The Effect of Total Body Irradiation on Immunologic Tolerance of Bone Marrow and Homografts of Other Living Tissue

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Nuclear Weapons nfects Research No. 03.031 Sub-task Title: T h e Elfcct of Total Body Irradiation on Immunologic Tolerance of Bone Marrow and Homogrdts of Other Living Tissue Directing Agency: DASA - Contractor: Baylor University College of Medicine Project Coordinator and Prof c s mor of Radiology Baylot University College of Medicine (Reproduction in whole or in part i s permitted for any purpose of the Unttcd States Government)

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Investigations in the effect of total body irradiation have been carried out in this department for more than 10 years and this find report i# based on data collected during thir time. The project was initiated when comparis on of response of patients receiving therapeutic total body irradiation with that of patients receiving chemotherapy indicated that, in the dose r a n g e used, total body raidation was well tolerated and could be used as a s adjunct to treatment of disseminated cancer (1, 2). Intensive studies on response of erythropoiesis were undertaken (3) and findings gave new directions for further study so that, in the final years,the protocol included a large series of clinical, hematologic, biochemical and physiological tests (41 as -11 as studies in protection. The investigation includes observations on 112 patients receiving therapeutic total body irradiation: pilot and parallel studies were carried out on experimental animals. The fundamental problem hag been to define effect of irradiation and qtiantitate effect with amount of radiation exposure. S i n c e quantitation is possible only to the degree that measurement of both effect and amount of radiation is possible, it was necessary to consider all the variables that would influence measurement. Comprehension of the problem begins with the recognition that a simple numerical expression cannot define dose of irradiation. The physical characteristics of irradiation require th rt dose be described not only by the number of units (roentgens, r a d s , rtc.) but also by distribution and intensity in a given volume of tissue, and time or duration of exposure. For each irr8di8tiOn procedure planned, dos ime try studies were carried out so that uniform distribution of irradiation could be achieved. Several methods, and types of dosimeter s, were used for comparlson.8nd for accurate measurement of dose to specific anatomical sites. These methods assured even distribution of radiation and produced comp arab te data on radiation exposure throughout the entire study. Simi iar dos ime try studies were carried out for animal experiments. Protocols required animals of similar age, weight and physical structure so that vulume irradiated and responne could be compared. All animals received immunization vaccine, w e r e quarantined for two weeks, and all were well nourished and in good health prior to experimental work. Although variable + associated with patients requiring therapeutic total bcdy irra.iiation arc present,certain aspects were comparable. All patients were adulis w ffe ring from dis-eminated cancer, all rece:ved evenly distributed exposures of irradiation and, except when reaction waq severe, none received supportive treatment that would mask effect of irradiation. Since prediction of effect is the basis of radiotherapy, experience in this field is helpful in evaluating response to treatment and i n estimating rer pons e to heavy exposures by extrapolation of data obtained d th th cr a -

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&%aminationsand laboratory tests were dom on all patients prior to therapeutic total body irradiation to obtain a base line for comparison with tpsts made during and following treatment. Records of all clinical findings, results of a11 tests, factors, technique and dose of irradiation w e r e maintained. Follow-up continued as long as the patient survived and, when possible, autopsy was obtained to determine whether or not there was cvidencc of radiation change. These records formed the basts for analyses of changes by various parameters as presented in annual pr oR res s The patients were divided into 3 groups according t o duration (elapsed time) of radiation exposure. T h e s e are defined as: I - Single Exposure, tolerance to radtation increase - with protraction of time, there is a tendency to emphasize protraction while overlooking the amount that can be given safely in a single exposure. When nearing the terminal stage of disease, fewpatients are likely to survive a protracted course of therapy and dose, which is nec er gari ly low for each treatment of a protracted course, is not likely to prove beneficial in the brief time available for therapeutic effect. Thus, the map rit y of patient- (71/112 - 63q0) in this gerics rec rive d single e ~ po sure s. It seemed pos-ible that response in this group might be compared with daio obtained from study of accident victim r and exposed Japanese populations who received single exposureq. Group 11 is composed of 34 (3040) patients receiving protracted irradiation. The - cwere selected because of generalized disease that might be expected to respond to small repeated exposures. It w s expected that study of this group would provide information concerning response that might b e useful among military personnel when occupying a radioactive The third group is composed of 7 patients who had received either single or protracted exposures and who, after months or years of remission of disease, developed recurrent symptoms requiring further treatment by total body irradiation. lhese7 patients received a total of 16 separate courses of treatment or3 studies in addition to the 112 patients. The number of patients, amount and range of irradiation exposure, and elapsed time, iR summarized in Table I. Cat ego ry Patients Range of Exposure and Time

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Table2summarizes the number of patients rcccivinl total body i rrr di ation in a single exposure. Amount of exposure ranged from ZSr to 250r, depending upon the therapeutic indications for treatment. No. of Patients Total Body fr rad ht a on Table 3summarizes the number of patients receiving therapeutic total body irradiation, protracted over periods ranging from 2 to 33 days. No. of Patients Amount of Irradiation Table4 outliqcs the amount of radiation with duration of txpc-sure and time :apse briwcen each course for the 7 patients receiving tepeated courses of thetaF cutic total body irradiation.

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Amount of Radiation reaction following therapeutic total body irradiation is difficult to evaluate because of the influence of disease, medication, and psychogenic factors. Malaise following irradiation was recognized and reported as early as 1897 but the train of symptoms, in 1912 termed which he believed accounted for "radiation sickness." S i n c e symptoms may appear following exposures too light to produce dctectablc biochemical changes, 8nd may not develop following marked changes, other factors must Ellinger summarized a series of biochemical changes (5) For evaluation of the present series, symptoms were graded according to severity: 0 I no symptoms, 1 Ianorexia only, 2 - nausea only, 3 I nqusea and vomiting one day, and 4 m nausea and vomiting more than one day. TWGpatients are excluded from this rtudy: one, terminal at the time of treatment, died vrithin 24 h o u r $ , and one, a n out-patient with concurrent tubcrculorig, m s lost to follow-up. Table5summarizes ;he severity of symptoms according to single, protracted and repeated courses of exposure

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Radiation Exposure No. of Symptoms(grades) *One Datient with Grade L and one baticnt with Grade3symptoms had nausea and vomiting prior to irradiation. A total of 21 patients (19%) developed reactions varying f r o m mild to s ev pre but this cannot be accepted a s an indication of incidence that might occur in an exposed population. In this group any or all symptoms could be due to disease(2 patients had symptoms prior to treatment), but there is no clue to explain why 89 patients (81%) developed no symptoms In evaluating radiatior ,,ickness according to amount of 4 rtadiation, patients receiving single exposures are studied because response is easily recognized and is not complicated by cumulative effect of repeated exposures. Table 6 shows the reaction a! 69 patients receiving single exposures of therapeutic total body irradiation Amount of No, of Symptoms (grades) had nausea and vomiting prior to irradiation. Study of the table shows the incidence of symptomatic response to total body irradiation is practically the same for patients receiving 50r a s for those receiving 200r, but 14 patients receiving 75 t o 125r failed to develop complaints. Review of the clinical histories of the 5 patients with symptoms following 50r reveals that 4were occupants of the same ward at the same time. The subject of radiation sickness had been publicized in the popular press, was discussed by all occupants of the

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ward and anticipated by the 4 scheduled for treatment. T h e 5th patient, terminal at the time of treatment,was receiving heavy doses of narcotics !or pain from d de spread involvement of d is e are from primary breast cancer ; in this case, qymptoms could have been caused by disease, medication, motion and manipulation, ora combination of these factors. A careful study of all patients who developed symptoms following therapeutic total body irradiation indicates that, for levels up to 2OOr in s in ale or protracted exposures, radiation sickness may be avoided by proper management. T h e attitude and experience of profesqional personnel, the intentions of personal acquaintances in contact with the patient, the reliabiljty of information in the popular press, and the stability of the patient,- - d l theqc enter into the problem of motivation or suggestion. It is probable that, with correct information and proper preparation, normal healthy individuals could tolerate even higher exposures wathout The goal of treatment by total body irradiation for patients wdth dis - seminated cancer is relief of symptoms. Depsite the fact that many patients were approaching the terminal stage when referred for treatment, therapeutic response was evident in many by dec re cee in :ize of nodes, relief of impending obstruction and by decreased narcotic requirements rubsequent to relief of pain. In some instances, response was dramatic ; a few completely bedridden patients became ambu!atory and several experienced tong term remissions. Among the 112 patients there were more than 30 different types of cancer ; since total body irradiation was given only for generalized disease,a survival of one year or even temporary remission was gratifying. In Table 7, the diagnoses are show in 17 related groups with t h e number of patients in each group. Diagno-is No. of Patients T es ticula r canc e r C y neco logical canc er Carcinoma to s is (primary unknouvl) 5 liver, kidney, prostate, & malignant melanoma)

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Among patients with far advanced cancer, effect of treatment cannot be measured in t e r m s of survival but survivals, through the expected period of depression and recovery, provide information on immediate biologic and physiologic response to total body irradiation. Table8 summarizes the sur viv ri of all patients in the study. Survival Time Number of patients Died Lost to F.U. Living Of the 95 patients known to have died, 93 died of disease within 3years following treatment. T e n patients ( 9 % ) w e r e lost to follow-up but 4 of these were observed for periods ranging from3 to 7hears before they were lost. Seven patient& are living with survival ranging from 3 to low years. Although patients with disseminated disease from many types ~f cancer received therapeutic total body irradiation (see Table 71, greatest benefit is derived by those uith lymphoma, manifested chiefly i n enlarged lymph nodes without marked bone marrow isvolvement. Over the past 10 years, the increasing activities of the Chemotherapeutic Trials Committee have reduced the number of referrals of such patient* fpr radiotherapy to practically zero. Thus, the majority of pat is nts are those who failed to respond to chemotherapy or those who mere refused chemotherapy because of anemia and poor general conditiop. Among cancer patients, anemia may be caused by infiltration of cancer cells in bone marrow with replacement of normal pre - cursor cells and by shortened red cell survival (6). With widespread cancer, anemia, *ether frank or subclinical, is prc qm t and death within a short time is inevitable. When patients are referred ar a "last resort," the radiotherapist does not wish to withhold treatment that may offer possible benefit but h e cannot be certain that the benefit will outweigh the risk. The risk is not that the patient a11 die but that the undesirable effects of radiation will appear more severe in the terminal cancer patient and that the time of death may be destined to coincide dth the undesirable effects of radiation. Supportive treatment, even th,aG;Rh

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itmay not influence the course of disease,must be included in the plan of treatment for such patients. The follo-ng case history illustrates some of the problems involved. A.S. This 73 year old lawyer was admitted with history of hacking, productivr cough, left chest pain, f e v e r 1020 and generalized lymphadenopathy of 7 weeks duration. On admission, examination revc-aled bilateral cervical, supraclavicular, axillary b inguinal nodes 1 - 3 cm. cost al margin. Chest x - ray - enlarged hilar nodes; lymphangiogram demonstrated enlarged pelvic nodes, bilateral, with filling defects & replacement of normal architecture by tumor. Urine b sputum culture - Rone marrow: diagnosis - diffusely involved by tumor, No nausea or vomiting blood to combar in' ction; 50%rc gr t q sion incite of nodes and masses. Sputum stilt positive; R x colymycin, isolation Re-infusion of marrow not feasible Comment. Anemia and infection =re present on admission and treat - ment was delayed for nearly a month while a n attempt was made to improve the patient's Re nerd condition. During this time, nodes and masse1 continued to enlarge, anemia progressed, and it was evident lymphosarcoma was offered. hlarked rt grc s sion of nodes indicated good therapeutic tes pon qe bit this u as overshadowed by bone marrow depression in thc pre sen cr of extensive hone marrow involv-ment and infection. Figure 1 ohowi rec po nrc of white blood cell count compared with respon-e of total circulating granulocytes. Although 68 patients died Pf disease within 6 months fol lovin ~therapeutic total body irradiation, many Df these experienced terr.porary remission and contributed valuable informhtion to the study, The following case hi-tory is an example of good the raw u tic effect providing opportunity too her vr response through the perio of bone marrow deprey*ion and recovery.

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1.C. This 37 year old man was admitted complaining of epigastric pain with hematemesis of 5 years duration: jaundice with enlarged liver (7 em. below costal margin) and retroperitoneal m a r s ( 6 x 8 cm.) d t h ddesprcad lymphadenopathy had been present for 3 months. Biopsy of cervical node revealed lymphosarcoma. 68 Remarkable improvement: patient ambulatory Patient very ill, bedridden, requiring heavy narcotics Bone marrow aspiration (320 cc. stored Regression of all nodes and masses, jaundice cleared Re-infusion of bone marrow Recurrence of symptoms, d eveloping lymphad enopathy Radiotherapy to enlarging abdominal mass …