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Cdt tee on use of radioactive t o t h e ma.nagem+nt of advanced, generalized cancer (1); A comparison of the effecti ve ness of *the radiation from internally distributed sources i s of interest, and there is a pos$ibLLity that such radiation will be more effective than therapy with internal sourcbs has not been established and observations pertinent to this phase of t h e problem are an inportant prelude t o €ull scale therapeutic trials. therefore popbsed that the studies outlined below be undertaken for the pwpose of evaluating the feasibility of using whole body irradiation from internally distributed sources as a inbde of therapy in advanced cancer. Totd body irradiation with X-rays has been shown t o be a useful addition The tblerance of huuan beings to therapeutic doses of radiation from History of tots bods irradiation described in t h e form o f an "X-ray bath" by Dessauer (3) in 1907 hut were n o t applied until k923 when Chaoul and Lange (4.) reported favorable results i n 1 2 cases. o f Rodgkin's disease treated with small doses o f roentgen rays to the entire body. Although TescQendorffs (5) results of treatment of leukenia and Hodgkin's disease by total SOdy irradiation were first reported in 1927; he i s given credit for having introduced this method or' therapy i n Europe.m Medibger and Craver (2) have reviewed the early uses of total body irrzd - The basic principles of the method of total body ir ra diet ion were first On dhe basis of their own experience involving 270 cases, mostly with lymAphmatoic'diseases, using t h e Heublein (6) method, Nedinger and Craver ( 2 ) re Fort that 340 r of 185 Kv X-rays given over 10 days appears t o be the upper limit of safe dosagd. 5.5 mm CU and with a working distance of 3 meters, 100 r was delivered i n 6 days. They used continuous irradiation with 185 %v, 1ma, filtered with Grayer (7) lster (1947)reported a study of6 patients having advanced metastatic cater and who were exposed t o up t o 300 r of 180 Kv X-rays delivered i n count that midht not reasonably be ascribed t o the progress o r complications of deterioration in general health not reasonably entirely attributable tothe progress growth of neo$lasm by t h e whole-body exposure t o radiation." In a personal comfiudcation to Dr. Nickson, Dr. Craver said that some ofthe patients in this series were still alive 20 t o 22 years later without known harmful effects relating to "in no case did there occur any deterioretion i n t h e blood In the 3 cases followed for longer than 6 montns there was no In no instance was there observed any suggestion of stimulation Of
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E’roq a series of 30 patients treated with large doses of X-radiation, et. Id.,(8) report .4 cases with serious camplications i r ~ vol vh g myelJopoiesis with agranulocytosis. These cases received 475 t o 1600 r. Thede i s an extensive literature on the use of whole body irradiation inthe treatmdnt of polycfihemia vera; a couple o f references (9, 10) are included wet (11) reports a1 series, primarily of lymphma a116 leuk da patients Daily doses of 25 t o 50 r. Oft r e a t e d with btal body radiation with good results. 200 Kv X-ray $ i lte red Kith 0.5 mm Cu were used, and total doses were 300 t o 4W r. as consequencss of two nuclear 1ccidents at the Los Uamos Scientific Laboratory. Although the jbatients in t b i s series received a mixture of several kinds of radiation, the data was used to support t h e conclusion t h a t 100 r. of 200 Kv X-rays could be delivered t o the entire body of a normal subject without causing serious Hem elmann et. al. (1 ) describe the acute radiation effects suffered Loe f l e r et. al, (13) campare the e?fects in 4 cases with carcinomas mut ard and.tTiethylene melamine. %e irr & ated. ? at i ents did not show appreciable As oll in s and Loeffler (1)point out, ufron the different techniques, Fusing varying formulas of intensity, dose and -the, it is difficult to assess the tolerance t o byole body irradiation. resFonse o f *e patients’ disease can only be considered as indicative tl<a”. t o t a l bo@ ir radi at bonin sinzle doses up t o 200 r. has therapeutic possibilities. The tolerated dosle i s beyond that necessary or desirable for leukenia, but it i s in the effective1 range f o r lymphosarcoma and multiple myeloma.” I n discussing their own results (l), I n lgeneral, t h e therapeutic dosas of isotopes such as I - 131 and P - 32 are chosen o q the basis of their concentration in and the ref we selective irradiation of certain qe cia l tissues; the whole bod-j dose of radiation is us - d ly too small t o se-ptre as q basis for the evalUa’Aon of the tolerance to h tz r nel radiation. There i s everiy reason, however, t o expect the tolerance level to be roughly comparable to that for X-rays. t luo qh out tye body i s required. does not produce untovard pharmacological effects and tn at the isotope have a led to a sel@ction of sodium - 24 a s best fitting the criteria of acceptability. Other isoiop4s coilsidered were cillorine 38, tritium and fluorine 18. Fort whole body irradiation an isotope which becomes uriformly distributed It is also necessary that the material adainistered Discussion among t h e people who will participate in this study activity for Clj8 i s not quite high enough for administration vithout danger of pna-rmacolo@il. effects. Present Production are inadequate. Tritium woulci give tile xlost uniform dose but it start with an isotope having a shorter effect iv a half-iife.
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= Beta dose i n rep, integrated toir _ l " Wte time = Average beta energy i n Xev = geonetry factor 1'' for center of k ~ n k 24i n 70 kg adult assuming honogenous distribution of Na "hebefore 1.38 mc./kg. delivers 150 repto tine center o f the body. The center i s spebified because at tLe surface tie ga;;ma dose i s odJ about half its value atthe Icenter, so the total at the skin KiU. be about 6$ rep when that in the center i s 1C9 rep. The ge met q - factor lor the extremities is also smaller th m that for the trunk, so the dose t o them will be corres-pndlngly reduced.
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Tiie Selection of patients is a difficult part of the project, requiring, ' the selection c$f patients unsuitable for beatmeat by established procedwes, yet < i n good enough geqheral condition that they will survive long enough for the effects of the irradiatiorb t o be studied, for the proposed studies will be selected by the Radiology Kemorial Center, New Pork City, on the basis of the a. be patients will have malignant disease and all non-experiaental Fpproaches t o therapy (local irradiation, surgery, chaotherapy) twill have been ruled out because of failure o r contraindications. (Each patient will have had fond consultations With the Bpartslent 'Of Surgery and the Department of Chemical TheraFy of the Nmorial k enter and it will have been stated in writing that the patient is nota candidate for any form of tre a bent in those departaents. b. Alife span of 6 months o r more will be predicted, and benefit t o the2a tien t from the radiation can be expected. d. Normal liver profile studies (bilirubin, total protein, A-G ratio, alkaline phos-phatase, prothrombin time, trans ese,tipo l turbidity, e, Normally functioning renal tract;. The patient nust be maintaining his nutrition by mouth and be expected t o naintain this througnout the period of observation. The irradiation and the studies outlined i n this props & will be conchcted a t ithe Srookhaven National Laboratory I,;edical Center. Stuwes during the period of a week o r so prior t0 irradiation Will a. Frequent blood cell and platelet counts, hemoglobin and hematocrit. c, Ekchmuesble so dim pot as dm and water, using tracer quantities of Maa, and H3. Cr51 red cell mass and initiate survival study possibly combined Ashkj and/or auto labelling,
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calculated to be liver up to 150 rep total G&Ji r radiation. The first few patients will ece ive half this dose and subsequent patients will receive larger doses deemed tb be safe on the b a s i s of accwrmlated experience. Radibactive sodium, a s (Na )zC ~ will be given intravenously in doses The /followirg d0sa.e schedule will be used: nus?, to give a Yokg patient 150 rep will require 96.6 nc of Na .A t the B.N.L. Iresearch reactor this activity can be obtained by activation of 100 mg. of Na, o r 230 mg. of Na;zC03. will accumub.de on the following schedule: If &ere is no loss of ra&ioactivity by excretion, the radi sion dose Time . Fraction of Eqxx5mental work in animals and, in a lesser de gee, in for the dose levels in question little change has been worthwhile, i n order t o nail down this point a s firmly a s possible, t o look at skort range peturbations in time of the commoner electro b%es and pH of the1 blood. Included would be along range evaluation of alterations in total ex cn de able potassim. exchangeable pot as sim has been noted following doses o€ the order of 15G r. This evidence is sl till tentative, but in our o+nion, warrmts followup Therefore, It should be noted that evidence or" shift in
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after adminisaration ol" the !$az4, bloods will be drawn for the blood ch&stry studies Tor Wch base l5ne stud in s were mde(plasa sodium, potassLum, cuo ride, carbon dioxidd and pZ) at intervals to be decided on. radiation dose has been received by the patient, After 20, 50, 62.5, 75, and 85 per cent of the t o t a l EkchanEfeable Ea, K and water studies d l be made at a3tfour days after the administrdtion of the dose. in the body a$ this time; corrections may be necessary for the tracer studies, but should not pr$clude them. About 0.01 of the injected Na KJU. still be Studies performed before irradiation will be'repeated If si,&icant platelet derxession OCCUTS, aqpropriate be performed. Studies vill be continued u n t i l Signs of irradiation appears t o have becane UnbpOrtant i9. Radiation dose deterninations. The do e estimates given i n this proposal are based on calculations. The chizf assumpt Pon, that of uniform distribution tiroughout the body, i s open t o question, butlis,as good for sodium as for any other pro-posed isotope, of exchange o r the sodium in the bones With that in the circulation is relatively slow and has b negligible effect on the dose calculations, Vigo rob efforts to obtain determinations of the radiation dose *wphpiiccal measurments kill be =de. a suggestion being considered isthe use _of Seivert ionization cnanbers introciuceci into tha esophzqs o r other divisions of the gastro-intestinal tract. The techniques t o be used have not been agreed upon, but As is shown i n tine dose calculations, the gamma dose will not be unifom throughout thle body. than 150 rid order t o achieve a total-body effect comparable t o 150 r delivered by other mearis. It nay be necessary to give the center of t h e 'sody more
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Fhe Therapeutic Use of Single Doses of Total So@ Irradiation p. J. b e n t . Rad. Ther. and Nuc. Zed. 22, 542-547 (1956) kine Neue Anordug zur A%entgensk@dmg bber Lymphogranulomatose und beber Bestrablungen des ganzen menschlichen ' Korper bei Blutkrankheiten Preliminary Report on Continuous Irradiation of fi tire Body 'Tolerance t o T&01&30dy Irradiation of Patients with Advanced Cancer 8. D. den Xoed, Bo Lsvie and 14. Straub Serious Injury of the 3lood i n Consequence of Teleroentzen ' her a py of the Whole Body 'Treatment of polycythemia Vera by Roentgen Irradiation of the & tire Bod s Roentgen Irradiation in Polycythemia Vera by Multiple 3naJ.l Doses t o Large Areas of the BW ,Comparative Effects of Tetal Body Radiation, Nitrogen lbstard, and Triethylene Melanine on Hematopoietic System of Terminal Cancer Patients, Science 118, 161-163 l c G 3 )
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Ap tops al far studies involving the use of Na'- to deliver whole-body irradiation3 selected patients with malignant disease i s presented. Permission to deliver up to l ? Orep b: this inethod is requested.