University of California School of Medicine, San Francisco, Radiological Laboratory Program October 10, 1958, Atomic Energy Commission Contract No. at-11-1-Gen-10, Project No. 2

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University of California School of Medicine, San Francisco Department of Radiology Atomic Energy Cormnieeion Contract No. AT-U-1-OEN-10, Project No. 2

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TABLE OF CONTENTS :4e F PHYSICS SECTION PROGRAM AND ACTIVITIES Patient Treatment Program BIOLOCY SECTION PROCRAM AND ACTMTIES Factors That Influence X-Ray Sensitivity Fractionation and Recovery tCU N ICAL RADIOLOGY SECTION PROGRAM AND ACTMTIES & Rellability of Apparatus Knowledge of RBE Source of Patients Selection of Dose Selection of Treatment Plan for Each Patient Examples of Specific Treatment Plann and Mortality Data as of September 30, 1958

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University of California School of Medicine Research work relating t o biomedical aspect8 of atamic energy, supported initially by 0 and l a t e r by the Manhattan District, wae Introduced Into the University of California Medical Center i n 1942. concerned with hematological studies on patients receiving substantially lating t o the effects of radioisotopes, particulsrly I1". activities have been rl shed to "foUow-up" status and the follow-up is expected t o be maintained. !Che first project wae. I n 1945 the work was expanded t o Include studies reBoth of these Synchrotron Project History I n 1947, particularly as a result of activities of the National Adviso r y Cancer Council, interest was generated in the extension of radiation therapy of cancer with the multimilUon-volt range. worth of radiations attainable I n this range could not be evaluated a priori. Because of i t s early experiences (1934-lgbg) with million-volt x-radiations, the University of California Medical Center, San Francisco, was chosen 88 a place where physical, biological, and cllnical studies using multimillionvolt radiations should be done. Quite obviously, the The choice of the 70-Mev synchrotron (LB a primsry tool i n these studies resulted from maay iactore. 31 MeV would be adequately covered by installatione elnewhere. able availability of electron beams had recently been denmistrated when, in 1949, the choice of machine had t o be decided. It appeared, however, that t o penetrate 10 cm, of tissue with adequate dosage might require a betatron operating at 50 MeV. Although such a betatron had been made, a conversion of this basic machine produced a 8ynchrotron operable a t 70 MeV. The General Electric Can- agreed t o manufacture such a synchrotron with adequate shielding and wm ting for clinical. utilization. Installation of the synchrotron In a small laboratory building, specifically erected t o house the program, W a s completcd In mid-1952. It appeared that the energy range t o nate the activities In the new building. Radiology l e that branch of medi c a l sciences which deals with ionizing radiatione in the treatment of physics, biology, and cllnical. by eection of the program and major activities of the Radiological LaboraFor operational purposes, the Laboratory has three main sections: The remainder of this report is a review

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Currents. Radiation Res. 3: 210, 1955. A d w , G. D., Sane Observations on the Difference Between Intensity and 35 '5 United Nations, New York, 1956. ness. In: Proc. of the International Conference on the Peaceful Uses of Atomic Energy, Geneva, A u g u s t 1955, Vol. ll, pp. 26M6.5, .- Atomic Energy, Geneva, August 1955, Vol. 10, pp. 89-94, United Nations, Proc. of the International Conference on the Peaceful Uses of a 70-Mv X-Ray Beam. Rev. Sci. Instr. 27: 586588, 1956. qj Adams, G. D., An Experimental Determination of Energy Abeorbed in Water from an X-Ray Beam. Radiology 69: 867-880, 1957. ';g Iron Dosimeter. Radiology 68: 101, 1957. Adam, 0. D. and Balkwell, W. R., Advances Towards 8 Stable, Sensitive Adam, G. D., Problems i n Dosimetry of X-Radiation. 1957 IRF: WESCON Con vention Report, Part 9, Sees. 34, pp. 7-11, Institute of Radio Engiand Sinclalr, W. K., Clinical Dosimetry. Radiolopy 70: 96-97, 1958.

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Experimental wwk i n the Biology Section began early i n 1952, after a Program had been fomuhted that gave priority t o a st* of the m. (relative biological effectiveness) of x-ray and electron beams of clinical interest, but also looked forward t o studies dealing with (a) the mechanisms underlying the utility of fractionated dosage, (b) certain factors ing on the fundamentals of radiology. The RBE I s evaluated by the ratio: when the absorbed e of each beam produces the same biological effect. Frm a review of the literature made in 1952, it vae concluded that variations i n RBE reported for the various x-ray and electron beam of clinical interest were small enough t o have resulted from imperfections i n dosimetry and experimental design, yet w e r e large enough t o be of potential clinical which ( a ) biological methods for RRE determinations would be studied and a set of four would be selected and standardized, (b) dosimetric methods would be made t o conform t o the recommendations of the ICRU, and ( c ) the formal and IIlformai coUabcr:tion of other clinical laboratories would be edllsted so that one or m.x est dard i zed " determinations of the REE could be made in each of them, thus malsing possible signlflcant interlaboratory A general attack on the problem was eventually decided on i n The first of +,he staudardized tests carried out at San Francisco by the biology group were v i t h the x-ray beam from the 1-Mvp unit in the University's radiation therapy cllatc. Detexmhations w e r e made with four kinds of bacteria, two kinds of yeast, the chick embryo, the moue testis, and the mouse ID,,. determinations at other lnetitutiom (Sloan-Ketterhg Institute, New York; isons may be illustrated with the results frcrm one of the standardized detemlnations (Table 1): Laboratories A and Bwere In agreement, but not Laboratory C, and that laboratory is now repeating its determina%on. The average value of the R9E was -0.85. The biology group also collaborated actively i n two series of RBF: The data point t o error in the reference beam LD, of

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+(LD,, of reference beam)/(LDso of test beam) At this Laboratory in 1956, just prior t o the initiation of patient treatment with the 70-Mev synchrotron, em estimate carried out I n collaboration with the physics group Indicated an FiBE of - 1. four determinations with yeast and one wlth the chick embryo. The estimate was considered t o be a preliminary one, since the calorimetric procedure used with the synchrotron had not been employed t o calibrate the the RBE is somewhat below 1. with special reference to clinical practice has been made. (It Includes adequate reference t o the various preparatory studies and determination8 fran this Laboratory.) Several trends have been o b s e m d along wlth and presumably as a result of the increased interest I n precise dosimetry and correct biological design. ( a ) The values of the FBE for the clinical spectnrm are less dispersed than previous*; the values for super- and megavoltage radiations, although not yet finally determined, cluster In the range 0.8Oo.gO. (b) There I s decreasing evidence that the FBE i s very sensitive t o the biological end-point wed In I t s determination. ( c ) Inferentially, it appears that the RBZ is relatively ineeneltive t o many of the variations that occur in such phyeiologlcal parameters aa pH, temperature, oxygen tension, etc. This, of couTse, docs not Imply that radiation sensitivity may not depend on temgerature, f o r example. It does Imply that the RBE determined a t one temperature w i l l not differ fran the RBE determined a t another when both fall within the range ueually employed or that anticipated t o occur in me un ma be H. I. ~ohn, The Relative Biological Eifectiveneslr of External Beema of Ionizing Radiations. In: Progress in Rsdiation Therapy, Or une b Stratton, This w a s based on Since then, the clinical Impression has been that Plans have been made for a "final" deted - A comprehensive revlew * of the current statue of the RBE problem

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Factors That Influence X-Ray Sensitivity To study inherent, genetically determined differences in x-ray sens it iv it y, various microorganisms were tested with a rigorously standardized procedure in which death w a s the endpoint of radiation effect. Major differences both i n sensitivity and in type of sur v ld curve were found that have proved t o be stable over a period of yema, and that cannot be attributed toa chance selection of experimental cond it iW usuaUy died before completing a division, whereas the yeasts usually budded at leaat once. in Gunter and Kobn, 2. Bacterlol. 72: 422, 1956). (Table 2). It was noted that, regardless of sensitivity, the bacteria _ - (Work thus far published is reported o r referred t o Table 2. Sensitivity of Microorganisms Pseudomonas fluorescens one h i t 1.0 Rhodopseudomonas spheroides one hit 1.8 Escherichia coli 14851, one hit 2.1 Azotobacter agile multihit 8-3 Saccharomyces cerevisiae, multihit 24.O *The results f o r the survival curve and ID,, of 2. cere- -visiae, haploid and diploid, confirm the work of others. Current studies deal with the protective mode of action of cysteine and related. compounds. of the protected state i s dependent on a temperature-sensitive process which, under certain experimental condition6, cannot be accounted for by the auto-oxidation of cysteine in the suspending medium nor (probably) in the organiem. "sensitivltf of the organism is independent of the temperature (0-37 at which irradiation occurs. tigation in E. s,and we hope t o study it in another type of organism selected from the list i n Table 2. Evidence has been obtained that the development Once the protected state has been developed, the The nature of the process l e under invesMicroorganisms were chosen f o r the sensitivity study, since the RBE program did not requlre the --time use of the microbiology laboratory that had been set up f o r it. We plan t o discontinue the microbiology laboratory sometime after the detennlnation of the RBF. of the synchrotron beam is completed. Although the work on sensitivity is of interest, it is f e l t that the available apace for the Biology Section (600 W quarters) can be used more effectively by concentrating on m l m d

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Fractionation and Recovery In many biological systems, but not in all, fractionation will reduce the effectiveness of a dose of x-rays, presumably aring t o recovery between the administration of successive fractions. Fractionated dosage is of value In radiation therapy, but the underlying mechanism is not clear. deteminhg the effects of fractionated dosage began with experiments in which the whole animal was exposed and in which the a t various intervals thereafter. the initial exposure, and thus the RT, (time for 50 per cent recovery) could be calculaed (Table 3). _ -The program of the biology 50up t o study the role of recovery in y88 used ae the After exposure t o about 300 rads on day 0, the LD50 was determined -- From such data the injury remaining from Table 3. Recovery by the R a t After 315 r (Whole-Body The ms0, which varied from 1.6 t o 6.1 -8, was found t o tween species and even between strains of the same species (TabhT. ? k e recovery curve was practically an exponential function of time in the mouse and rat, but was some other function in the hameter. various studies from t h i s Laboratory and a discussion of the llterature may be found in the paper cited below.+) The IDso, Death Rate, and Recovery Rate. Radiation Res. 7: 85-97, 1957.

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Table 4 . Type of Recovery C w e and FIT50 Species Strain Recovery * 5 0 Hamster Syrian no The studies with whole-body exposure were planned t o provide ccmparative orientation and t o t e s t the hypothesis that genetic factors may play 1 an important role. are being initiated this fall. First, to which system in the animal should the recovery rate be assigned? Second, can a phyeiological factor be found that will influence the RT50? under t e s t in the late effects program (see next section). series of these mouse experiments Kill not be completed until January, 1959, some indications of the results are now beginning t o appear. the survival curves, it may be tentatively stated that 550 r x 1 is not always significantly more effective than 275 rx2 (8days aparc). Experiments deaUng with two more specific questions The hypothesis that fractionated dosage has a sparing effect is also

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Although not o rigid y anticipated, the hazards of radiological exposure Judged by their l a t e somatic effects have gradually become a major interest of the biology group. Campus, 17 miles from our Medical Center) w h i c h supplied the needed animal quarters and care until the summer of 19%. Aspects of the general problem that have been under investigation include changes in the exposure as a determinant of vulnerability. statistics is also under way. acute changes after whole-body x-ray exposure and (b) the late changes i n the terminal state, Uttle was known concerning the gradual development of lesions during the long intermediate*period between (a) and (b). Some of the more general conclusions reached i n a histological study of this period w i t h CAFl and BALE/c mice are the folloving. changes i n the female moue are the result d a change in endocrine Etatu, secondary t o ovarian atrophy. mogo us changes were not identified with certainty in the male, although i t - w a s observed that several orgsns which respond t o the anabolic acticm of testosterone were smaller. Perhaps the most striking general effect w a s a selective one on organ when smaller, there may have been a failure to grow (e.g., male heart), or a net loss of substance (testis). crease in size during adult =e, the animals having been irradiated at in: Kohn, Kallman, Berdjis, and DeQPe, Radiation Res. 7: 407, 1957). The studies were initiated in 1953 A study of human cancer Intermediate period. Although much was known concerning (a) the A number of prominent The irradiated organ was never larger than its age-specific control; The growth referred t o here is the in- (Reference t o this work and related studies will be found Partial- v e r s u whole-body exposure. The principal hazard in radiological practice stems from partial-body exposure, but the induction of l a t e effects from this type of exposure.has received practically no labthe life-shortening effects depended on.the region exposed and the magnitude of dose i n such a way aa t o make.extrapolation from whole- t o partial-body exposure difficult, if not impractical. For example, it is not Unukely that a threshold exists i n the case of certain types of partial-body exposure (Ka.Uman and Kohn, Science 1.28: 301, 1958). rently i n progress is a study with …