UNIVERSITY OF CINCINNATI INTERDEPARTMENTAL CORRESPONDENCE SHEET TO E.A. Gall, M.D. FROM Ben I. Friedman, M.D Date April 13, 1967 Dear Dr. Gall: Enclosed is the revised proposal covering "The Therapeutic Effect of total Body Irradiation followed by Infusion of Stored Autologous Marrow in Humans." I think that this revision answers all of the questions which have been presented by the Faculty Committee on research. Should there be any additional questions, please contact me. I would appreciate hearing about this as soon as possible, Sincerely yours, BIF/rla Enclosure TO: Faculty Committee on Research FROM: Ben I. Friedman, M.D. Principal Investigator Eugene L. Saenger, M.D. Department Head SUBJECT: The Therapeutic Effect of Total Body Irradiation Followed by Infusion of Stored Autologous Marrow in Humans Purpose of Study: The goal of this study is to test the hypothesis that total body irradiation followed by infusion of stored autologous marrow is effective palliative therapy for metastic malignancy in human beings. Total body irradiation has been used for palliation by others (1,4,5,6) but the dose used has been limited to less than 200 R because of the bone marrow depression which follows large doses of radiation. A combination of total body radiation and infusion of autologous bone barrow may make it possible to use larger doses of total body radiation. Effective total body radiation therapy without the hematologic morbidity would be the most innocuous and least disturbing form of therapy available for the palliation of patients who have extensive neoplasm. Patients given this type of treatment have less morbidity from their therapy than comparable patients given 5-fluorouracil or many other chemotherapeutic agents. It is also planned to investigate techniques of marrow storage and to evaluate the optimum times for storage and infusion. Since we have already successfully separated viable peripheral blood lymphocytes from polymorphonuclears, in the future we expect to be able to separate bone marrow cells. Ultimately, by tissue culture techniques, we intend to grow relatively pure cultures of "stem cells" from the fractionated marrow. Intravenous infusion of a few milliliters of multi- potential "stem cells should repopulate the marrow space as well as 6OO ml. of the crude marrow cell suspension used at this time. According to Pegg(1) "Autologous marrow aspiration and storage may be considered a wise precaution when new drugs and treatment schedules are being explored; it may then be possible to treat the occasional unexpectedly severe hemopoietic depression bore effectively." Mathe(2) has demonstrated in one patient that after 800 rad total body irradiation, preceded by 4 days administration of methyl-nitro-imidazolyimercaptopurine, a successful take of homologous marrow occurred. It has already been proved that intravenous administration of bone marrow cells will repopulate the marrow space in mice(19) guinea pigs(19), rabbits(20), and dogs(21). In mice(22), rabbits(23), and dogs(21) intravenous administration of stored marrow cells prevented death after an otherwise lethal dose of radiation. It is not possible to apply this information directly to human beings because of the variable response of different species. We, and others(24) have established in vitro viability of bone marrow cells stored at -80c for as long as one year. However, almost all in vivo studies in human beings where marrow transplant has been attempted did not involve total body radiation or adequate doses of radio-mimetic chemotherapy. Therefore, it is necessary to test in humans the effectiveness of marrow In repopulating the marrow space following total body radiation and to proceed with developmental techniques and refinements of marrow infusion. In the management of patients with malignancy who are to receive myelotoxic agents or of patients who incur marrow injury in other ways (.e.g., warfare, nuclear accident or exposure in space) the availability of stored autologous marrow may well be life saving. Proposed procedures: Five groups of patients will be investigated. Three groups of patients will receive or will have received 150-200 rad total body irradiation as treatment for metastatic malignancy. The first group (Group I) will include patients who have already been irradiated at the 150-200 rad dose level and did not receive bone marrow infusion. A second group (Group II) will be given filtered autologous bone marrow two weeks after irradiation. The third group of patients (Group III) will be treated with 150-200 rad total body irradiation, followed by infusion through filters* of their previously stored marrow on the second day after irradiation. The Group III patients will test the hypothesis that bone marrow "take" is best obtained early after radiation when presumably the narrow space is relatively empty and can accept viable cells more readily(3). Patients selected for Groups Il and III will be those who are to receive total body irradiation in the treatment of metastatic malignancy from various primary sites, excluding neoplasms which are treated by internal radiation, e.g., carcinoma of the thyroid. They will have stable hematologic values and may have received local radiation previously. Patients will be treated with 150-200 rad (midline absorbed tissue dose) of total body irradiation at an exposure dose rate of 4-6R/min. from a Cobalt 60 source. This dose of _____________________________ * The marrow will be infused intravenously with filtration through successive #50, #100 and #200 mesh filters (corresponding to openings of 297, 149 and 74 microns). Filters and tubing will be sterile and pyrogen free. Initially, all marrow will be infused through the filters. If the filtered marrow does not repopulate the marrow space, then unfiltered marrow will be infused to determine whether filtration was the reason the infusion was not effective. radiation approximates the therapeutic and hematologic effects of 0.4-0.6 milligrams of nitrogen mustard per kilogram body weight (1, 4, 5, 6). Complete blood counts including hemoglobin, hematocrit, erythrocyte count, leucocyte count, platelet count, reticulocyte count, differential smears and cell indices will be obtained three to five times in the five to fourteen days pre-irradiation period and l, 2, 3, 6, 9, 12, etc. days after irradiation according to the standard test days of Thoma and Wald(7). Additional counts will be obtained as clinically indicated. In Group II, bone marrow specimens for cytologic and pathologic examination will be obtained from the sternum and anterior ilium prior to irradiation, the day of infusion (prior to infusion), and at weekly intervals after infusion. In Group III, bone barrow specimens for cytologic and pathologic examination will be obtained from the sternum and anterior ilium prior to irradiation, two days after irradiation (prior to infusion), and at weekly intervals after infusion. Bone marrow from the posterior ilium will be stored during the week prior to irradiation by the method of Kurnick(8,9). The bone marrow will be cultured for sterility prior to freezing. In vitro viability of the marrow will be estimated by trypan blue exclusion initially(8), but tests utilizing tissue culture(10), DNA synthesis (Il), and acridine orange(l2) are being developed. Peripheral blood data will be compared to those which we have already obtained in the sixteen patients (Group I) who have been irradiated at the same dose level but have not been infused. Total leucocyte count has been the most valuable variable in assessing hematologic injury following irradiation. The specimens of bone marrow will be studied for morphologic evidence of recovery. All of the studies outlined for Group II and Group III were not performed on patients in Group I. Ideally, all groups should be run concurrently but it would seem unjustified to withhold autologous bone marrow therapy in patients exposed to these doses of radiation when marrow is available. There will be a continuous review of the results as they are being obtained. If it becomes obvious that the results are statistically significant, the study will be terminated. A maximum of thirty-two additional subjects willb be needed for this investigation. Since there are 16 patients in Group l who have already been irradiated, it is advisable to have 16 subjects in Groups II and III respectively. The data from these three groups of patients will be compared with data obtained from patients with similar neoplasms who have been untreated (Group IV) and from patients who have received chemotherapy (Group V). Patients in Groups IV and V will be paired with patients in Groups I, II, and III according to age, sex, race, type, duration and extent of neoplasm. As a result of this comparison, it will be possible to determine the palliative value of total body irradiation at this dose level with and without bone marrow infusion. Potential Hazards: (a) With any irradiation therapy there is the danger of radiation injury. We have observed consistent depression of hematologic values in the control group. One might wonder why 150-200 rad of total body radiation is selected as the treatment in this group of patients. As has been noted earlier, this dose range has therapeutic effectiveness equal to 0.4-0.6 mgm/kilo of nitrogen mustard. It is proposed because an observable therapeutic effect would be anticipated. At 150-200 rad, the effect of marrow reinfusion will be detectable. There are important differences between radiation and radiomimetic chemotherapy as well as certain similarities. A particular difference is of importance in this study. The margin of safety separating marrow death and lethal effects on other systems is smaller with chemotherapy than it is with total body irradiation; i.e., the amount of chemotherapy treatment to produce equivalent change in peripheral blood is more hazardous. Marrow infusion has no detectable effect unless very large doses of chemotherapy are used which then result in significant injury to other systems. In this study the prodromal morbidity (anorexia, nausea, vomiting) would approximate 60%, As to mortality figures at the dosages to be evaluated, in human beings bone marrow aplasia occurs at 450 R and "intestinal death" occurs above 1000 R. Without hospital care it is felt that a human LD 50 may a pproximate 500 R and with hospital care about 700 R. Therefore total body radiation between 450 R and 1000 R is the dose where death from bone marrow aplasia is expected. The doses proposed are below these levels. When the mean survival time of patients treated with less than 100 rad, 125 rad, 150 rad, and 200 rad are compared there is no progressive decrease related to dose (Tables I, II). If the patients with survival times of 9 and 10 days are excluded and the patients still living at the present time are included there is still no significant difference in survival time which can be associated with the irradiation as determined by several statistical tests. In fact the data suggests that a therapeutic effect from the radiation therapy has been obtained. The use of autologous and isogeneic marrow in humans has been investigated by others (8, 9, 13, 14). When marrow has been infused too rapidly, cerebral hemorrhage, hemoglobinemia and hemoglobinuria have been observed. These hazards have not been encountered when the rate of infusion has been maintained below 60 drops/rain. There is disagreement as to the need for filtration. Kurnick does not feel it is necessary at the time of infusion; T homas, Ferrebee, and Pillow (13, 14, 15) recommend its use to minimize the incidence of pulmonary embolism. A series of filters will be used with the now operational constant rate infusion pump. To date, we have infused unfiltered marrow intravenously in five patients. One patient had hemoglobinuria. Autopsy material from three of these patients has been studied by Drs. E. A. Gall and B. Yamaguchi. No evidence of pulmonary emboli, pulmonary infarction or other disease as a result of marrow infusion was found on microscopic examination. b. All patients will be followed carefully clinically. Hematological data are accumulated at frequent intervals and all measures to control infection will be used. They may include plastic barrier and reverse isolation if needed. Prophylactic antibiotic therapy will not be prescribed. Previous work done in this area: During the past five years an ongoing study of the metabolic effects of total body irradiation has been in progress. To date, forty patients have been treated with 25 to 200 rad total body irradiation. Eighteen of the patients were given 150-200 rad. The clinical course of these patients has paralleled that of comparable patients treated with other agents. Bone marrow from twenty-three patients has been stored; it has been infused intravenously in five. Marked hematologic depression occurred in all eighteen patients who received more than 125 rad total body radiation. There was a total leucocyte count depression below 2000 WBC/mm3 and platelet count depression 25-40 days after irradiation. The mean minimum leucocyte count of previously untreated patients who received 150 rad total body radiation only was 1264 +- 1140, and was 1140 +- 816 when there had been previous therapy. The nadir of the leucocyte counts of patients who received 200 rad was 983 +- 369. A comparison of the hematologic changes in patients receiving partial body irradiation with those who received total body irradiation revealed a paucity of change in the total WBC, platelets, and hematocrit even when the patient received more than 200 rad partial body radiation. In two of the ten patients who were given partial body irradiation, lymphopenia did not occur until 48 or 72 hours after exposure. Infusion of stored autologous bone marrow has been completed in five patients. The marrow was infused intravenously without filtration(13). In one patient the response suggested marrow space repopulation. Chromosome studies have been performed in these patients. In four patients who were studied in detail, endore duplication has been seen with increased incidence in the peripheral blood chromosome preparations(16). This observation may be associated with malignancy but was increased following total body irradiation. As an outgrowth of the experience with endore duplication, the question as to whether the malignant cell was the one which might be undergoing endore duplication wad considered. Therefore, a method of cell separation utilizing a Ficoll gradient and ultracentrifugation was undertaken. Friedman et.al., have reported adequate separation of lymphocytes from granulocytes. Chromosome culture techniques following this cell separation have revealed metaphases(17). Another facet of considerable interest in patients receiving large doses of total body irradiation has been the question of immunologic response. In cooperation with A. J. Luzzio, studies of serum obtained from patients before and after total body irradiation have been performed. These data suggest an alteration in the antigenicity of human serum gamma globulin as a result of in vivo irradiation(18). Method to be used in procuring consent of subjects above: Consent forms, as attached, have been used since May 1, 1965. These forms are signed only after the patient has been advised of the research and study aspect of the procedures to be used. The patients are told this is a form of therapy but that benefits cannot be guaranteed. They are advised of the possible complications, including the possibility of pulmonary infarct following marrow infusion. Since total body radiation is another mode of treatment for patients with an ultimately fatal disease, it is only correct to indicate the possibility of therapeutic advantages. All patients are informed that a risk exists, but that all precautions to prevent untoward results will be taken. General Remarks: Many studies have been carried out in animals regarding the protective effect of bone barrow following radiation. They are well summarized in these paragraphs from Pegg's book. "The possibility of protecting mice and guinea pigs with allogenic hemopoietic cells was first demonstrated by Lorenz and Congdon (Lorenz, et.al., 1952; Congdon, et.al., 1952). Similar results have been obtained in rabbits (Hilfinger, et.al., 1953; Porter, 1957; Porter and Murray, 1958; Hupka, et.al., 1961); rats (Gorizontov, et.al., 1963) and, after some initial failures (Weston, 1958; Rothberg and Akeroyd, 1958), successful protection has also been obtained in the monkey (Crouch and Overman, 1957); (Overman, 1958). Similarly, there have been many failures in irradiated dogs (Porter and Couch, 1959; Stecher and Sullivan, 1959; Alpen and Baum, 1958; Puza, et.al., 1961; Jordan, et.al., 1961) but the Cooperstown group using more closely related dogs have reported more successful allogenic protection (Ferrebee, et.al., 1958; Thomas, et.al., 1958; Thomas, et.al., 1959) Others have since confirmed these findings (Trumbull, et.al., 1963; Winchell, ct.al., 1963)." "The survival of irradiated mice infused with guinea pig marrow was reported by Congdon, et.al. 1952, but others have been unable to confirm this (Barnes and Loutit, 1954a). There is, however, wide agreement that rat bone marrow will protect the irradiated mouse (Vos, et.al., 1956; Nowell, et.al., 1956; and Gengozian and Makinodan, 1957)." As was indicated under the "Purpose of this study," it is most important that methods of protecting against the undesirable effects of therapeutic efforts--radiation or other cytotoxic agents--be developed. Since hematologic depression is one of the earliest limiting biologic responses to such treatment, it is the first for which protective methods must be developed. Based on animal work, it would seem that autologous marrow is the safest protective technique to be used initially. This study is proposed as a continuation of the work cited for the following purposes: 1. To evaluate the role of total body radiation and autologous bone arrow in the treatment of extensive neoplasms. 2. To evaluate bone marrow transfusion in the treatment of bone marrow depression from chemotherapy. 3. To determine whether stored autologous bone marrow therapy may play a role in treatment of bone marrow depression following acute radiation exposure in warfare occupationally induced accidents. This work is considered to be of vital importance not only for improving the survival of patients with far advanced cancer but for the survival of the citizens of this nation in the event of nuclear warfare or a major radiation accident. References 1. Pegg, E.E. Bone Marrow Transplantation. Year Book Medical Publishers, Inc., 35 East Wacker Drive, Chicago, Illinois, 1966. 2. Mathe, G., Aniel, J. L., Schwarzenberg, L., Cattan, A., and Schneider, M. Haematopoietic Chimera in Man After Allogenic (Homologous) Bone-Marrow Transplantation. Brit. Med. Jour., 2:1633, 1963. 3. Congdon, C. C. Recovery frog Radiation Injury, with Special Consideration of the Use of Bone Marrow Transplantation, p. 21 in Progress in Hematology, Vol. II, Tocantins, L.M. ed., Grune and Stratton, 1959. 4. Miller, L.S., Fletcher, G.H., and Gerstner, H.G. Systematic and Clinical Effects Induced in 263 Cancer Patients by Whole-Body X-irradiation with Nominal Air Doses of 15 to 200R. School of Aviation Medicine, USAF, Report No. 57-92. 5. Collins, V. P., Loeffler, R. K. and Hyman, G.A. Comparative Effects of Total Body Radiation, Nitrogen Mustard and Triethylene Melamine on the Hematopoietic System of Terminal Cancer Patients. Science, August 7, 1963, Vol. 118, No. 3058, pages 161-163. 6. Collins, V. P. and Loeffler, R. K. The Therapeutic Use of Single doses of Total Body Radiation. The Amer. Jour. of Roentgenology, Radium Therapy and Nuclear Medicine, Vol, LXXV, No. 3, March, 1956. 7. Thoma, G.E. and Wald, N. The Diagnosis and Management of the Accidental Radiation Injury. Jour. of Occupational Med. 1:421, 1959. 8. Kurnick, N. B., Feder, B. H., Montano, A., Gerdes, J.C. and Nakamura, R. Some Observations on the Treatment of Post- Irradiation Hematopoietic Depression in Man by the Infusion of Stored Autogenous Bone Marrow, Ann. Int. Med. 51:1204, 1959. 9. Kurnick, N. B. Autologous Bone Marrow in the Treatment of Severe Iatrogenic Myelo-Suppression. Diagnosis and Treatment of Acute Radiation Injury; 1961, Geneva, World Health Organization, p. 309. 10. Moorehead, P. S., Newell, P.C., Mellman, W. J., Battips, D.M., and Hungerford, D.A. Chromosome Preparations of Leukocytes Cultured from Human Peripheral Blood, Experimental Cell Research 20:613, 1960. References (continued) 11. Lewis, J. P. Assay of the Transplantation Potential of Bone Marrow, Proc. Inst. Med. Chicago 24:227, 1963. 12. Hathway, W.E., Newby, L.A., Githens, J.H. The Acridine Orange Viability Test Applied to Bone Marrow Cells, I. Correlation with Trypan Blue and Bosin Dye Exclusion and Tissue Culture Transformation. Blood 23:517, 1964. 13. Thomas, E.D., and Lochte, H. L., Lu, W. C., and Ferrebee, J. W. Intravenous Infusion of Bone Marrow. New Eng. J. of Med. 257: 491, 1957. 14. Pillow, R. P., Epstein, R. B., Buckner, C.D., Giblett, E. R. and Thomas, E. D. Treatment of Bone-Marrow Failure By Isogenic Marrow Infusion. N. Eng. Jour. of Med. 275:94-97, 1966. 15. Ferrebee, W., Atkins, L., Lochte, Jr., H. L., McFarland, R. B., Jones, A. R., Dammin, C. J. and Thomas, E. D. The Collection, Storage and Preparation of Viable Cadaver Marrow for Intravenous Use. Blood 14:140-147, 1959. 16. Friedman, B. I., Saenger, E. L., Kreindler, M. S. Endore- duplication in Leucocyte Chromosomes, Preliminary Report of its Relation to Cancer and Whole-Body Irradiation. The Lancet, September 5, 1964, pp. 494-495. 17. Friedman, B. I. and Toler, S. J. Chromosome Studies of Peripheral Blood Leukocytes Separated by Centrifugation in a Ficoll Gradient, Experimental Hematology, No. 9, 1966, p.34. 18. Luzzio, A. J., Friedman, B. I., Kereiakes, J.G. and Saenger, E. L. Specific Proteins in Serum of Total-Body Irradiated Humans. Jour. Immunol. 96:64, 1966. 19. Lorenz, E., Congdon, C.C., and Uphoff, D. Modification of Acute Irradiation Injury in Mice and Guinea Pigs by Bone Marrow Injections, Radiology, 58:863-877, 1952. 20. Porter, K. A. Effects of Homologous Bone Marrow Injections in X-Irradiated Rabbits, Brit. J. Exper. Path. 38:401-412, 1957. 21. Cavins, J. A., Kasakura, S., Thomas, E.D. and Ferrebee, J.W. Recovery of Lethally Irradiated Dogs Following Infusion of Autologous Marrow Stored at Low Temperature in Dimethyl- Sulphoxide, Blood, 20:730-734, December, 1962. References (continued) 22. Ferrebee, J. W., Billen D., Urso, I.S., Lu, W.C., Thomas, E. D. and Congdon, C.C. Preservation of Radiation Recovery Factory in Frozen Marrow, Blood 12:1096-1100, 1957. 23. Porter, K.A. and Murray, J. E. Successful Homotransplantation of Rabbit Bone Marrow After Preservation in Glycerol at -70 c., Cancer res. 18:117-119, 1958. 24. Lochte, H. L., Jr., Ferrebee, J. W. and Thomas, E. D. In Vitro Studies on the Preservation of Marrow Cells in Glycerol at Low Temperatures, J. Lab. Clin. Med., 53:117, 1959. TABLE I Survival time in days Dose <50 rad 1 0 rad 150 rad 200 rad 9 32 10 28 73 49 25 36 80 85 30 194 113 91 32 298 438 121 33 649 740 197 54 885 L* 200 74 239 151 324 262 446 270 646 592 650 830 L L *Living TABLE II SURVIVAL TIME OF PATIENTS TREATED WITH TOTAL BODY RADIATION* Dose 50 rad 100 rad 150 rad 200 rad N 6 12 12 6 Mean 242 257 197 348 Median 96 198 64 246 *Excludes patients living at this tine TO: Dr. Edward A. Gall FROM: Dr. George Shields DATE: March 13, 1967. SUBJECT: Protection of Humans with Stored Autologous Marrow I regret that I must withdraw myself from the subcommittee studying this proposal, for reasons of close professional and personal contact with the investigators and with some of the laboratory phases of this project. The following comments are sent to you in confidence, at your request. This protocol is difficult to evaluate The purpose of the study is obscure, as is the relationship of the experimental groups to the purposes. The significance of the study in relation to the health of the patients under study may be considerable if the investigators succeed in prolonging life of these patients with malignant disease, but the risk of treatment may be very high if the authors' hypothesis'( that bone marrow transfusions will ameliorate bone marrow depression due to radiation) is incorrect. The radiation proposed has been documented in the author's own series to cause a 25% mortality. I recommend that this study be disapproved, because of the high risk of this level of radiation. Admittedly it is very difficult, in fact impossible, to balance potential hazard against potential benefit in experiments of this sort. The stakes are high. Our current mandate is that we evaluate the risks on some arbitrary scale. I believe a 25% mortality is too high, (25% of 36 patients is 9 deaths) but this is of course merely an opinion. If it is the consensus of the investigators and the review committee that a 25% mortality risk is not prohibitive, then the experiment could be reconsidered from the standpoint of informed consent - provided the patient is appraised of this risk in a quantitative fashion. I believe that the conditions of informed consent will have been observed if the authors change "all patients are informed that a risk exists, but that all precautions to prevent untoward results will be taken " to the-equivalent of "all patients are informed that a 1 in 4 chance of death within a few weeks due to treatment exists, etc." Finally, although it is not our concern directly, a comment as to experimental design is indicated in this particular protocol. The authors' stated purposes are vague in the first page of the application, but on the last page three purposes are listed and numbered. The first of these cannot be evaluated by the experimental design proposed since it would require an untreated group and no reference has been made by the authors to such an untreated group of patients. The second purpose can be fulfilled by this protocol only with the retrospective group (Group I). The evaluation of bone marrow transfusion in the treatment of bone marrow depression would require a concomitant control group of patients treated only with radiation. It is apparent that the authors feel the radiation risk is too high to re-expose another group to this level of radiation without some effort at radio-protection, and therefore the authors have chosen to use the retrospective group as a control. There is considerable question whether this retrospective group will be entirely similar and therefore whether it will serve the second purpose. The third purpose, "to determine whether autologous bone marrow therapy may play a role in treatment of bone marrow depression following acute radiation exposure in warfare or occupationally induced accidents", is not the subject of this experiment because normal individuals are not being tested. -2- It is problematic whether the information gained in this study will apply to normal individuals following acute radiation exposure. Therefore, it is my definite opinion that the third purpose of this experiment would not justify the risk entailed. For these several reasons I feel that the experimental design is inadequate, and because of the high risk inherent in this level of radiation, I think experimental design should be a proper subject for our consideration in this instance. Enclosure: Protocol DASA-1844 UNIVERSITY OF CINCINNATI INTERDEPARTMENTAL CORRESPONDENCE SHEET Dr. Richard Gall, Chairman Clinical Research Committee FROM Dr. Thomas E. Gaffney Date 4/17/67 I cannot recommend approval of the proposed study entitled "The Therapeutic Effect of Total Body Irradiation Followed by Infusion of Stored Autologous Marrow in Humans" for several reasons. The stated goal of the study is to test the hypothesis that total body irradiation at a dose of 200 rad followed by infusion of stored autologous marrow is effective, palliative therapy for metastatic malignancy in human beings. I don't understand the rationale for this study. The applicants have apparently already administered 150-200 rad to some 18 patients with a variety of malignancies and to their satisfaction have not found considerable morbidity associated with this high dose radiation. Why is it now logical to expand this study? Even if the study is expanded, its current design will not yield meaningful data. For instance, the applicants indicate their intention to evaluate the influence of 200 rad total body radiation on survival in patients a variety of neoplasms. This "variety" or heterogeneity will be present in a sample size of only 16 individuals. It will be difficult if not impossible to observe beneficial effect in such a small sample containing a variety of diseases all of which share only CANCER in common. This gross deficiency in design will almost certainly prevent making meaningful observations. When this deficiency in experimental method is placed next to their previously observed poor result and high morbidity with this type of treatment in a "variety of neoplasms" I think it is clear that the study as proposed should not be done. I have the uneasy suspicion, shored up by the revised statement of the objectives, that; this revised protocol is a subterfuge to allow the investigators to achieve the purpose described in their original application; namely, to test the ability of autologous marrow to "take" in patients who have received high doses of total body radiation. This latter question may be an important one to answer but I can't justify 200 rad total body radiation simply for this purpose, "even in terminal case material" (italics are mine). I think there is sufficient question as to the propriety of these studies to warrant consideration by thc entire Research Committee. I recommend therefore that this protocol and the previous one be circulated to all members of the Committee and that a meeting of the entire Committee be held to review this protocol prior to submitting a recommendation to the Dean. Sincerely, Thomas E. Gaffney, M.D. DATE: 29 April 1967 To: Dr. Edward A. Gall From: Edward P Radford, M.D. Subject: Application of Dr. Ben I. Friedman and Dr. Eugene L. Saenger The present proposal has been modified to emphasize, at least initially, the potential therapeutic value of the irradiation. I am somewhat concerned, nevertheless, that (page 5) "If it becomes obvious that the results are statistically significant, the study will be terminated." Significant of what -- increased survival, or just a better hematologic picture? In the previous work cited, there is no mention of the possibility that this dose of whole body irradiation is at all palliative for metastatic cancer. Are no animal experiments available, and if not, why not? The previous work done on Group l patients is meaningless with regard to therapy and I think they prejudice their case by even mentioning them. The consent from and procedure for its use is good. Recommendation: Approval, but with the proviso that a further statement concerning the possible therapeutic aims be made, specifically with regard to previous work done with whole body irradiation. UNIVERSITY OF CINCINNATI INTERDEPARTMENTAL CORRESPONDENCE Dr. Edward Gall From Dr. Harvey C. Knowles, Jr. Date May 5, 1967 I reviewed the study proposal of Drs. Friedman and Saenger entitled "The Therapeutic Effect of Total Body Irradiation Followed by Infusion of Stored Autologous Marrow in Humans." After careful perusal, I approve of the study. I realize that hazards are involved, but I believe that careful monitoring will keep these to a minimum. HCK: jam UNIVERSITY OF CINCINNATI INTERDEPARTMENTAL CORRESPONDENCE SHEET TO E. A. Gill, M.D. From R.L. Witt, M.D. Date May 9, 1967 It is not clear to me from the protocol (although if I were to read the references I might learn) whether total body radiation used by others for palliation is in any way effective in man or animals in the palliation of widespread malignancy. I have the feeling from the protocol that the real intent is to work on the problem of infusion of marrow. I do not think I can approve the project until the matter of the likelihood of benefit to the individual patient being treated is cleared up. UNIVERSITY OF CINCINNATI INTERDEPARTMENTAL CORRESPONDENCE SHEET TO Dr. E.A. Gall From Dr. H.C. Knowles, Jr. Date May 5, 1967 I received the study proposal of Drs. Friedman and Saenger entitled "The Therapeutic Effect of Total Body Irradiation Followed by Infusion of Stored Autologous Marrow in Humans." After careful perusal, I approve of the study. I realize that hazards are involved, but I believe that careful monitoring will keep these to a minimum. HCK:jam UNIVERSITY OF CINCINNATI INTERDEPARTMENTAL CORRESPONDENCE SHEET To E. A. Gall, M.D. From R. L. Witt, M.D. Date May 9, 1967 It is not clear to me from the protocol ( although if I were to read the references I might learn) whether total body radiation used by others for palliation is in any way effective in man or animals in the palliation of widespread malignancy. I have the feeling from the protocol that the real intent is to work on the problem of infusion of marrow. I do not think I can approve the project until the matter of the likelihood of benefit to the individual patient being treated is cleared up. UNIVERSITY OF CINCINNATI INTERDEPARTMENTAL CORRESPONDENCE SHEET To Dr. E. A. Gall From Dr. H. C. Knowles, Jr. DateMay 17, 1967 This concerns the research proposal of Drs. Ben Friedman and Eugene Saenger entitled "The Therapeutic Effect of Total Body Irradiation Followed by Infusion of Stored Autologous Marrow in Humans." After study of the proposal and listening to testimony this morning from Drs. Ben Friedman and Harry Horwitz (serving as consultant) I give provisional approval to the proposal. I have two suggestions, however. First, I believe a statement should be inserted to the effect that the radiation therapy to be used is an accepted form of treatment and that beneficial therapy is not being withheld. Second, I believe a statement might be made that means of measurement of dependent variables in question are judged satisfactory to determine a difference between groups II and III. In addition, some statement might be made to the effect that sampling of the population will be at random and that all efforts will be made to reduce the number of independent variables and keep heterogeneity at a minimum. I assume all this is present in the investigators' mind. It would help to have it on paper. I realize that my second request deals with experimental design, a matter which is really not the responsibility of the Committee. Nevertheless, we are balancing the good to come against hazards encountered, and the good to come is related to the experimental design. I believe that merely a few sentences can be added to the protocol to clarify these points. I am leaving all of this to your discretion, however. UNIVERSITY OF CINCINNATI INTERDEPARTMENTAL CORRESPONDENCE SHEET To E. A. Gall, M.D. From R. L. Witt, M.D. Date May 17, 1967 In regard to the recent committee deliberation on the total body radiation project, the recommendation I would suggest be included with the approval is: A simple sentence or paragraphshould be inserted to clarify the therapeutic implications and/or possibilities. UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE DEPARTMENT OF INTERNATIONAL MEDICINE MAILING ADDRESS:DEPARTMENT OF PHARMACOLOGY DIVISION OF CLINICAL PHARMACOLOGY EDEN AND BETHESDA AVENUE CINCINNATI, OHIO 45219 872-5621 May 18, 1967 Dr. E. A. Gall Dept. of Pathology Cincinnati General Hospital Cincinnati, Ohio 45229 Re.: The Friedman Proposal for studies in total body radiation. Dear Dr. Gall: The only proviso I would suggest is that the applicants give at least some consideration to the basic rudiments of experimental design which are necessary to the completion of studies of the type contemplated. Sincerely, Thomas E. Gaffney, M.D., Director Division of Clinical Pharmacology American College of Radiology: 20 North Wacker Drive, Chicago, Illinois 60606 (312) 236-4963 Washington Office: 6900 Wisconsin Ave, Chevy Chase, Maryland 20015 (301) 654-6900 January 3, 1972 The Honorable Mike Gravel 1251 New Senate Office building Washington, D.C. Dear Senator Gravel: This letter represents our response to your request of us to inquire into the whole-body radiation therapy project being conducted by Dr. Eugene L. Saenger and his colleagues at the University of Cincinnati. We have made our inquiry and our broad conclusions are as follows: l. In the normal context of a clinical investigation, the project is validly conceived, stated, executed, controlled and followed up. The appropriate scientific and professional committees of the University of Cincinnati have performed their functions during the course of the project. 2. The process of patient selection based upon clinical considerations conforms with good medical practice. 3. The records, publications and patient follow-up are voluminous and commendable. 4. The procedure used for obtaining patient consent is valid, thorough and consistent with the recommendations of the National Institutes of Health and with the practice of most cancer centers. 5. Should this project come before the Senate or one of its committees in some fashion, we would urge your support for its continuation. Though physicians do not invariably share with the public the ways in which they reach professional conclusions, we think it appropriate to your inquiry to detail below the way in which we reached these conclusions. Our acceptance of your request gas based upon the realization that senators have need of expert, impartial medical and scientific advice in evaluating complex biomedical problems. Should you desire further information, we will again endeavor to be responsive. The committee As I noted in my earlier letter to you, the College is seldom called upon to investigate the scientific efforts of any of its members and thus has no standing committee with such a charge. Instead, I asked two leading radiation therapists and a third distinguished physician to undertake the inquiry. They are: Page 2 Dr. Henry Kaplan, chairman and professor of radiology at Stanford University, Medical School in Palo Alto, California. Dr. Kaplan is internationally known for his pioneering work in several areas of cancer therapy. He has been a member of various cancer study and advisory groups including the Committee of Consultants to Conquer Cancer which recently advised the Senate. His extensive bibliography includes descriptions of his work on Hodgkin's disease involving extensive radiation of patients. Dr. Kaplan is currently chairman of our commission on Cancer. Dr. Frank R. Hendrickson, chairman of the department of radiation therapy at Chicago's Presbyterian St. Luke's Hospital. Dr. Hendrickson is also a faculty member of the University of Illinois College of Medicine and the Rush Medical College as well as a consultant to the Veterans Administration and a member of various national cancer bodies. His bibliography includes reports of his treatment of children afflicted with Swing's sarcoma with radiation. He is the present chairman of our Commission on Radiation Therapy. Dr. Samuel Taylor,III, a distinguished internist and oncologist at Presbyterian St. Luke's Hospital in Chicago. He is the founder of the American College of Physicians cancer program. He is a professor of medicine at Rush. Dr. Taylor's wide experience as a senior investigator in the field of cancer provided us with a view from another discipline. He is a long time expert in chemotherapy of disseminated cancer. Mr. Otha Linton, director of our Washington office, provided staff support to the group and coordinated their inquiry with Dr. Saenger and his colleagues. Nature of the inquiry Drs. Kaplan and Hendrickson and Mr. Linton met with Dr. Saenger and Dr. Charles M. Barrett, director of radiation therapy at the University of Cincinnati November 29 in Chicago. The discussion covered the background of the project and the purposes, objectives and achievements of the effort to date. Dr. Saenger then provided the committee with published papers and summary materials about the project. on December 16, Drs. Kaplan, Hendrickson and Taylor met in Cincinnati with Dr. Saenger, other members of his team, two members of the University of Cincinnati human investigation committee, and the chairman of the special university committee which was created by the president to review the project. Those interviewed were, from the UC Human Research Committee, Dr. Evelyn V. Hess, professor of medicine and Dr. Harvey C. Knowles, Sr., professor of medicine, from the special university committee to review the Saenger project, Dr. Raymond R. Suskind, professor of environmental health and medicine, from the department of radiology and the study team, Drs. Charles M. Barrett, Harry Horwitz, Bernard S. Aron and Edward B. Silberstein, physicists, Drs. I-Wen Chen and James G. Keriakes, and the psychologist, Mrs. Carolyn N. Winget. Page 3 Dr. Saenger and everyone at the university were willing to recognize our competence and to cooperate fully without inquiry. The committee members were extended full cooperation and can conclude that they apprised themselves of the situation to the same extent that they would have needed to do as members of an NIH study section or site review team. Each member of the committee has served in such a capacity. The committee viewed the project as it was designed---as a clinical investigation of a modality for the care, of cancer patients with extensive and incurable disease. Phase one investigations follow basic animal work and always precede randomized clinical trials which may or may not be justified on the basis of the first human applications. In the opinion of the committee, the team at Cincinnati had abundant bases in the literature for undertaking its study. The participants are fully qualified to undertake the investigation from the viewpoint of good patient care and importantly the possibility that new and valuable clinical information could be obtained. Our committee did not concern itself with the implications which have been raised concerning partial funding of the effort by the Department of Defense. We did note that DOD funds were used only to support the laboratory and psychological studies but not the treatment or the care of the patient. The basic costs were borne by the university and its teaching hospitals. Because of the prevalence of cancer which has been noted so recently by the Senate, the House of Representatives and the President those charged with the care of cancer patients have need for every possible bit of information concerning the methods and modalities which we use to treat these patients. In our opinion this project has the possibility of contributing useful clinical information. It is worth noting that if others have had access only to the reports made to the DOD on its part of the project or if they somehow failed to understand that the fact of extensive follow-up in no way departed or detracted from fundamental precepts of good patient care, then it follows that they might reach conclusions different from those of our committee. The nature of cancer investigations and treatment In clinical investigations of cancer, we are concerned both with the basic cancer process and with its manifestations in humans and specifically in the patients who present themselves for care. The treatment of an individual represents a series of choices for his physicians which are based upon diagnostic findings and their best judgement. Since humans respond to the assault of cancer and to attempt to treat it as uniquely as they do to most other things, generalizations here have statistical value but limited application to individuals. Page 4 There are many forms of cancer. Each type has in common the loss of intracellular control upon which normal cells depend to regulate their growth. The cancers differ in cellular types and in the site of origin of a primary lesion within the body as well as the bodily pathways through which they may spread. Thus, for example, the problem of defining and treating a solid tumor may differ radically from the approach to a form of leukemia. Physicians have three fundamental modalities which may be used singly or combined to attempt to cure or control cancers. These are extirpative surgery, high energy radiation and chemicals. Hormones also are used to attempt to alter the course of certain cancers involving the endocrine system. The choice of treatment must be decided for each patient. The decision is based upon the type of cancer, its location, its, size, its degree of spread and upon the age and general health of the patient. Ideally, the therapeutic decision is made in a cancer conference involving physicians from the different disciplines appropriate to the problem at hand. By the nature of the disease, any cancer therapy must be regarded as heroic. The cancer patient must accept lesser probabilities of success and bore stringent side effects of treatment than usually befall sufferers from other diseases. Timing is all important in the treatment of most cancers. A small, early cancer may be removed surgically or destroyed with radiation. But if the cancer has begun to spread beyond its original site and beyond the surgical or radiation field, the destruction of the primary lesion will not suffice to save the patient. Unfortunately, many patients still are diagnosed as having far advanced cancer which must be judged unlikely to respond to any standard curative effort. These patients may have undergone various treatments without success or they may have had a "silent" primary cancer which was diagnosed only after it began to spread through the body. The physician having the care of a patient with advanced cancer has three practical choices. One is to do nothing, allowing the disease to take its course. Another is to attempt palliation, an effort to retard the tumor growth and/or to ease the pain of the patient. The third is to attempt drastic or radical treatments not commonly accepted as reliable or efficacious for patients having a greater chance of success. The third approach carries the long- shot possibility of direct patient gain. The doctor and patient must agree that something of benefit to others may be learned from the effort. Thus, the effort to improve Cancer treatments has been based upon the first application of new or questionable technique. to those patients having nothing to lose by their failure because there is no known treatment available. Often, the effectiveness of the technique must be measured in time of survival, relief of pain, or from certain, body measurements, rather than in terms of overt tumor destruction. Efforts must be made to isolate and measure the specific timing, dosages, procedures and restraints which can be observed to alter the course of the disease. Then a form of treatment has been shown to have some measurable beneficial effect on far advanced patients it can be considered for general use. Page 5 The nature of cancer investigation requires that more than one therapist bust undertake a new modality at each stage of its development before it can be accepted for general usage. If an improvement in some tool or resource becomes available, such as the advent of supervoltage radiation sources then previous studies may be repeated with profit. Both the high energy radiation and the several chemicals now used,in cancer therapy have harmful effects upon patients. So does radical surgery. The choice must be made to refrain from curative efforts when the destruction of the tumor would involve unacceptable side effects of a localized or systematic nature. Thus, efforts to control or relieve side effects are equally significant with those to destroy the tumor. When radiation is used as the tumoricidal agent, the effort is made to limit its effects by tailoring the dose to the suspect area and by using a series of tolerable exposures to destroy the cancer cells without damaging vital organs and adjacent normal tissues. If a cancer is widespread, then a tumoricidal dose of radiation presents problems which, for the most part, remain unsolved. Lesser amounts of radiation have been used in various ways as part of efforts to retard tumor growth, to relieve pain or to alter the pattern of cancer development. The literature of radiation therapy offers substantial numbers of citations of efforts to use whole or partial body radiation for the palliation of advanced cancers. The conclusion, broadly, trust be that the concept has not been sufficiently productive to recommend generally nor so lacking in effect to be abandoned as an approach. The Cincinnati Project The actual treatment of patients was begun in 1960 by Dr. Saenger and his colleagues as a clinical assessment of the use of sublethal whole body radiation for the palliation of patients with a variety of disseminated cancers. The premise was that the level of radiation selected would have a retardant effect upon the growth of the tumor cells throughout the body and that the patient,for the most part, could tolerate the side effects of systemic radiation. The second part of the premise was that patients who were closely followed after their cancer treatments could indicate both the physical and psychological reactions to the therapeutic effort over a period of several weeks. This clinical assessment provided a new dimension to previous studies of the use of whole body radiation. Beginning in 1964, the group began to use the technique of autologous bone marrow transplants as a means of overcoming the marrow depression otherwise inescapable after whole body radiation. The technique after some modification involves the extraction of 300 to 600 cubic centimeters (about a pint or so) of marrow from the posterior iliac crest just before the radiation exposure. The same day, the marrow is filtered and reinjected into the patient. As a clinical procedure, this has succeeded in averting most of the extended radiation syndrome effects previously observed in patients in this series and in other whole body studies. Page 6 Efforts to minimize late effects, such as the drop in white cells and platelets and,the decrease in red blood cells which are classic to radiation syndromes, before in 1965. This method using autologous bone marrow immediately after radiation therapy, became practical early in 1969. The concept of whole body radiation as a method of treating cancer is not new with the, Cincinnati project. There is voluminous literature reporting controlled animal experiments which are highly useful but not indicative of human responses to human tumors. The literature reporting on human exposures dates back to efforts in 1923. A review of reports to 1942 showed more than 270 patients thus treated with fairly little encouragement. Since these patients in All cases had disseminated tumors and the radiation sources available were in the orthovoltage range, the results were not surprising. The advent of supervoltage generators and particularly cobalt 60 sources prompted additional studies to assess the effect of higher energy radiation and led to a new round of studies. In 1953, V. P. Collins and R.K. Loeffler called the use of 200 roentgens whole body "a useful addition to the management of advanced cancer. A current bibliography contains some 86 scientific articles on the subject, excluding Dr. Saenger' s contributions. Whole body projects have been undertaken in more than 42 U. S. medical centers. At present, efforts are underway using whole or partial body radiation for the control of leukemia, Hodgkin's disease, polycythemia vera, multiple myeloma, and disseminated cancers of the breast, thyroid and prostate. In very small groups, whole body radiation has been used successfully in curative efforts against Ewing's sarcoma, a bone tumor primarily of children. The Cincinnati study through the end of 1970 involved a total of 106 patients referred from the Tumor Clinic of the Cincinnati General Hospital. These were patients found by biopsy and clinical examination to have disseminated tumors. They "were chosen because they suffered from advanced and widespread neoplastic disease such that cure could not be anticipated," in Dr. Saenger's words. All of the patients underwent a 7 to 14 day assessment period to reaffirm the diagnosis and to determine whether their disease and their general health would make the radiation attempt feasible. Some 24 patients were rejected and received no radiation on the basis of their clinical assessment. Some of the 82 patients later treated received sham radiation sessions during, the assessment period but none actually were exposed until after a decision by the team which determined the treatment could be beneficial. The patients had a variety of tumors. The largest group was 25 with cancers originating in the colon and rectum. A second group of 14 bad tumors of the bronchus. Fifteen women had disseminated breast cancer. There were 25 patients with miscellaneous tumors. Three children had Ewing's sarcoma and were treated for curative effect. One of the 25 patients with miscellaneous tumors had Ewing' s sarcoma with metastases too widespread for a curative effort. Page 7 Discussions with the patients and members of their families are standard in any cancer therapy situation and we're a part of this project from its beginning. Specific patient consent forms have been used since 1965, when this step was recommended by the National Institutes of Health. Since 1968, patients selected for the study were interviewed on succeeding days by the internist in the project before being asked to sign a consent form for the therapy. When possible and in all cases of children, the interview included one or more members of the family who also consented to the treatment. Except for the three children with Swing's sarcoma, all were told that their cancers had been defined as incurable and that the treatment would be attempted in an effort to prolong their lives and possibly to retard or shrink the tumors. They were told that the information gained from the study was hoped to be helpful to other patients. In the last few years they were told that the information might have military as well as clinical significance. The patients were told that there could be some side effects from the radiation exposure and that the team would wish to keep in close touch with them for a period of weeks to study their reactions both to the advances in their disease and to the impact of the radiation. The possible side effects were not described in detail nor emphasized to avoid subjective inducement of the symptoms. So far as the side effects were concerned, the team reported that 45 percent had no vomiting or nausea after the radiation. Some 24 percent experienced transient vomiting and nausea within three hours and another 17 percent had the same symptoms within 12 hours of exposure. Another 9 percent continued vomiting up to 24 hours. Only five percent had prolonged and severe vomiting and nausea. It is worth noting that these symptoms are certainly no greater than those experienced by patients treated either by surgery or by any of the systemic drugs now being used clinically on disseminated Cancers. The patients were selected by clinicians at the Cincinnati General Hospital from the population served by that institution solely on the basis of their tumor diagnosis. Since CGH is an institution, none of the patients were private patients. The three children with Ewing's sarcoma were referred by physicians at the affiliated Cincinnati Children's Hospital. Extensive psychological studies were done on 39 patients. It was possible to establish their IQs. The median on the studied group was 87. The range was from 116 to a low of 63. Some 31 of the treated patients were caucasian and 51 were negro. In both race and IQ the group was representative of the patients served by CGH. The three children who were treated definitively for Ewing's sarcoma remained alive from one to four years after treatment. From the other 79, for whom only palliation was expected, five others survived as of October of 1971, the longest by more than six years. Page 8 The clinical assessment of the effort indicated that (with overlapping percentage 29 percent felt relief of pain, 30 percent showed a measurable decrease in primary tumor size, Il percent reported an, increase in activity on their own part following treatment and 29 percent reported an increase in "well-being." About 29 percent showed no evidence of improvement or change. Four percent were lost to follow-up. A group of 10 percent or eight patients died from 20 to 60 days after the whole body exposure. It is not possible to determine positively that those patients who died within 60 days of the treatment would not have succumbed to their disease within that period, even though the clinical assessment had been that their disease was stable enough to justify their inclusion in the study. However, it was noted from the follow-up studies that their bone marrow function was subnormal and thus relatable to radiation syndrome. In terms of survival, the Cincinnati group reported results showing an extension of days over untreated patients in each of the tumor categories. However, results were not markedly superior to the survival results reported by other investigators using various chemicals or other combinations. The survival figures are clouded by the fact that many of the patients included in the sample had already undergone one or more types of treatment unsuccessfully, often only a short time before their inclusion in the study. Some of the patients in the study also received extensive follow-up treatment, sometimes involving further radiation of the primary tumor area. Thus, the patients received a therapeutic regimen which was clinically judged more efficacious for their survival and palliation, however much the added efforts blurred the observation of the effects of the single whole body exposures. In specific terms of survival, Dr. Saenger was able to draw rough comparisons which indicated the benefit of some treatment over none. He found that his results compared to those gained by other investigators using surgical resections, drugs such as 5- fluorouracil and, for the breast cancer patients, estrogens and androgens. In Dr. Saenger's words, "The relatively small numbers of patients in these groups (his and the ones compared from the literature) preclude any claim to therapeutic superiority. On the other hand. it scams reasonable to continue therapy for these gravely ill individuals since this method of treatment is less elaborate and with no greater rise than many present forms of chemotherapy." In this conclusion, the ACR committee would concur. The committee would also observe that the protocols reviews by appropriate institutional authorities, attention to patient interests and responsibilities and reporting are all consistent with accepted good clinical and scientific practice. Page 9 Responses to Senator Gravel's questions: Some of the points raised in the questions in your letter of November 10 are covered at least in general above. Some are not. Hence, the questions and specific responses are detailed below. 1. ANIMAL DATA: Don't experimental animal trials as a rule precede human new medical therapies and drugs? What animal trials using partial or whole body irradiation to treat cancer were completed before Dr. Saenger began his human experimentation? Did Dr. Saenger begin his special "therapy before or after Defense Department support? ANSWER: The literature on radiation biology is substantial with regard to animal trials of whole body radiation for a variety of purposes. One bibliography is appended. Almost always, clinical researchers have had the benefit of animal work to test' the toxicity of their materials and to develop general patterns of biological response. )However, since interspecies differences never allow the total transfer of animal data to human usage, it is necessary to undertake clinical trials under proper conditions to test any new therapy or agent. It is not, necessary for a clinical researcher himself to undertake animal work if be has access to and a good understanding of the literature on the subject. This was the case of Dr. Saenger and his colleagues. As an example of the application of animal studies to human uses, the use of autologous bone narrow transplants and the basic understanding of the influence of marrow stem cells on mammalian survival after whole body radiation exposure were worked out in animal experiments. The marrow transplants are a most important part of the Cincinnati investigation. The detailed biochemistry not only permits a more complete analysis of the response of these patients but also could point the way to other researchers who are attempting systemic therapy with radiation and with investigative chemicals. It was a necessary part of the clinical investigation for Dr. Saenger to determine the optimal amount of marrow to extract, the most effective way to handle it and the best timing for its reinjection into the patient. At the beginning of their work, Dr. Saenger and his group extracted the marrow and froze it to retain it for the 18 to 21 days during which blood white and red cell levels are expected to decline. With subsequent patients, they determined that the prompt reinjection of the marrow the same day the radiation was administered averted much of the blood depleting effect of the radiation. Since Dr. Saenger in this instance applied to the Department of Defense, rather than another funding agency, for the support for the extensive biochemical workups which would provide the "new" element of information from the survey, his preparations preceded the 1950 data at which the actual project was funded by DOD and patient treatment began. As noted, the support for the patient treatment and management was provided by the University of Cincinnati and its hospitals. The DOD funds were applied only to the biochemistry and subsequently the psychologiCal testing which allowed a more complete assessment of the effort. Page 10 2. FOLLOW-UP STUDIES: How does Dr. Saenger follow up his own patients to find out if his "treatment" has been helpful or harmful to them? Does he measure the tumors he hoped to reduce, for instance? ANSWER: As noted, the follow-up on these patients is considerably more complete than is possible for most tumor clinics. The follow up consisted of clinical observations and diagnostic studies and frequent doctor-patient contacts between both the internists and the radiation therapists on the team with the patients who had been treated. In addition, the team psychologist maintained contact, not only for her tests but also as a further supportive measure. The data on biochemical responses and upon psychological reactions is valuable but simply too expensive in terms of manpower and laboratory facilities to be possible for every cancer patient. even in the best of cancer centers. The assessment of results was made by clinical observations of the patient which indicate the elements of well-being and systemic function plus laboratory analyses of blood condition and voiding functions plus x-ray diagnosis to check the size and penetration of solid tumors. In many of the patients. the primary tumor had been excised surgically or treated previously with a prophylactic dose of radiation, leaving management of the metastases as the major clinical concern. It is worth noting that only 4 percent of the 82 patients in the 10-year series were lost to complete follow-up. A detailed report on these results is cited in the preceding section. 3. CONTROL GROUPS: What control groups does Dr. Saenger have, or has he arranged for at our great cancer research institutes so that he can determine how his special "treatment" is working? ANSWER: The question of specific control groups and randomized samples does not usually arise until after the completion and evaluation of the type of study currently underway by Dr. Saenger. He advises that planning for a more elaborate phase three study began last June on the basis of assessment of the 10-year results of the present effort. The literature contains sufficient studies of similar patients and comparable sized samples treated by other methods to allow basic comparisons of tumor regression, post-treatment symptoms and survival times after palliation. Again, it is worth noting that the extent of preparations and follow-up on each patient and number of cancer patients at CGH who are suitable for an aggressive palliation study have combined to limit the size of tee group under investigation., A phase three study appears,, feasible at Cincinnati but will require a substantial commitment of staffing and financing from some source other than patient care funds. 4. PRIVATE PATIENTS: Does Dr. Saenger treat any private cancer patients, or offer consultation on private cases? Does he recommend or use his partial or whole-body radiation "therapy" on paying patients? Does he know any doctor who does? Page 11 ANSWER: Dr. Saenger and his colleagues are full-time faculty members of the University of Cincinnati College of Medicine and have no private practice in the ordinary sense. Their patient care responsibilities are restricted to patients at the city operated Cincinnati General Hospital and its affiliated institutions. A very few patients were referred to the group from doctors at the Holmes Hospital, a private practice institution affiliated with the university. However, those patients were not charged for the treatment and medical care involved in their participation in the study. At this point, Dr. Saenger does not use his treatment on "paying patients" because he has none. He does not recommend his technique to other physicians because the investigation is not yet complete and the results are not indicative of immediate application to clinical situations apart from a research effort. Dr. Saenger would encourage other qualified researchers to duplicate his project or to modify his techniques on the basis that results to date are sufficiently promising to warrant further investigation both by his group and by others. As noted above some type of partial or whole body radiation is used in more than 42 different U.S. medical centers. A total list of these is not available, but they do include both public institutions like the University of Cincinnati and private ones where most patients are charged for their care and. treatment. Thus, it is likely that instances could be found in which patients did pay for this treatment approach. However. the scientific literature does not ordinarily cite the question of payment in reporting on clinical research. The ACP committee was not in a position to make any extended inquiry on this point. 5. TRICKERY: Is there any trickery of the patients involved? a.) Do the patients really understand the experiment is largely to help the Defense Department prepare for nuclear warfare? b.) Do you consider the release the patients sign to be sufficient evidence that they understand? c.) Do the patients understand that the experiment may cause them severe discomfort. such as hours of vomiting? d.) Do the patients understand that partial or whole-body irradiation may shorten their lives, and if so, by how much? e.) Do the patients understand whether or not there exists any basis for suggesting that the "treatment" may reduce the size of their tumors or reduce their pain (as Dr. Saenger suggests in the Washington Post, Oct. 8, 1971)? The question of informed consent was investigated extensively by the ACR committee. The University of Cincinnati Committee for Human Investigation was formed in 1965, as it was in most other institutions, and has had a parallel development under the guidelines of the national Institutes of Health. Their consent forms have been gradually modified over the years and the sophistication of their (UNREADABLE TEXT) has increased in a parallel fashion. Page 12 It is the opinion of the ACR committee that at the present time and through the years the UC committee has functioned effectively and comparably to similar committees at any of the other leading institutions which conduct cancer research. It is likely that the UC committee has performed its function better than the average group because of the volume of projects generated by the medical faculty and the professional competence of the people involved. The current consent seeking procedure was reviewed by the ACR committee. The team internist (Dr. Silberstein) interviews patients two times at least 24 hours apart and discusses in extensive detail the procedures that will be undertaken. This is don" not only for the patient but also for members of his family, when available. The specific and detailed consent forms are not presented to the patient until the completion of the second interview. The form in use is modified for specificity from the basic ones prepared by the National Institutes of Health. Except in the case of the three children with Ewing's sarcoma who were treated curatively, the patients knew before being referred to the study team that they had malignant disease for which no curative treatment is possible. They knew that the efforts of the study team were not offered as curative. Many patients expressed a desire to participate in the study and possibly to help the plight of other cancer patients in the future. The documented psychological studies which were incorporated in the project beginning in 1965 give the study group more, than the usual assurance that their explanations and the required forms were understood by the patients and by their families. The ACR committee felt that the patients were adequately informed about the nature of the proposed therapy and about the consequences. As noted above, the patients were not informed in detail about the side effects of radiation because of the psychological influence of expectation involved in both nausea and vomiting. As mentioned in the project narrative, about half of the patients did not experience unpleasant side-effects and most of the others had only transient symptoms. It should also be noted that since most of the patients had undergone previous cancer treatments, often involving radiation or systemic chemicals, they were aware from previous experience of the types of sequellae which might be encountered. The patients were advised that the project was designed in the hopes that the radiation would relieve the pain of their cancer, that it might shrink the size of the primary tumor or retard the development of metastases. No guarantees of any of those results were offered. In the ACR committee, the assertion in question 5 a. that the, experiment is largely to help the Defense Department prepare for nuclear warfare is not correct. This is not the primary purpose of the effort and to have advised the patients to that effect would have been misleading. Page 13 The patients were not specifically informed that the partial support came from DOD any more than other patients in other studies at Cincinnati or elsewhere are advised of the specific agency support of projects in which they are involved. The Cincinnati patients were told that support came in part from a national agency. At the time the patients were counseled prior to the request for execution of the informed consent form, they were advised that the possible findings may have more than clinical implications and could be helpful to persons receiving whole body radiation in industrial accidents, military activities or as fallout from a nuclear detonation. The question of the source of support for a project is not construed by the ACR committee or by most medical investigators as being relevant to the issue of informed consent. In this case, the DOD exercised no control over patient selection or clinical treatment and indeed did not require descriptions of that part of the project been directed primarily toward the assessment of whole body effects of radiation rather than the management of disseminated cancer by radiation, the study group could not have incorporated the autologous marrow transplants which so drastically altered the classic radiation response. Though this letter has extended to substantial length, it obviously represents a summary of the facts of the Cincinnati study and a precis of the opinions of the College's committee members on that study and on the basic issues of cancer investigation in humans. As we indicated at the beginning of the letter, we would be happy to attempt further discussion of any point on which you may still have concern. Sincerely, Robert W. McConnell, M. D. President American College of Radiology