuringvolume 6 mm. long and 5 mm. in diameter could be inserted intothe exact position of the lens and tlhtus measure the amount oflirect and scattered radiation to this strtuctuLre. The eye is hlollow
FIGURE 2. PLASTIC EYE USED FORMEASURING DOSE TO LENS
Ionization chamber is inserted through -hole in side into position of the lens.
FIGURE 3. PHANTOM IN POSITION
FOR PERORAL TREATMENT SUCH AS
WAS USED FOR CARCINOMA OF HARD
PALATE OR NASOPHARYNXIonization chamber can be seen in posi-
tion to meastire scattered radiation.
tested for transmission for quialities ranging fronm 15 KV througli g9 KV, 920 KV, amillion volts, and gamma rays from raditumn, and no appreciable variations friom theresults with water have been cletecte(l at any quality. (Information supplied by therincolnshire Radiotherapy Center, Wkar Memorial Hospital, Scunthorpe, Englanid.)
George R. Mer-rilam, Jr.
and can be filled withi bolus. T-lie apexes of the orbits of the phan-tom were filled with wax, so that the eyes were in their normal posi-tions. Lids, also of wvax, were made, and at the lateral canthi aportion was cut away to allow the clhamnbers to be inserted andremoved.The plhantom was treated as wvas the patient for all the variouis
types of lesions included in the series. The types of lesions forvhich measurements wvere taken include hemangiomnas of the lids,
FIGURE 4. ONE OF ORIGINAL MASKSUSED IN TREATMENT OF A CARCI-NOMA OF THE ANTRUM AND NOSE,SHOWN IN POSITION ON THE
PHANTOM
FHGIJRE P.PHANTONI IN POSITION
FOR TREATMENT, UJSIN(G LEAD MASK
SHOWVN IN FIGURE 4tIhe eye is in the (lirect bearn, although
shiel(led 1)w92.0 111111. lead.
orbit, clheek and moutlh, and variouis types of carcinomas of thelids, eye, nose, nasopharynx, sinuses, clheek, palate, and gutm. Oraltreatments wvere reduplicated on the phantomn whlen indicated(Figure 3). In each case the factors, slhielding, and positioning verereduiplicated as closely as possible fromi the data available in the
fi32
A Clinical St i(ly of' Radiation Cataracts
chart, wvhiiclh usually included diagrams or plhotograplhs. In somecases, particularly for the group of retinoblastomas, the position-ing was clhecked by taking radiographs witlh the therapy machine,tusing lead markers placed at the estimated site of the lesion. Theoriginal slhields or duplicates were emiployed. Every mieasuremnentwvas reclhecked several timnes. In miiost instances nmeasurements were
FIGIURE 6. PHANTl-OM IN POSITION FI(GURE 7. PHANTOM WIT'H 2.0 MM.
FOR TREAT'MENT'OF CARCINOMA 01 LEAD SHIELD PROTFECTING THE EYE
ANTRUM THROUGH AN ANT'ERIOR Dose to b)oth eyes measure(l.PORT
The eye is at the edge of the beam aIl(Iis not shielded. Dose to b)oth cyes
measured.
made to both eyes. Somne of the types of setuips anid shiields are
shl(wn in Figures 4, 5, 6, and 7.It is appreciated that in attempting to reduplicate therapy tlhere
are numerous uncontrollable variables. Among sUchi factors arevariations in the size and shape of skulls, the thickness of thetissues, the interorbital distance, the configuration of the nose,movement by the patient, and the shielding of the X-ray tubes.
6)33
(634 (George R. Merriam, jr.It is for this reason that intervals of 2oor hiave beeni chlosen, as wvillbe seen, in tabulating the dose to the lens.The X-ray voltages employed ranged from 100-250 KV with a
H.V.L. of i.o mm. Al to 2.o mmii. Cu. The chambers were cali-brated for the quality of radiation uised, and freqtuent checks madefor leakage. The clhambers vere read in a Baldwvin-Farmer elec-trometer.When raditum plaques wvere employed, the original plaqtues,
loaded in a similar manner, vere taped or strapped to thephantom. Every effort was made to reduplicate the positioning ofthe plaques. In most instances plhotographs of the original lesionwere available, wvhiclh greatly aided in the proper placing of theplaques.
WVIhen gold seeds wvere used, these wvere distributed in a piece ofcork the same size as the area treated, and taped to the proper areaon the phantom. If treatment had been by a naso-pharyngealapplicator, this wvas inserted into the phantom in approximatelythe same position it had occupied in the patient. The ionizationchambers were calibrated for radium whenever it was used.The X-ray and radium doses have been grouped in this study,
and are all reported as roentgens at the lens. This was done pri-marily because much of the radium was implanted at somedistance from the eyes, and therefore the quality of the radiationwas decreased somewhat by scattering before reaching the lens.Also, a relative biological effect of the twvo is known fairly defi-nitely only for a skin threshold erythema (38). Moreover, thedosage intervals taken in plotting the findings in Figure 9 arerather wvide (200r intervals), wvhich would largely mask any relativebiologoical effect. In the recent experimental wvork of Upton andhis group (22) on mice, a relative biological effect for severe lensopacities of 1.2 to 1.3 was found wvith X rays of H.V.L. 0.55 mmn.Cu compared to Co 60 gamma rays taken as i. A similar ratio wasfound for X rays of H.V.L. 1.93 mm. Cu as compared to gammarays from a nuclear detonation. This is wvitlhin the 2oor limits usedin Figure 9 before the ioo percent incidence is reached. Thisfigure includes all degrees of opacities. In the other tables thedosage intervals are even greater.
A Clinical Study of Radiation Cataracts
RESULTS
DOSE TO LENS WHICH PRODUCED A CATARACT
In general, for a given (quality of radiation and dturation oftreatment, it wvouild be expected that because of individuial vari-ations of the patients there wvould be a threslhold or miniinum doseat whlich a small percentage of the lenses wvould showv a certaindegree of opacity. As the doses increased, a larger and larger per-centage of tlie patients wvould be expected to slhowv lens changes,uintil, at a large enouiglh dose, ioo percent of the lenses slhouilddevelop cataracts.
In an uncontrolled series suich as this, it is impossible to deter-miine accurately the absoltute tlhreshold. The miniium ldoses givenbelowv tlhus represent the smallest amount of X or gamma radiationthat prodtuced any degree of opacity in the cases studied.
It is also impossible to classify the cases according to dose anddegree of lens opacities, as can be done in large numbers of con-trolled experimental studies wvitlh animals. Many of the casesreported here are dead and numerous others have refused to returnfor examination. Repeated efforts wvere made to contact all theliving patients and reexamine their eyes, btit the response wvas notsuifficient to permit a correlation of dose atnd degree of opacity.Trhe miost that can be done, as will be discussed below, is to classifythe cataracts according to wvlhetlher the opacities wvere stationary or
progressive and attempt to relate tlis to dose.For the entire group of moo cases of radiation cataracts, the
dosage range was from 2oor to 6,goor at thie lens. This includessingle and multiple treatments and a wvide range of duration oftherapy. For more accurate analysis the group has been subdividedinto single treatments, inultiple or divided treatments from threewveeks to three months, and divided treatments over a periodgreater thian tlhree montlhs. The results for 97 cataract cases and 70non-cataract cases are showvn in Figture 8. Tlhree cases wvith lensopacities are oInitted from-n Figure 8, since their treatmnent timeswvere twvo days, ten days and twvo wveeks. These do not fit into anyof the tlhree categories showvn. The dose to the lens in these cases
635
636 C(eorge R. Merrhtiam, Jr.
wvas 65or, i,95or and 3,75or, respectixvely. Flhree noni-cataract caseswere also excluded, since they hiad treatmlenit tiiimes of one, twvo,and two and a lhalf weeks. Their doses wvere 8or, 8or and 25r. Alldoses are given in r to lens. Eaclh line above the lhorizontal linerepresents a cataract, and those belowv are non-cataracts. Individuialcases are not slhown separately for doses over 2,ooor.
200 400 600 800 1000 1200 1400 1600 1800 2000
s SINGLE TREATMENT - RADIUM ONLYCATARACT
11I1 1 1111111 Ii __111111 111111 ' __
NON-CATARACT
DURATION OF TREATMENT - 3 WEEKS - 3 MONTHSRADIUM AND X-RAY
CATARACT
+ 13 GREATERI |I I l llTHAN 2000r
91l11111111111 11I I 11P1111 t IIII llNON- ICATARACT
DURATION OF TREATMENT - OVER 3 MONTHS
CATARACT RADIQM AND X- RAY 1-15 GREATER+ THAN 2000r
111 111I lll 11 II 1 1 1, 1NON- tCATARACT
200 400 600 800 1000 1200 1400 1600 1800 2000
DOSE IN r AT LENS
FIGURE 8. DOSES OF X OR GAMMA RADIATION TO LENS11n 97 cases of radiation cataract and 70 cases withouit lens opacities.
Sinigle Treatments. There are 37 patients whlio received theirirradiation in a single treatment, and 20 of these developed lensopacities. The other 17 patients received doses from 4or to 175r tothe lens witlhout developing lens clhanges. Above this dose, fromn2oor to 1,15or, all the cases developed cataracts attribtutable toirradiation. The fifty-tlhree-year-old patient wvith the lens opacitythat resuilted fromn thie minimum dose of 200r lhad hlis first eyeexamination twenty-two years and one montlh after treatment.The cataract wvas stationary. --
It is interestingo that all of these l)atients wvere treated wvitl
A Clinical Study of Radiation Cataracts
radlitimi plaqtues. This (toes niot l)er se iindlicate a greater sensitivityof the lens to gamma radiationi, but simiply ineans that there wereno single exposures to X radiation in this group.
Aliltiple Treatments (three wveeks to three months). A total of87 cases in this grouip vas measured, anid of these 49 developedradiation cataracts wvithi doses to the lens from 4oor to 6,ioor of Xan(l gamma radiation, delivered in three wveeks to three months.Of the four lowvest doses in this grouip, twvo cataracts resulted fromX rays and twvo from radium. The lens opacity wvith the dose of4oor wvas first seen twvo years five montlhs after treatment, and thiecataract was stationary. The duration of the treatment wvith radiumseeds has been taken as three weeks. At this time, about 97 percentof the total radiation has been given. These 87 cases include adultsand children. The latter wvill be disctussed separately elsewhere.
Divided Dose (over three months). There are 43 cases in thisgroup, of whichC 28 developed cataracts wvith doses to the lensrangin,g froln 55or to 6,goor. The lens opacity with the dose of55or wvas first seen three years eight months after treatment, andthe cataract wvas progressive.A comparison of the lowvest dose at wvhich the lens changes began
to appear in each group is interesting. For the single treatmentgroup the lowest cataractogenic dose fouind wvas 2oor, for the groupwvith divided doses of tlhree wveeks to tlhree imonths, it wvas 4oor, andfor the groupi) wvitlh greater fractionatioin it vas 550r. This is idi-cated by the arrowvs above the lines on Figure 8. These figuressuiggest that the tlhreslhold dose increases vith the duration oftreatment.
It shouild be emplhasized that in the single treatment group thefact that there vere no cases wvithouit cataracts above 2oor probablydoes not mean that the lens cannot tolerate higher doses adminis-tered in a single treatment. Ratlher, because of the small numberof cases (fouir) wvitlh doses to the lens in the range of 2oor to 5oor,no non-cataract cases wvere found. Fuirther studies at these dosagelevels are necessary to determine imore exactly the upper limit oftolerance.The same quialifications apply to the orotup wvitlh a treatment
timne in excess of tlhree imionitlhs. Howvever, the nuimber of cases inthe grotip wvitlh a treatmnent timne of tlhree veeks to three montlhs
(i'17
George N. Merriamn, Jr.
is the laroest, and tlherefore the resuilts would be imiore accurate.This is the lengtlh of time in which imost treatmlent is given, whliclhaccounts for the larger size of the group. By the saimie token, it alsomakes this information the most applicable clinically.
In these samie three categories, the highest dose at the lens thatdid not produce lens opacities is of some significance. These pointsare indicated by the arrows belov the lines on Figure 8. In tllesingle treatment group the maximutm non-cataractogenic dose wvas175r in a patient followved eight years and seven months. In thegroup whose treatment was fractionated from three weeks to threemonths the largest dose found wvithout lens changes wvas i,ooor.The treatment time was twvo months twvo wveeks and the patientwvas followed thirteen years and eight months. WVhere the frac-tionation of therapy wvas greater than thiree months, the maximtumdose without a cataract was i,ioor. In this case the treatment tinmeextended over one year and six imionths and the patient wvasfollowed twenty-twvo years. This seems to indicate that, as theduration of treatment is prolonged, the dose at which there is aioo percent incidence of cataracts also increases.This effect of fractionation is in agreement with general radio-
therapeutic experience, in which it is known that if a certain doseis given in several fractions the effect wvill be less than if the samedose wvere delivered at one time. However, there are several vari-ables, among which are the time between exposures and theamount of each exposure. This suggests that recovery takes place ina given tissue between treatments. The recovery rate is different fordifferent types of cells, and, as Quimby (39) has pointed out, is thebasis for divided dose therapy. Little is known regarding thedegree of recovery of the human lens from single or fractionatedradiation. The findings in the present study, however, tend toindicate, as suggested by Failla (40), that there may be some degreeof recovery, in that with greater protraction of treatment a hiigherdose is necessary to produce a clinically recognizable opacity. Noindications as to the mechanism of this recovery are available frointhis study.
INCIDENCE OF CATARACTS AT VARIOUS DOSAGE INTERVALS
In order to deterinine the incidence of lens opacities at varioulsdosage intervals, a group of patients who had received measturable
638
A Clinical Stuidy of Radiationt Catariacts 6)39amiotunts of radiation to the eye wvitlh a similar duration of treat-ment wvas sttudied. For eaclh dosage interval, the number of cata-racts wvas compared to the number of non-cataracts.The results are showvn in Figure 9 for a group of i i i patients.
This includes 49 cataracts and 40 non-cataracts wvith a treatmenttiine of three wveeks to three months, and 22 cataracts wvith a treat-inient tiine of over three montlhs. The cases are tabulated at 2oorintervals for the reasons previously given. The single treatmentgroup is not slhowvn, since it lhas been discussed above. Also ex-cluded are the three cataract cases wvith treatment times of twvodays, ten days, and twvo wveeks, and three non-cataract cases Nwitlfractionated treatment times of less than three wveeks.Only one of the entire series showved a significant amount of
radiation to the lens from 100-140 KV X ray, and this wvas due toinadequate shielding. This quality of radiation, tlherefore, doesnot contribute significantly to that part of the histogram slhowvinga p)ositive incidence of cataracts. The injury to the lenses resultedfrom treatment wVith 200-250 KV X ray and radituiml.
In the grouip wvith a treatment time of tlhree wveeks to tlhreemonths there wvere no cases in the dosage ranoge from 1,15or to1,35or. However, there wvere thlree cases, all of wvhomii had cataracts,in this range in the group wvith a treatment time greater tlhani threemonthls. If the group wvith the longer treatment timle reaclhes ioo
percent incidence at 1,15or, it can be assuLmed that the cases vitla slhorter treatment time wvould also be at this ioo percent level.Furthermore, all 43 cases over 1,15or, irrespective of dturation oftreatment, developed lens opacities. Therefore, in order to comn-plete the histogram, the cases with doses to the lens over i,i5orthat had a treatment time of over thlree months are slhowvn inFigure 9.
It is apparent in Figure 9 that in the group of cases wvitlh atreatmnent time of three veeks to tlhree months no cataracts wvereobserved in the 20 patients whlose lenses received froln 40 to 35or.In the range from 35or to 55or, 4 of 9 developed lens opacities.Thie mninimum dose in this range wvas 4oor. From 5sor to 75or, 6of lo patients developed lens changes. From 75or to 95or, 15 of 25patients lhad cataracts, and from 95or to i, 15or, 3 of 4 developedopacithes.
In the o-rotip of cases in ikTI-iich divided treatiiieiits ivere ,given,
6George R. Merriam, Jr.
over a period greater than three months, there were 5 patientswhlose lenses received less than 35or, and in whom cataracts didiot develop. In the same dosage range from 35or to 55or, I of 4
patients developed a lens opacity. The dose for this case was 55or.In the range from 55or to 75or, 2 of 4 cases developed cataracts;from 7sor to 95or, 3 of 5; from c9or to l,l or, 1 of 2, and above
21OVER 1350r
100 (~) (!21 OVER 1350 )
80 Duration greoter than 3 months
w0Z 60w
z40 NUMERATOR a CATARACTS
Z 4 6 15 3 DENOMINATOR z NO. OF CASES
0 9 10 25 4cr 20Non-catoroct cases followedw 20-
a. 203 yeors to 28 yeors. Av. 9 yrs.0
200 400 600 800 1000 1200 1400100 300 500 700 900 1100 1300
DOSE IN r AT LENS
FIGURE 9. INCIDENCE OF CATARACT S
TI'reatment time three weeks to three months.
this the incidence wvas ioo percent. The number of cases is smallin each dosage range, and for this reason the cases wvithl less tlhan1,15or at the longer duration have not been showvn on thehiistogram. However, as wvould be expected, the group wvitlh a treat-ment time of over three months showved a lower incidence of cata-
racts for a given dose than the group wvith the treatment time ofthree wveeks to three montlhs.The single treatment grouip showved a 1oo percent incidence
above 2oor. The ioo percent incidence for the group wvitlh a
treatment time of three weeks to three montlhs falls betwveen theincidence of the shorter and longer times, as would be expected.
In viewv of the small number of cases in each step of the histo-gram in Figure 9, percentages have been avoided. Further studiesare necessary to more exactly define tlhe percent incidence of cata-
640
A CliTnical Study of- Radiation Cataracts
racts, particularly at the dosage levels of 350r to 55r,5ror to 7sor,and gsor to i,i5or. Nevertheless, the cases reported here give anindication of the incidence that may be expected if a lens receivesa given dose in the usual couirse of therapy. Furthermore, thegroup of 25 cases in the dosage range from 7sor to 95or is of suf-ficient size to make the incidence seem reasonably accurate. Thusone could expect that if, in the coturse of therapy, it vas calculatedthat a lens would receive this amount of X or gamma radiation inthree wveeks to three montlhs, the patient would have about a 6opercent chance of developing a cataract. In addition, as is shown inTable 3, about half of the cataracts would be progressive, wvith
TABLE 3. STATIONARY AND PROGRESSIVE CATARACTS
Treatment Time Three Weeks to Three Months (dose in r at lens)
Dose 35or to 55Ir to 751r to 951r to II5Ir and55or 75or 95or I I 5or over *
Number of cases 3 6 15 3 24Progressive o I 6 2 2 IStationary 3 5 7 I 2Indeterminate I 0 2 0 I
* Over I45or there were progressive cataracts in only 20 cases.
considerable loss of vision. Similar reasoning can be applied toeach dosage range, wvitlh the reservations imentioned above.
TINME CATARACTS FIRST 0)BSERVED) AFTER TREATMENT
The latent period fromi the time of treatment wvith X or gammaradiation to the tine of the appearance of the lens opacities inhumans has been estimated in the literature as from six months tothirty-five years, vith an approxiimate average of twvo to three years(3, 28, 29, 31, 33). This is a difficult time interval to estimateaccturately, since most of the cases in the literature and in thispresent series wvere not examined rotutinely. Many of the cataractsreported lhere vere discovered only wvhien the patients complainedof impaired vision, or during an examination for some otherocular difficuilty. Otlhers wrere discovered in the course of this studyduiring the special follow-up examinations. The only group ofpatients in this series which lhad regtular examinations wvas theclildren wvith retinoblastoma. The timie of onset of cataracts ismore accurate for them.
641
George R. Merria n, Jr.The timiie at wvlhich the cataracts wvere first observed after the
completion of tlherapy is shown for each case in Table 1. Theminimum was four months and the maximum twenty-four yearsand six months. This time interval is calculated after the com-pletion of therapy, since it is impossible to determine wvhen theinjury to the lens was initiated. Because of the lack of regularexamination, the time interval after treatment at whichi the lensopacities wvere first noted might be considered as a maximtum timneof onset.
Effect of Dose for a Given Duration of Treatmetnt on Time ofAppearance of Cataract. It has been showvn in experimentalanimals that as the dose increases the time of onset of the cataractdecreases, and it seems reasonable to assume that this wvould holdtrue for humans (3, i i). An exact correlation is impossible in aclinical study such as this, where the follow-up examinations wereso irregular. Furthermore, if this time interval is to have realsignificance, it is necessary to determine the time of onset or ap-pearance of the lens changes for single and multiple treatmentsand in relation to a given dosage range. The number of cases ineachi group is somnewvhat variable, but this is unavoidable. XVithinthe limitations jtust mentioned, the results seemi to shiowv an indirectrelationslhip betwveen dose and the time of appearance of thecataract.
TABLE 4. RELATIONSHIP OF DOSE TO TIME CATARACTS FIRST SEEN
Single Treatments (dose in r at lens)
Dosage rangeAverageNumber of casesRange of time of onset
2oor-65or45orIO
2 years, 6 monthsto 22 years, I month
65ir-I 150r8oor
I 0
I year, I monthto 8 years, 7 months
Average time of onset 8 years, 7 months 4 years, 4 months
The effect of single doses of varying amounts of gamma radiationupon the time of onset of the cataracts is shown in Table 4. Theaverages for the twvo dosage ranges showv an inverse relationshipbetween dose and the time of appearance of the cataracts, in thatas the dose increases the latent period decreases. Thus, wvith anaverage dose of 45or at the lens, delivered in a single treatment, theaverage timle of the clinical appearance of the lens changes was
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George R. Merriam, Jr.eight years and seven months. When the single dose was an averageof 8oor at the lens, the average time of onset was four years andfour months. In this study there were no cases whose lensesreceived over i,15or in a single treatment.A comparison of the effect of single and multiple or fractionated
treatments and varying durations of treatment on the time of onsetof a radiation cataract is of interest. The results are shown inTable 5. In such a clinical study, there are necessarily patients ofvarying ages who were treated with a wide range of doses deliveredover varying periods of time. In this table, the cases have beengrouped according to five dosage ranges and three durations oftreatment. In this way similar cases can be compared. The chil-dren under one year of age have been excluded. The reason forthis will be given below. Also excluded from Table 5 are the casesof retinoblastoma, since these children had regular eye exami-nations. This fact, irrespective of other factors, makes their time ofonset shorter than for the group that did not have periodic ocularexaminations.
Single treatments.-In the dosage range from 2oor to 35or(average 25or), there were four cases with an average time of ap-pearance of the lens changes of eleven years and eight months. In ahigher dosage range, there were 14 patients whose lenses receivedfrom 4oor to 1 ,ooor (average 65or) in a single treatment. Theaverage time of onset or clinical appearance of the cataracts wasfive years and three months.
Divided treatments (three weeks to three months).-The effectof increasing doses of fractionated radiation delivered in threeweeks to three months is also shown in Table 5. There were 9 casesin the dosage range from 4oor to 1,ooor at the lens (average dose65or), which showed an average time of clinical appearance of thecataracts of six years and six months after the completion oftherapy. In the next higher dose range, from i,ooir to 2,ooor(average 1,6oor), there were io cases with an average time of onsetof five years and two months. A group of 9 cases, whose lensesreceived 2,ooir to 4,ooor (average 3,o5or), showed an average timeof clinical appearance of the lens opacities of two years and eightmonths. In the 4 cases where the dose to the lens was over 4,ooor,the average time at which the cataracts were first seen was two
644
A Clinical Study of Radiation Cataracts
years and six months. Thus, there was an inverse ratio betweenthe dose and the time of appearance of the lens changes-thehigher the dose the shorter the latent period before the cataractsappeared.
Divided treatments (over three months).-Table 5 also showsthe effects of increasing doses of divided treatments over a periodgreater than three months on the time of appearance of the lensopacities. In the dosage range from 4oor to i,ooor (average 700r),there were 3 cases with an average time of onset of ten years andeight months. In the next dosage range, i,ooir to 2,ooor (average1,450r), there were 7 cases with an average time of onset of sixyears and two months. In the dosage range from 2,00ir to 4,ooor(average 2,15or), there were 2 cases with an average time of onsetof four years and four months. In a group of 7 patients whoselenses received over 4,ooor, the average time of the appearance ofthe cataracts was three years and six months. The fact that thelatent period decreases as the dose increases is again apparent.
Effect of Varying Durations of Treatment for a Given Dose onTime of Appearance of Cataract. The effect of increasing pro-traction of treatment, for a given dose, on the time of onset orclinical appearance of a-radiation cataract is also indicated inTable 5. The number of cases in some of the groups is small, but,nevertheless, the general tendency seems to be that for any dosagerange with increasing duration of treatment the time of appearanceof the cataracts is delayed. Thus, in the dosage range from 4oor toi,ooor, the average time of onset for the 14 cases in the singletreatment group was five years and three months. In this samedosage range with a treatment time of three weeks to three months,the average time of onset was six years and six months. When theradiation was given over a longer time, the average time of ap-pearance of the lens changes was further delayed.Although the number of cases in each group is small, the figures
seem to allow these conclusions to be drawn:1. The higher the dose, irrespective of duration of treatment,
the more rapidly the cataract will develop.2. Within the dosage levels studied, the more the radiation is
fractionated the longer the latent period for the development ofthe lens opacity. There seems to be a direct relationship between
645
George R. Merriamn, Jr.the length of timie of the treatment and the latent period of tilecataract.
RELATIONSHIP OF DOSE TO PROGRESSION OF CATARACTS
It is of considerable importance clinically to knoNv wvhether ornot, for a given dose, a cataract is likely to remain stationary or toprogress. In this study, progressive signifies those lenses in whichthe opacity continued to increase, so that ultimately the lens be-came completely opaque wvith a corresponding decrease in vision.In many instances, smuall early opacities wvill progress for severalmontlhs and then become stationary, with little effect on vision.These have been classified as stationary.The indeterminate cases are those wvlio lhad only one eye exami-
nation within such a slhort time after treatment that the ultimatestatus of the lens could not be determined, or cases in whichcomplicating factors developed after the appearance of the radi-ation cataract (hemorrhage, surgery, glaucoma or uveitis) whichcotuld hlave been responsible for the progression. In order ac-curately to evaluate the data, it is necessary to conmpare lenses tllatreceived comparable doses delivered over a similar period.
TABLE 6. STATIONARY AND PROGRESSIVE CATARACTS
Effect of Single Treatment (dose in r at lens)
Dosage range 200r-65or 65Ir-ul5orAverage dose 45or 8oorNumber of cases Io IoProgressive 3 7Stationary 6 2Indeterminate I I
In Table 6 are slhowvn the resuilts for the 20 cases who receivedthe total radiation to the lens in a single treatment. In the dosagerange fromn 2oor to 65or (average 45or), there are io cases. Threeof the cataracts progressed, 6 reliiained stationary, and 1 was in-determinate. In the ligher dosage range, 65ir to i, ior (average8oor), there are also io cases, of whiclh 7 showed a progressive typeof lenis opacity, 2 remained stationary, and i wvas indeterminate.In tlis series, it wvould appear that the highaler the dose deliveredin a single treatmienit the greater the incidence of a progoressivetype of cataract.
(i 1
A Clinical Stutdy of Radiation Cataracts
The effect of dose and duration of treatment on the productionof progressive or stationary opacities is shown in Tables 3 and 7.In Table 3, the cases are divided into the same dosage intervals asin Figure 9. It is evident that, as the dose increases, the percentincidence of progressive opacities increases. Above 1,45or at thelens, all the cataracts were progressive. In Table 7 the single dosesare divided into dosage ranges different from Table 6, in orderto compare them with the other durations of treatment. The inde-terminate cases have been omitted. The retinoblastoma cases overone year of age have been included, since the regularity of theireye examinations was not a factor in whether the cataracts re-mained stationary or progressed.There are 14 cases, in the dosage range from 4oor to 1,ooor, in
which divided treatments were given from three weeks to threemonths. Two of the cataracts were progressive, and i2 were sta-tionary. For this same duration of treatment, as the dose increasedthe incidence of progressive opacities increased. Thus in the dos-age range from 1,oo0r to 2,ooor, 7 of io determinate cases devel-oped progressive cataracts, and only 3 remained stationary.In the higher dosage ranges, for the same treatment time, none ofthe cataracts was stationary. In the group with a treatment timegreater than three months, the number of cases under 2,ooor issmaller. However, in the 1 2 cases with a dose to the lens of 2,oooror more, all of the cataracts were progressive.The effect of protraction of therapy, for a given dosage range, is
also apparent in Table 7. At the dosage level of 4oor to 1,ooor, inthe single treatment group, 8 of 13 cases developed a progressivetype of opacity. When the same dose was delivered in three weeksto three months, 2 of the 14 cases showed this type of lens change.At the next higher dosage level, i,ooor to 2,ooor, there were 2
cases in the single treatment group, and both were progressive.There were 1o cases with a treatment time of three weeks to threemonths, of which 7 developed progressive cataracts. In the groupwith a treatment time greater than three months, there were 6cases, of which 2 had progressive opacities. In the higher dosageranges, irrespective of the degree of protraction of therapy, all ofthe cataracts were progressive.The effect of fractionation and protraction of treatment upon
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A Clinical Study of Radiation Cataracts
the progression of a cataract is also shown by determining thepoint at which there is a ioo percent incidence of progressivechanges for each of the three groups shown in Table 7. For thecases with single treatments, all of the lenses that received over7oor developed progressive opacities. There were 6 of these in thisgroup. When the duration of treatment was three weeks to threemonths, the 1oo percent incidence was not reached until 1,45or. Inthis group, there were 20 cases with doses to the lens greater thanthis. When therapy was protracted over three months, this criticallevel was reached at 2,15or, and there were 13 cases with dosesgreater than this.
RELATIVE SENSITIVITY OF YOUNG LENSES
It has been assumed as the result of experimental work on ani-mals (2) that the lenses of children are more radiosensitive thanthose of adults. The most recent study of this type was that ofCogan and Donaldson (11) on rabbits.This question is of obvious importance, since radiation is fre-
quently given to or near the eyes of children for various types ofbenign and malignant lesions. If the young lens has a greater sen-sitivity to ionizing radiation, it might be expected to manifest thisin one or more of the following ways:
1. A cataract should result from a lower dose than for adults, orthe children should have a higher incidence at a given dose.
2. The lens opacity should appear sooner for a given dose andduration of treatment.
3. A higher percent of the cataracts in children should becomeprogressive for the same dose and treatment time.
In a clinical study such as this, with a wide diversity of ages,dosage, and duration of treatment, it is difficult to interpret thedata available. In respect to dosage alone, there is evidence to sug-gest that the very young lenses are more sensitive. In the singletreatment group there are no children. There are 29 children un-der six years of age and i i adults in the dosage range from 53or to1,o5or. The incidence in the group of 1 i children under one yearof age is 73 percent, and for a group of 18 children from one tofive years of age it is 50 percent. The incidence for the group of 11adults is 64 percent.
649
(l;eorge R. Merr(ian, Jr.
The 8 clildlreni tinid(er one year of age with cataracts, wvhoselenses received from 56or to goor (average 77or) in tlhree wveeks tothree months, had an average time of onset of twvo years and sevenmonths with a range of one year and seven months to four yearsand one montlh. About twvo thirds of the cataracts wvere progressive(Table 8).
TABLE 8. EFFECT OF AGE ON TIME OF ONSET AND INCIDENCE OF
PROGRESSIVE OPACITIES
Treatment Time Three WXeeks to 7hree Months (dose in r at lens)
Children Childreniunder Y'ear I to 4 Years Adults
Average age 6 months 2 years, I month 64 yearsDosage range 560r-goor 65or-goor 53or-io5orAverage dose 770r 85or 79orNumber of cases 8 9 6Average time of onset
of cataract 2 years, 7 months 3 ycars, 8 months 3 years, I I InOllthsProgressive 5 2 IStationary 3 6 2Indeterminate o I 3
There wvere 9 children from one to four years of age wvith cata-racts in the dosage range (65or to goor-average 85or). In thisgroup, the average time of onset of the lens opacities was threeyears and eight months, vith a range of one year and eight monthsto six years and nine months, and about one fourth wvas progres-sive. Although the twvo groups are small, it vould appear that thelenses of the children under one year of age showved a higher inci-dence of cataracts, wvhich developed more rapidly wvith a largerpercentage of progressive opacities.
All of the children had regular eye examinations, so that thetime of onset is reasonably accurate. These shouild be compared toa group of adults witlh the same approximate dosage and treatmenttime. As stated before, the adults did not lhave regular eye exam-inations. Howvever, all of the adtult cataracts shown in Table 8wvere found wvithin five and one-lhalf years after treatment exceptfor one stationary case which lhad the first eye examination nine-teen years and four months after therapy. This case has beenomitted because of the long time interval vithout eye examina-tions. The dose to the lens wvas from 53or to 1,o5or (average 79or),the average time of onset of the cataracts was tlhree years and
(i5()o
A Clinical Study of Radiatiotn Cataracts
eleveni imontlhs, and one of the determiiiiate cases wvas p)rog'ressive.Tlhis would ten(l to suggest that the lenses in this series of clildreniover one year of age had soimewvlhat the samiie sensitivity as theaduilts.
SUMMARY
The dose of X and gamma radiation to the lens lhas been mneas-tired for loo cases wvvith radiation cataracts and 73 cases wNrho receivedradiation to the lens, but did not develop cataracts. Tile mieasuLre-inents were done on a special phantom, wvhich has been described.The cases lhave been divided into three grouips: single treatmient,divided treatment three wveeks to three months, and divided treat-ment over three montlhs. The minimum cataractog'enic dose foreach group wvas 2oor, 4oor, anid 55or respectively.The incidence of cataracts for the grouip with the treatment time
of three wveeks to tlhree montlhs lhas been sliown, and its siognificancediscussed. Thuts, if a dose of 7r5or to gsor were deliveredl to a lensin three wveeks to tlhree imontlhs, there would be approximately a6o percent probability that a cataract wvould develop, and about a5o percent chance that it WoUld be progressive with a correspond-ing loss of vision. All cases wvlio received over 1,15or to tile lens,irrespective of the duration of treatment, developed cataracts.The loo percent incidence level occurred at the lowest dose forthe single treatinent group. In the cases with multiple treatmients,the longer the duiration of treatmnent the lower the incidence at agiven dosage range below 1,1 5or.The effect of dose and varying treatment times on tile tine of
onset and progression of cataracts has been considered. The hiigherthe dose for a given duration of treatment the shorter the time ofappearance of the lens changes and the higher the incidence ofprogressive opacities. In general, fractionation delays the time ofappearance of cataracts, and results in fewver severe opacities. Thelenses of children under one year of age appear to be more sensi-tive to radiation than those of older children and adults.
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Gt)
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