THE WHOLE BODY RADIATION STUDY AT THE UNIVERSITY OF CINCINNATI A REPORT To The Dean Of The College of Medicine By The Ad Hoc Review Committee of the University of Cincinnati January 1972 INTRODUCTION 1 I. BACKGROUND, RATIONALE AND OBJECTIVES 4 II. REVIEW AND APPROVAL BY MEDICAL CENTER COMMITTEES A. Faculty Committee on Research 17 B. General Clinical Research Center 24 III. SELECTION OF PATIENTS, CARE AND FOLLOW-UP 26 IV. FINANCIAL SUPPORT OF PROGRAM 43 V. INFORMED CONSENT AND HUMAN RIGHTS 47 VI. EXPERIMENTAL DESIGN 57 VII. RESULTS OF STUDY AND EVALUATION OF DATA 63 INTRODUCTION On November 12, 1971, Dean Clifford G. Grulee, Jr., appointed an ad hoc committee to review the "whole-body radiation study" which Dr. Eugene Saenger and his colleagues have been conducting at the University of Cincinnati Medical Center. The committee was charged with reviewing the scientific content, methodology, and data treatment of this study, as well as any other aspects which, in the judgment of the committee, were appropriate and necessary. The committee felt additional issues should include the ethical and social aspects of the study, and the quality of patient care. The committee agreed initially that any research effort at a University could be, properly reviewed by a peer grow for the benefit of the research effort itself and the University. At the initial meeting of the committee, the objectives, scope and process of review were defined. Subsequent to this, the committee convened on numerous occasions. It reviewed the history of the study, its scientific purposes, rationale, design of research protocols, selection and care of subjects, the medical Center internal processes of review and approval, financial support, conduct of the study, the results of the study, as well as the evaluation of the data. In the process of review, the committee had several conferences with Dr. Saenger, and bet with Mrs. Winget and Dr. Kunkel who carried on the psychological studies. Since the committee's assignment was prompted by numerous questions about varIous aspects of the study, it was decided that -1- the report format consist of series of pertinent questions and answers. The documentation of many of the answers is contained either in the text of the answers themselves or in the several appendices. At the end of each section there is a short summary statement of findings and recommendations for the future. In the Committee's judgment, the circumstances which led to its appointment is a symptom of the intense concern for the rights and dignity of every citizen. The convening of the committee provided the opportunity of discussing in considerable depth not only the scientific merit of a single program but also the recent evolution of, as well as the customs and practices in, biomedical research involving human subjects. We hope that in providing answers about the project under review we have underscored the need to exert great care and good scientific judgement in the planning of research programs, particularly those involving human subjects. -2- Members of Ad Hoc Committee Bernard S. Aron, M.D., Associate Professor of Radiology Gene Conway, M.D., Professor of Medicine Robert S. Daniels, M.D., Director, Department of Psychiatry and Professor of Psychiatry Paul Herget, Ph.D., Sc.D., Director, Cincinnati Observatory; Distinguished Service Professor Evelyn V. Hess, M.D., McDonald Professor of Medicine; Chairman of Faculty Research Comm. Daniel L. Kline, Ph.D., Director, Department of Physiology and Joseph Eichberg Professor of Physiology Harvey C. Knowles, Jr., M.D., Professor of Medicine; Director of General Clinic Research Center Alvin M. Mauer, M.D., Professor of Pediatrics Milton Orchin, Ph.D., Director, Hoke S. Greene Laboratory of Catalysis; Professor of Chemistry Edward L. Pratt, M.D., Director, Children's Hospital Research Foundation; B.K. Rachford Professor of Pediatrics Raymond R. Suskind, M.D., Director, Department of Environmental Health; Jacob G. Schmidlapp Professor (Chairman) of Environmental Health and Professor of Medicine -3- I. BACKGROUND, RATIONALE, and OBJECTIVES 1) What are the normal steps or phases of a study involving the development of a new therapeutic approach in humans? Before human studies are begun, satisfactory information concerning effectiveness, toxicity and, if possible, mechanisms of action are obtained from investigations in animals. Studies in humans are then started and conducted in three phases. In phase one, the toxicity of the modality is assessed. In the case of a cancer therapeutic agent, these studies are usually carried out in patients with far advanced disease, in whom all effective methods of treatment have already been tried. Careful evaluations of toxic reactions and dose limitations are made. Phase two is an assessment of effectiveness. In the case of anti-cancer agents, a variety of tumors are usually studied. Evidence for response is determined by measurement of tumor size, change in well being of the patient, amelioration of symptoms caused by the cancer, and effect on survival. If the evidence developed from the phase one and two studies is favorable, a phase three study is mounted to compare the new treatment regimen with other modalities currently in use and to determine if the new method is a superior form of treatment. In summary, phase one is for toxicity, phase two for effectiveness, and phase three for comparison. -4- 2) What studies in animals have suggested that whole body irradiation might be effective in treating human cancer? There are three reported studies in mice by one group of investigators in which transplantable tumors were used (1,2,3). In the first study (1), a radiosensitive lymphosarcoma was implanted and a comparison of results with injected radioactive material, whole body irradiation, and whole body irradiation with local tumor irradiation was made. There was a suggestion that whole body irradiation in some way potentiated the effect of local tumor irradiation. In the second study (2), an attempt was made to define the nature of this potentiating effect. The major findings were that if tumor blood supply was changed during whole body irradiation, the effect on tumor regression was lost. It was also found that if the irradiation to the tumor and the whole body was not done at the same time (i.e., within five minutes) a marked decrease in the synergistic action occurred. In the opinion of these authors, the potentiating factor of whole body irradiation was released at the time of irradiation, disappeared quickly thereafter, and was carried to the tumor by the blood stream. In the third paper (3), further studies to characterize the effect were carried out. In these studies not only was the radiation sensitive lymphosarcoma used, but in other experiments the effects on a relatively radiation resistant transplantable mouse mammary carcinoma were also evaluated. One important aspect of these studies was the demonstration that surgical procedures in which the -5- spleen was mobilized and shielded during whole body irradiation, yielded better results. However, it was the effect of the operative procedure and its attendant stress that was the influential factor because equivalent results were obtained when spleen was mobilized but no shielding used. It was also found that maximal potentiation of effects on the results of local tumor irradiation were obtained with whole body doses of 50 r. Greater doses gave no better results. In the mammary carcinomas, whole body irradiation increased tumor regression after local irradiation from 9 to 30 percent, but was not nearly as effective as in the lymphosarcomas. 1. Hollcroft, J., Lorenz, E., and Hunstiger, H.: J. Nat. Cancer Inst. 11:1-16, 1950. 2. Hollcroft, J., Lorenz, E., and Matthew's, M.: J. Nat. Cancer Inst. 12:751-763, 1952. 3. Hollcroft, J., and Matthews, M: J. Nat. Cancer Inst. 14:527-535, 1953. 3) Do these animal studies provide sufficient background to plan treatment protocols for humans? The authors of these papers did not define or characterize adequately the nature of the potentiating factor or its mechanism of action. The studies have not been extended and no confirmatory reports are available from other investigators. However, reports on the effect of whole body irradiation in humans were already available from other centers at the time the University of Cincinnati studies were planned. 4) Have studies of the effectiveness of whole body irradiation on tumor regression or its mechanism of action been done in animals at the University of Cincinnati? No. -6- 5) Is there such work in progress at other institutions? The committee has no knowledge of such work. 6) What was the rationale for having whole body irradiation to humans with cancer in relation to the state of knowledge at the time the study was being planned (1959)? In answering this question, three categories of patients should be considered: A. Patients with widespread tumors which are relatively radiosensitive. These tumors include the neoplasms of blood cells (leukemia, lymphoma), bone marrow cells (multiple myeloma) and tumors which widely disseminate to bone (Ewing's sarcoma). An attempt to treat these diseases with irradiation must include the whole body because of the generalized distribution of tumor cells. Programs in which whole body irradiation is currently being used as a form of treatment for such problems are described under question 9. At the time the University of Cincinnati studies were being planned, other research programs with whole body radiation for radiosensitive tumors were at a Phase III level, in which its effectiveness was being compared with chemotherapeutic agents. A special category in this group is the treatment of Ewing's sarcoma at the time of diagnosis when no demonstrable metastatic lesions are present. Here the rationale is that following intensive local irradiation to the primary tumor site, whole body irradiation can be given to kill small, undetectable nests of tumor cells which have spread from the primary site before or during the local treatment. These studies are reported under question 9 -7- and are in a Phase II stage of therapeutic evaluation currently. B. Patients with widespread tumors which are relatively radioresistant. These tumors include such malignant neoplasms as lung and breast cancer which disseminated widely to bone. Dissemination is manifested by widespread bone pain, symptoms of bone marrow failure, and other systemic side effects for advanced Metastatic cancer. A well designed Phase II study can determine if temporary relief of symptoms might be obtained by whole body irradiation even in these relatively resistant tumors. C. Patients with tumors in which the spread is limited to the abdominal and/or chest cavities. Such tumors are colon cancer, or other tumors which may not be widely disseminated from the primary site. The rationale for using whole body radiation involves the potentiating factors ascribed to this for the of treatment found only in the animal experiments of Hollcroft and co-workers. An argument could also be made in these cases to spare the extremities or other non-involved areas in order to reduce the undesirable side effects of irradiation. If the animal work demonstrates a therapeutic effect and is considered adequate and valid, a Phase II study may be designed to determine if a similar effect in humans is demonstrable. At the time the University of Cincinnati radiation study was initiated, the rationale for treating patients would have appeared reasonable for categories A and B, and questionable for patients in category C. -8- 7) What are the potential hazards of whole body irradiation? At the doses of whole body irradiation used in these studies, the primary hazard is that of bone marrow suppression which occurs 3 to 4 weeks after irradiation and which may lead to bleeding, infection, and anemia. This hazard is well documented in the available literature and the dose relationship to side effects well understood. A possible, but not evaluated, risk is the resultant immunosuppression which leads to more rapid tumor growth. The relationship of radiation to immunosuppression was not well understood at the time that the project was designed and is still being extensively studied. 8) What reports of studies in humans are available which evaluate the effectiveness of whole body irradiation? The following reports have been reviewed to determine their applicability to the present study: A. In 1942, Nedinger and Craver (1) reported results of whole body irradiation in 270 patients. The method of delivering the irradiation differed from the Cincinnati study in that 100 r was given over a period of 6 days by continual exposure to a low dose source. All but 35 of the patients were in the radiosensitive category. In the 35 patients in whom a relatively radioresistant tumor was present, treatment was given early in the evaluation of the method (1931 to 1933). Results were described as discouraging in this group of patients "except for transient relief of pain in a few cases." B. Loeffler and co-workers (2) reported results of whole body irradiation in 4 patients in comparison with treatment by mustard chemotherapy agents in 6 patients. Two (2) patients with lung and colon cancer respectively -9- received 50 r, one patient with scalp cancer 100 r, and one patient with cancer of the sigmoid colon 150 r. Side effects in the irradiated group here minimal and one patient with colon cancer receiving 50 r said he felt better for two days after treatment. No other evaluation of effectiveness was described. C. Collins and Loeffler (3) reported a study of 5 patients given 150 to 200 r whole body irradiation. All of these patients were in the radiosensitive, widespread tumor category. D. Miller and co-workers (4) have reported observations in 233 patients in whom the total body irradiation dose varied from 15 to 200 r. This paper deals primarily with the dose dependent side effects and satisfies reasonably well the requirements of a Phase I study. In this group, 30 patients with a variety of solid tumors received 200 r. Unfortunately, no evaluation of therapy effectiveness is given and the reader is referred to a paper in preparation, which apparently has not appeared. E. Pegg and co-workers (5) reported a study of 10 patients. Only one had total body irradiation in a dose of 300 to 350 r, and that patient had reticulum cell sarcoma, a radiosensitive tumor. He died 20 days after treatment. F. Jacobs and Marasso (6) gave whole body irradiation to 52 patients, 16 of whom had cancer of the radioresistant type. All of these patients had far advanced cancer with estimated survivals of less than one month. They received 300 r whole body irradiation. Eleven (11) died within one month of treatment; the remaining 5 having survivals of 1-1/2, 2, 3, 4, and 9 months. -10- Two (2) of the three (3) Patients with colon cancer survived 4 to 9 months, and the patient surviving 9 months is described as having had good tumor regression following treatment. The statement in this paper suggesting the need for further evaluation of this form of treatment refers most probably to the radiosensitive, widespread neoplasms rather than the results in the 16 patients with radioresistant cancers. In summary, from the articles reviewed, the criteria for a Phase I study have been fulfilled. The Phase II criteria for whole body radiation were not adequately satisfied at the time the original protocol was designed in 1960 and evidence for its effectiveness was incomplete. The results which were available for interpretation were not encouraging Hence, the need for mounting a Phase II study at that time was indicated. 1. F. G. Medinger and L. F. Craver: Am. J Roent. 48:651-671, 1942. 2. R. K. Loeffler, V. P Collins and G. A. Hyman: Science 118:161-163, 1953. 3. V. P Collins and R. K. Loeffler: Am. J. Roent. 75:542-547, 1956. 4. L. Miller, G. Fletcher, and H.B. Gerstner: Radiation Research 8:150-165, 1958. 5. D. E. Pegg, et al.: Brit. J. Cancer 16:417- 435, 1962. 6. M. L. Jacobs and F. J Marasso: Radiology 84:452-456, 1965. 9) Are any other medical centers currently using whole body irradiation for treatment of cancer? Yes. There are 3 papers in the literature since 1968 (1,2,3) reporting the results of whole body irradiation. One of these - 11 - reports (1) deals with treatment of radiosensitive hematopoietic neoplasms or lymphomas. The other two reports describe treatment or prophylaxis with whole body irradiation in conjunction with high dose irradiation of the primary site in Ewing's sarcoma (2,3). The centers reporting include the NIH, St. Lukes Presbyterian Medical Center in Chicago, and the University of Toronto. A yearly progress report from Oak Ridge National Laboratories indicates whole body irradiation is being used for hematopoietic neoplasms. Whole body irradiation is used in many centers for immunosuppression to prevent graft rejection in preparation for marrow homotransplantation. Although whole body radiation is widely used for many forms of radiosensitive tumors, no information is available to the committee which indicates that this form of treatment is used elsewhere in radioresistant, disseminated or localized cancers as used at the University of Cincinnati. 1. Johnson, R.E.: Cancer 25:787-791, 1970. 2. Milburn, L.F., L.O. Grady and F.R. Hendrickson: Cancer 22:919-925, 1968. 3. Jenkin, R.D.T., W.D. Rider, and M.J. Sonley: Radiology 96:151-155, 1970. 10) Why is it important to know the biological effects of whole body irradiation? It is vital to the proper management of people involved in industrial radiation exposures and accidents as well as atomic warfare. The identification of biological indicators of radiation dose levels in an exposed person would be very valuable in their management. Additional knowledge about the effects of whole or partial body irradiation would be helpful in developing more - 12 - effective therapeutic approaches in the management of exposed individuals and groups. 11) Why is it important to know the effect of whole body irradiation on psychological response and mental function? In the case of industrial radiation exposure accidents and atomic warfare, it is critical to know if mental function is impaired and to what degree, so that plans can be developed to cope with such circumstances effectively. 12) Would bone marrow transplants be a useful adjunct to whole body irradiation? Yes. If whole body irradiation were a useful therapeutic measure, a limiting factor in its application would be the marrow depression which results in decreases in all blood cells 3 to 4 weeks after treatment. This effect, as has already been described, causes the clinical problems of bleeding, anemia and infection. If such consequences could be prevented by marrow transplantation, whole body irradiation would be a much safer form of treatment and better tolerated by the patient. 13) What are the objectives of the study? According to the report of December 3, 1971 of Dr. Saenger, the primary purpose of the study is: "To improve the radiation treatment of the patient with advanced cancer and to improve ... his general clinical management. Other considerations were secondary to this goal." The other considerations referred to by Dr. Saenger are the biochemical, physiological, and psychological effects of different - 13 - dose levels of whole body radiation. The findings regarding these effects are the subjects of numerous publications and of reports to the DASA. The Committee, however, was unable to find any written protocol in which the purpose of the study was to determine palliative effects of whole body radiation until the protocol entitled "The Therapeutic Effect of Total Body Irradiation Followed by Infusion of Stored Autologous Marrow in Humans" was re-submitted to the Chairman of the Faculty Research Committee, by Dr. Ben I. Friedman, the then principal investigator, on April 13, 1967. The statement in that protocol is as follows: "Purpose of the study: The goal of this study is to test the hypothesis that total body radiation followed by infusion of stored or autologous bone marrow is effective palliative therapy for metastatic malignancy in human beings." 14) Why is there no record of a formal protocol before 1966? Prior to 1966, there was no forrnal review of study plans requiring human subjects at the University of Cincinnati. See Section II, question 2. 15) Does the data on palliative effects of radiation in this study indicate that this was its primary concern? Even though there is no record of a plan to study palliation prior to 1967, data concerning the survival time of patients treated with whole body radiation was collected from the very beginning of the study. - 14 - In 31 of 33 of the charts of patients treated from 1960 through 1964, there are notations that indicate that radiation was being used for therapy. In 11 of the charts, there are also notations describing additional opinions of one or more consultants who recommended whole body radiation for the individual patient. - 15 - SUMMARY AND RECOMMENDATIONS 1. The knowledge and experience developed through Phase II and Phase III studies for generalized radiosensitive neoplasms such as lymphomas, myelomas, etc., is quite adequate and is being extended by considerable use of this modality throughout the country. Indeed, the treatment of wide-field or whole body radiation is in progress at many other centers for these forms of cancer. Such tumors, however, comprise a very small segment of the study under review. 2. For radioresistant tumors which are spread widely from the primary site, such as cancer of the bronchus and breast, the evidence at hand when the U.C. studies were initiated, justified the development of a Phase II therapy program. With regard to radioresistant tumors, the dissemination of which is limited to one region, as in cancer of the colon, the supportive animal data is still inconclusive and unconfirmed. The human data developed since 1960 has not been encouraging except for data on colon cancer of the U.C. study itself, which are incomplete. If the U.C. study can develop positive evidence of effectiveness, it would justify the mounting of a Phase III study of whole body radiation in colon cancer. - 16 - II. REVIEW AND APPROVAL BY MEDICAL COMMITTEES A. FACULTY COMMITTEE ON RESEARCH (University of Cincinnati Medical Center) 1) Was the total body irradiation project submitted to a review committee concerned with safe-guarding human rights? The proposal entitled Protection of Humans with Stored Autologous Marrow was first formally submitted to the university of Cincinnati Medical Center Faculty Committee on Research (F.C.R.) in March 1966, which was the first year that the committee officially operated (for historical review of Human Rights Committee, see Appendix I). A revised and expanded protocol entitled The Therapeutic Effect of Total Body Irradiation followed by Infusion of Stored Autologous Marrow in Humans, was later resubmitted to the entire committee and approval was granted in May 1967, with the proviso that 1) the protocol be ratified to indicate that the purpose of the study be to determine the therapeutic efficacy of whole body irradiation, 2) infusion of stored bone marrow constitute a supportive measure, and 3) that parts of the protocol be rewritten, particularly in relation to the plan of investigation (Appendix II*). When a new chief investigator took over, the study plan was again changed and a revised protocol was submitted to the committee in October 1970. After a number of revisions dealing with a review of the data from 1960 to 1970. - 17 - a final revision was approved in August 1971 (Appendix 11**). *Dr. Clifford G. Grulee's letter of May 23, 1967. **Dr. Clifford G. Grulee's letter of August 9, 1971. 2) Why was the project not reviewed in 1960 when the work began? The first formal declaration in the United States of the rights of the individual in human experimentation was set forth in the Declaration of Helsinki in 1964. The American Association of Medical Colleges drafted its first code of ethics in 1965. The Surgeon General of United States Public Health Service first recommended review of Department of Health, Education and Welfare grants dealing with human investigation in February, 1966 (Appendix I). It should be noted that the investigators submitted their proposals as soon as the Medical College machinery for such review was made available. The information available to the Committee indicates that prior to 1965 consent forms were not used by the study group but verbal consent was obtained. 3) How is the Faculty Committee on Research constituted? The members of the committee are appointed by the Dean of the Medical College and represent senior members of the full-time faculty with experience in research and clinical investigation. The committee originally had eleven members (see page 3 of Appendix III). - 18 - The present committee is composed of thirteen members, with the Dean as an ex-officio member. The members are senior faculty from the Departments of Medicine, Pediatrics, Surgery, Obstetrics and Gynecology, and Pharmacology. There are two lay members of the committee who were appointed in 1971. The chairman is a Professor of Medicine. A secretary with part salary from the Dean's office has provided for the committee. It is the opinion of the Dean and Faculty Chairman that members should serve at least two years to acquire the essential expertise required for this important task. Only one member of the 1967 committee is still serving on the present committee and that is as a representative of the General Clinical Research Center of the Cincinnati General Hospital. 4) How are outside members of the committee selected? Outside members of the committee are appointed by the Dean of the Medical School. Prior to 1971, lay representation was not required for research committees. However, in March 1971, the Food and Drug Administration of the Department of Health, Education and Welfare enacted into law (Title 21) a requirement that Medical Center Committees have non-medical representation. After much discussion, the University of Cincinnati Medical Center Committee decided to have two representatives - a lawyer interested and knowledgeable - 19 - in medical matters, and a representative, of religion interested and knowledgeable in the moral and ethical aspects of medical affairs. 5) What guidelines does the committee follow? The committee is guided by the statement of principles issued by the committee in 1967 (see Appendix III) and by the guidelines published as a pamphlet by the U.S Department of Health, Education and Welfare in May, 1969 (see Appendix V). The DHEW is in the process of revising its guidelines and this committee has contributed to the revision of these guidelines. The new pamphlet will be available sometime in early 1972. 6) What are the mechanics of the committee review? A faculty member submits a research protocol to his Department Chairman for review and approval. After departmental review, three copies of the proposal, which must follow the guidelines suggested by the committee and with the accepted type of consent form, are sent to the Faculty Research Committee Chairman (see Appendix V). The chairman selects three members of the committee with expertise relevant to the submitted protocol and each is sent a copy. These reviewers submit their contents and decision regarding approval, in writing. The chairman forwards these questions and comments to the investigator who then replies in writing. This typed reply is - 20 - returned to the reviewers who then indicate by letter their approval or disapproval. If there are unanswered questions or there is indication of disapproval by any one member of the sub-committee, a meeting of the sub-committee with the committee chairman and the investigator is then called. If a unanimous decision cannot be reached, review by the full committee and outside consultants would follow. After the review process, the committee chairman forwards the committee's recommendations to the Dean who than writes to the investigator. Subsequently, the investigator submits a follow-up report every six months during the duration of the study. A consultant panel for this committee has been appointed by the Dean and appropriate members can be used for their expertise. This panel lists eleven senior members of the faculty with expertise in all areas including Radiotherapy, Biostatistics, Biochemistry, Physiology, Psychiatry, Sociology, Infection Control, etc. The committee is also free to request consultation from outside the Medical Center and even outside of the city. It should be noted that during the last two years: questions were raised by the reviewers on at least 80% of the proposals; revisions of the proposals were requested and obtained in about 25% of the proposals; subcommittee meetings were held on about 10% of the - 21 - roughly one hundred thirty proposals submitted each year. Two proposals were not approved by the committee. - 22 - SUMMARY Work on the total body irradiation project began in 1960, prior to the advent of Faculty Committees on Research. Fifty patients had been treated when the protocol was first submitted to the F.C.R. in 1966. After lengthy review, provisional approval was granted by the Dean in 1967. Because of changes in the study plan and because a new principal investigator became involved, the protocol was re-submitted in 1970, and the most recent revision was approved in August of 1971. RECOMMENDATIONS The ad hoc committee recommends: 1. That the Faculty Committee on Research be supplied with adequate administrative, secretarial and financial help to enable it to perform its ever increasingly complex and heavy work load. Such help would enhance the follow-through on recommendations and effectiveness of the follow-up system. 2. That representatives from the pre-clinical and younger clinical faculty be appointed to contribute their knowledge and skills to the decision-making process. This will disseminate a broader understanding of the problems of peer review within the faculty. - 23 - B. GENERAL CLINICAL RESEARCH CENTER (GCRC) OF CINCINNATI GENERAL HOSPITAL 1) What is the General Clinical Research Center? How is it supported? The General Clinical Research Center is a small unit organized for study of patients or normal subjects. The Center has its own nursing, dietary, and laboratory facilities. It is supported by the National Institutes of Health. Patients and normal subjects are hospitalized free of charge. They participate in research voluntarily and are fully informed of the aims and possible risks. 2) What aspects of the General Clinical Research Center? Center were used in support of the radiation project? Seven patients were hospitalized for whole body radiation treatment of disseminated cancer. The Center supplied housing and patient care. This represented 3% of the effort of the GCRC in 1970. Six received bone marrow transplants just after radiation. All had urines collected for nitrogen determinations by the Center laboratory, and special determinations by the Radioisotope Laboratory. All had blood and urine analyses carried out by the Core Laboratory of the Center and the Radioisotope Laboratory. 3) How are project utilizing the General Clinical Research Center reviewed? The applicant first discusses with the Center Director the appropriateness and feasibility of conducting the study in the Center. If it appears that the Center should support the study, - 24 - the application must first receive approval from the Director of the Department from which the proposal arose. The application is then sent to the Faculty Committee on Research for study and, if approved, forwarded to the Dean of the College of Medicine. If approval is given by the Dean, the application is forwarded to the Center Advisory Committee for further study. Comments are made by mail and final action taken at the next meeting of the Advisory Committee. 4) Was approval given for the radiation project? Yes. The GCRC Advisory Committee approved of the proposal of Dr. Silberstein in October 1969 and, again, a revised proposal in October, 1971. 5) Did any participants receiving radiation while on the General Clinical Research Center experience undue side effects? One patient had a fever following bone marrow transplant. The reaction lasted 24 hours. Full supportive medical care was furnished. 6) What is the current status of the radiation project and use of the Center? The radiation study is currently approved for Center use. The National Institute of Health is aware of the radiation study and has approved two applications submitted in the last five years for continued operation of the Center, including the radiation study. - 25 - III. SELECTION OF PATIENTS, CARE AND FOLLOW-UP 1) How many patients entered the study? A total of 106 patients gradually entered in the study over a ten-year period to December 31, 1970. Twenty-four (24) patients were not treated because (a) in three (3) patients another method of treatment was elected; (b) two (2) patients did not agree to be treated; and (c) in nineteen (19) patients either the pre-treatment evaluation revealed a significant risk of radiation therapy (e.g., poor bone marrow reserve due to previous chemotherapy or radiation therapy), or advanced stage of malignancy, or treatment was not considered to be helpful. 2) What types of cancer patients were treated? Of the 82 treated patients, 56 had dissemination of cancer which was generalized. Twenty (20) patients had extensive regional spread involving the whole abdomen or the whole chest, and three (3) patients had advanced primary malignancies. All of these patients were not treatable for curative purposes by standard anti-cancer methods. The three patients with localized Ewing's sarcoma were treated with whole body radiation after local radiation therapy in an attempt to cure the Ewing's sarcoma. 3) Were there other cancer treatment methods being used in the period 1960-1971? During the time period covered by the whole body radiation study, there were other concomitant studies which were conducted by other groups at the Medical Center evaluating therapeutic modalities. This restricted the number of patients that could be entered in the whole body radiation study. The other studies - 26 - (a) chemotherapy in advanced lung carcinoma (b) surgery and chemotherapy in colon carcinoma 4) How were the patients selected for the whole body radiation study? Most of the patients were selected from two sources*: (a) Patients were referred for treatment from the Cincinnati General Hospital Out-Patient Tumor Clinic. (b) The patients were referred from the Wards of the Cincinnati General Hospital. Patients were referred for consideration for whole body radiation through the usual methods of consultation by physicians involved in caring for cancer patients. Approximately eighty (80) patients per year were seen and evaluated by the study physicians; about thirteen (13) per year were entered; but only an average of eight (8) patients per year were treated. Some of the reasons for patient rejection included advanced stage of malignancies leading to disorientation, stupor, and/or coma, and terminal advanced malignant disease in which the life expectancy was only a few weeks. 5) What modalities of treatment for cancer were used before and after whole body radiation? All patients were treated by the usual modalities of cancer therapy -- surgery, radiation, and/or chemotherapy as indicated by the type and stage of their tumors. The treatment was usually given as indicated prior to the administration of whole body radiation. Following whole body radiation, the patients received further appropriate therapy as indicated by their clinical conditions. In some cases this was chemotherapy, and in others palliative local radiation therapy. * There were five (5) private patients referred to the study (see page 30, Question 10). - 27 - 6) Did all patients with similar advanced cancer at the Cincinnati General Hospital receive the whole body radiation as a routine form of treatment? The majority of patients to receive whole body radiation or partial body radiation were those in this study. Occasionally patients with leukemia or generalized neuroblastoma were also treated. These patients were not included in the study since whole body radiation is a standard form of treatment. 7) What other forms of supportive care were given to the patients treated with whole body radiation? These patients received comprehensive supportive care in terms of their medical, psychological, and social problems. The initial medical and psychological evaluation was performed in the hospital before treatment (page 46 of Progress report of December 3, 1971, Appendix VI - and the Report of Winget and Kunkel, which is found at the end of this section). Post-treatment evaluation was similarly comprehensive and was carried at least over a 6-7 week period. Even after discharge from the hospital, the patients were seen at least weekly and often at more frequent interviews by both medical personnel and psychologists on the study team. Most patients were followed by a social worker. The thoroughness of the psychological support is apparent from the Report of Winget and Kunkel. The attention given to the problems of the dying patient is impressive. 8) Fifty-one (62%) of the 82 patients treated in this study were black. Most of the patients treated were indigent. Some of the patients had relatively low intelligent quotients. What is the explanation for this distribution? This distribution reflects the patient population of the Cincinnati General Hospital. The Neoplastic Disease Follow-up - 28 - Register reports 1,614 non-white patients (53%) and 1,454 white patients over a nine-year period at the Cincinnati General Hospital. Indigent patients form a major portion of the Cincinnati General Hospital treatment population -- about 85%. Approximately 2% of the patients (both in-patients and out-patients) at the Cincinnati General Hospital during the ten-year period covered by the study were private patients. The patients who have been studied in the psychological assessment segment of the program do not appear to differ in any important way from the general patient population at the Cincinnati General Hospital -- in age, education, or intellectual functioning as indicated by a comparison of 42 Radiation patients with 214 patients studied in Physical Medicine an Rehabilitation, and 17 patients studied in the Stroke Clinic ( Table 1). An additional sample, for which the raw data are no longer available, consisted of 200 surgery patients admitted between October, 1953, and September, 1954. Dr. James Litchener, a member of that research team, reports that these patients consistently tested in the range of 85-100. 9) How was follow-up performed? Follow-up examinations in the immediate post-treatment period were carried out by the attending physicians in the hospital or at the time of the patient's weekly or more frequent visit as an out-patient. Patients were also seen at home by an attending physician if medically indicated. Patients were also seen by the - 29 - psychologists during this time. This close follow-up lasted for 6-7 weeks for all patients and for longer periods of time for some patients. Following this, patients were seen in the Cincinnati General Hospital Out-Patient Tumor Clinic and could be referred back to the attending physician in the whole body irradiation study as indicated. Patients were also seen at the patient's request by the psychologist in the study. All patients were seen in the Tumor Clinic at appropriate frequencies ranging from weekly to monthly intervals. All patients were followed permanently; none were lost in the study, although 4% of the patients were lost during the period of close evaluation or at some other time in their follow-up. The current status (living or dead) is known for all patients in thin study. 10) Are there any private patients included the whole body radiation study? There were five (5) private patients, of whom three (3) were hospitalized in the G.C.R.C. at Children's Hospital, one (1) was hospitalized at Holmes Hospital, and one (1) was admitted to the G.C.R.C. at the Cincinnati General Hospital. During the same period there were 77 ward patients treated. This ratio of ward to private patients reflects the patient census served by the Cincinnati General Hospital and is similar to other studies in advanced cancer which were carried out concomitantly by others. 11) Are any of the 82 patients treated with whole body radiation not described in the DASA Study? All patients treated in this study are included in the various reports submitted to the DASA. - 30 - 12) Why were most of the patients included in this study drawn from the Cincinnati General Hospital? The study was conducted by the department which provides services for the Cincinnati General Hospital. Therefore, most patients were drawn from this population group. 13) What kinds of patients are recorded in the Neoplastic Disease Follow-up Registry? The Neoplastic Disease Registry catalogues all patients with biopsy-proven malignant disease and other allied diseases at the Cincinnati General Hospital and at other hospitals both in the Medical Center and the surrounding communities. It catalogues many types of malignant tumors in the annual report with 44 types of carcinomas and 19 types of miscellaneous malignant tumors. From 1950 to 1969 there were 43,897 accessions to the Registry. - 31 - SUMMARY The methods used in selection of patients for this study were satisfactory. The patients treated in the whole body radiation study received excellent care in respect to both their medical illness and psychological needs. The psychologic support given to these patients far exceeded the support usually given to the dying patient. Follow-up care and evaluation was performed in a detailed manner for six weeks by the study physicians, and subsequently provided in the Tumor Clinic. RECOMMENDATIONS If and when a Phase III study is planned, much larger populations of patients will be required. In that event, it will be necessary to develop close cooperation with other departments. In future studies, plans should be made to provide long-term follow up for all patients by the physicians involved in the study. - 32 - TABLE 1 A COMPARISON OF THREE GROUPS OF CGH PATIENTS Type of Sample Physical Medicine a. and Rehabilitation Stroke Clinic b. Radiation Number 214 17 42 Sex 45% Female 29% Female 60% Female 55% Male 71% Male 40% Male Race 49% Black 71% Black 62% Black 51% White 29% White 38% White Age Range 15-80 33-75 10-84 Median 50 53 58 Mean 43.0 54.71(S.D.=11.62) 58.00(S.D=14.) Education (Yrs.) Range 0-16 2-10 0-12+ Median -------- 6 8 Mean 9.3 5.82 (S.D.=2.63) 6.83 (S.D.=3.5) I.Q. 55-134 59-107 60-118 -------- 81 87 85.29 (18.53) 83.29 (12.43) 86.81 (14.54) a. Data collected in 1969-1970 from in-patients and out-patients referred to Psychology and Vocational Services. All patients had some form of physical limitation of the limbs as a result of infection or injury to the neuromuscular or skeletal system or central nervous system dysfunction. b. These patients tested during 1963-1964 all had some type of vascular dysfunction. - 33 - REPORT OF PSYCHOLOGICAL STUDIES AND SUPPORT Carolyn Winget, M.A. Robert Kunkel, M.D. 1. The psychological-cognitive functioning objectives. Psychological studies of patients recruited for study in the total and partial body radiation program were instituted during 1965-66. The broad objective of this aspect of the study was to determine the effect of these types of radiation exposure on the emotional and intellectual spheres of functioning. In these early days of space probes, interest was focused on the possible effects of radiation exposure to astronauts in outer space; in more recent years this has changed to an interest in radiation & effects on ban in the earth's atmosphere. The schedule of patient contacts and types of testing are given in the list of procedures which follows. The testing protocol was designed to allow one to take into account the many complex variables which may influence the measurement of cognitive and emotional functioning after radiation treatment. 2. The nature of involvement of the psychologist or psychiatrist. Both the needs of these terminally ill patients and the design of the study facilitated the formation of a collaborative relationship between the patient and those involved in psychological evaluation. This relationship was warm, personal and supportive to the patient. Patients explored their life histories and were helped to see what the meaning of their lives had been. - 34 - In return they often felt pleased that by sharing their thinking and feelings with us they were giving to and possibly helping others. When necessary, assistance was given to the patient's family members, as well as to the patient. This help ranged over many areas and included: aid in securing food stamps and filling out welfare forms, referrals for transportation, crisis intervention with suicidal family members, counseling about juvenile delinquent family members, interpretation of family interaction patterns around the issue of the critically ill patient. Depending on the patient's physical status, follow-up interviews were conducted in hospitals, nursing homes, offices or the patient's private home. 3. The quality of the informed consent on this project. While the specific form of the informed consent has varied through the years, the quality and the appropriate nature of the consent have been consistent. Patients have generally exhibited a remarkable degree of understanding both about the procedures to be followed and of the experimental nature of the uses of whole and partial body radiation for those with advanced neoplastic disease. 4. Quality of patient care. Patient care on this project, both in-patient and out-patient, has involved a coordinated team approach. The ease of communication between team members has allowed for rapid and effective noting of patient needs, their referral to the proper team member, and an early attempt to meet the needs, Thus, the psychologist after a session with the patient might report to the doctor with - 35 - medical responsibility, on a suspected physical problem and the doctor very frequently alerted the psychologist to what be thought might be important emotional states in the patient. As a result, patients frequently expressed pleasure about their care. The physical aspects of patient care were greatly improved when Cincinnati General Hospital opened the new hospital building for in-patient care. 5. Is the care palliative? How did the patients feel? There are a number of evidences that patients felt that the supportive care of the psychologist or psychiatrist was beneficial in alleviating distress. One such evidence is the fact that no patient dropped from the six-weeks post-radiation study period and many continued informal contact after the official study was terminated. Another instance of this is the view of ward nurses who sometimes commented that they wished other patients on their wards could have the same type of help. Many patients, perhaps most, at one time or another commented on the importance to them and their daily functioning of the relationship with the psychologist or psychiatrist. In addition, family members often voiced gratitude for the support and care which had been given to the patients. 6.What were the positive findings, if any, from the studies of cognitive and emotional studies? Briefly, the findings regarding cognitive and emotional functioning of these patients (N = 36) are as follows: (1) There is evidence of a rise in cognitive malfunctioning immediately after radiation for all three types of radiation - 36 - groups (i.e., total body radiation <150 rads, total body radiation _>_ 150 rads, partial body radiation). This increase in dysfunction is especially significant far those who receive total body radiation. This effect is transient and decreases markedly by day 3, although a slight peaking is found on day 14 post-radiation. (2) As might be expected of any measure of intellectual functioning, those with higher levels of basic intelligence respond with less dysfunction than do those with basic intellectual deficits. (3) This finding with regard to cognitive impairment must be interpreted within the context of other variables which are specific to this particular patient group, such as: (a) High anxiety levels; (b) Evidence of moderate depression throughout the period of the study; (c) The confounding effect of impending death for some patients. - 37 - LIST OF PROCEDURES Procedures Used in Evaluation Since the procedures for psychological evaluation of the subject have been changed somewhat through the years, a brief outline of those research methods currently being used is given below. 1. After a patient is selected for partial or total body radiation and has agreed to cooperate in the study, arrangements are made with the patient for a series of initial interviews. During this series a detailed but relatively unstructured interview is conducted. The following measures are also obtained: (a) Reitan Trails Test, parts A an B. (b) Cattell's 16 Personality Factor Test, Form A (c) Wechsler Depression Rating Scale A. Attitudes and Feelings B. Physiological Functioning C. Observations of the Interviewer (d) Selected portions of the Wechsler Adult Intelligence Scale: Verbal: Information Comprehension Similarities Arithmetic Digit Span Performance: Picture Completion Digit Symbol (e) A memory scale similar to that developed by Wechsler. (f) A five-minute verbal sample which is transcribed and content-analyzed for the following Gottschalk-Gleser scales: - 38 - List of Procedures (continued) (1) Anxiety (2) Hostility Directed Outwards (3) Hostility Directed Inward (4) Ambivalent Hostility (5) Hope (6) Human Relations (7) Health-Sickness (8) Cognitive Functioning 2. Subsequently, the patient is seen and measurements are made on twelve additional occasions: pre- and post-sham, pre-and post-radiation treatment, and on days 1, 3, 7, 14, 21, 28, 35, and 42. On each such occasion those measurements labeled a, c, e, and f, above, are repeated. In addition, patients are seen for supportive care at any time they request or it seems necessary. - 39 - IV. FINANCIAL SUPPORT OF PROGRAM 1) What is the normal initiating procedure for securing external funding for research conducted under the supervision of a faculty member in the Medical Center of the University of Cincinnati? The faculty member (in contracts and grants known as the principal investigator) usually seeks agencies of government or private industry or foundations which, he thinks, may have an interest in his research ideas. He may be aided in contacting these agencies by officers of the University. Governmental agencies frequently advertise contracts and publicize availability of new funds for research. If such agencies know that a particular university has research interests and expertise in the subject area, the agency will send an invitation to these universities to submit contract or research grant applications. 2) What was the procedure followed in the case of the whole body radiation contract? Dr. E. L. Saenger, as Chief of the Radioisotope Laboratory of Brooke General Hospital, Fort Sam Houston, Texas, in 1954-55 was interested in radiation therapy and recognized the lack of systematic studies on the effect of whole body radiation on the patient suffering with cancer. When he came back to U.C. in 1955, he continued his interest in radiation therapy. In 1960, the University of Cincinnati first submitted a research proposal to the Defense Atomic Support Agency (DASA) of the Department of Defense (DOD), with Dr. E. L. Saenger as principal investigator. This research proposal was initiated by the University and was not solicited by DASA. - 40 - 3) Had any investigational work in whole body radiation either on animals or on humans been going on at University of Cincinnati's General Hospital during the years 1955-1960? There was no formal project at the Cincinnati General Hospital during this period. Dr. Saenger was, however, interested in and abreast of the published work in whole body radiation being performed by other groups of investigators. He treated occasional private patients suffering from leukemia and lymphoma with whole body radiation in his office. 4) Is it fair to state that if no funds had been forth- coming from DASA, the investigations on whole body radiation would not have been undertaken? In retrospect this is a difficult question to answer. In view of the principal investigator's interest in the topic, it might have been possible that he would have sought other support but this is moot. The DASA contract was activated in 1960 but obviously it must have been preceded by a great deal of thought and discussion prior to the actual date that the contract became operative. The first research protocol prepared for submission to DASA is dated September 25, 1958. 5) Would it have been possible to carry out the whole body radiation investigations without any external support? Conceivably, but external support was necessary to make possible the study of the metabolic changes in blood and urine which might be brought about by radiation. The DASA support made possible the biochemical investigations directed toward - 41 - finding metabolic indicators of radiation exposure. As early as 1963, a paper dealing with the elevation of deoxycytidine in the urine of patients receiving whole body radiation was published in Science by the Cincinnati group. 6) Was any support requested for all or part of this work from other government agencies or private foundations? In 1966, a research proposal was developed by Dr. Ben I. Friedman of the Department of Radiology as principal investigator. The subject of this protocol was "Protection of Humans with Stored Autologous Marrow" and it was designed to determine whether the fall in circulating leucocytes and platelets, which appears 25-40 days after the patient receives whole body radiation, could be prevented by withdrawing a substantial quantity of the patient's bone marrow before radiation and giving it back to him (intravenously) after the patient is exposed to whole body radiation. This proposal received a critical internal review and was submitted to the NIH in an application for a research grant. The application was not approved and the reasons for this decision were not disclosed. 7) Why wasn't this request for funds followed up? In 1967, Dr. Friedman left the University of Cincinnati and no other grant applications were submitted to NIH. Furthermore, the project was already being funded at a level by DASA which permitted most of the desired work to be carried out. However, HEW supports the General Clinical Research Center of the Cincinnati General Hospital as well as the Clinical Research Center of - 42 - 10) What part of the budget of the Radioisotope Division is supported by the DSA grant? 13% to 15% of the budget of the Division is supported by the DASA grant. All of the monies from DASA were used to support the biochemical, physiological and psychological studies. 11) Was any of this money spent for patient care? None of the money was spent directly for patient care. 12) Who paid for patient care? Most of this cost was borne by the Cincinnati General Hospital. It is estimated that the 82 patients treated in the approximate 11 years of this investigation spent a total of 3,804 patient days in the hospital. The present per diem cost of patient care is $114. 13) Has the DASA classified any suggestions or made any demands with respect to the kind of work that would be done or the type of patients that should be given this treatment? DASA has never made suggestions regarding the design of the experiments or the type of investigation to be carried out. They do require progress and fiscal reports. 14) Has the DASA classified any of the information sent to them as a result of these investigations? No. Nothing about this work has been classified. All the reports submitted to DASA are a matter of public record and are completely open to anyone requesting to see them. - 44 - 15) Has there been anything in the contractual arrangement between DASA and the University that differs from contracts or grants that the University negotiates with other external funding agencies? No. The investigators have had complete scientific freedom. There is nothing in the record to indicate that any specific kinds of test or treatment were dictated or even suggested by the supporting agency. -45- SUMMARY The request for financial support of this project by DASA was initiated by the University. The first formal proposal was prepared in September, 1958. The proposal was funded by DASA in 1960. The systematic investigation of whole body radiation at the University of Cincinnati General Hospital did not begin until the project was funded by DASA in 1960. The University of Cincinnati has negotiated three contracts with DASA, the most recent for the period 6/15/69 - 3/31/72. The total value of these contracts was $651,483, of which $612,274 was expended as of 1/30/71. There is no evidence that the DASA funding was made contingent on work, ideas, or suggestions proposed by DASA. The work was carried out with the complete scientific freedom appropriate for research conducted in University facilities. RECOMMENDATIONS If further studies are planned, the support for such programs should be sought from a federal health agency or foundation interested in cancer research. - 46 - V. INFORMED CONSENT AND HUMAN RIGHTS 1) What are the generally accepted standards for the protection of a research subject? The guidelines of the United States Public Health Service, the United States Department of Health, Education, and Welfare, were outlined in a pamphlet "Protection of the Individual as a Research Subject," published May 1, 1969. (Appendix IV) Research subjects are defined as "any human being exposed to any research procedure. Subjects may include, therefore, persons involved in behavioral science studies; normal volunteers; donors of services; in-patients and out-patients: living donors of body fluids, organs, and tissues; and members of the general population who may be involved in environmental or epidemiological studies. An individual should generally be accepted as a research subject only after he or his legally authorized guardian or next of kin has consented to his participation in the research. Such consent is valid, however, only if the individual is given a fair explanation of the procedures to be followed, their possible benefits and attendant hazards and discomforts, and the reasons for pursuing the research and its general objectives. The subject does not abdicate his rights by consenting to participate in a research project. He may withdraw his consent at any time. Further, he has the right to be secure in his person, to receive proper professional care, to enjoy privacy and confidentiality in the use of information about himself, and to be free from undue embarrassment, discomfort, and harassment." - 47 - 2) Describe the procedures utilized by the University of Cincinnati with regard to protecting the rights of research subject. The University of Cincinnati has well defined procedures of review and has established principles concerning the treatment of human subjects. The procedures for review are described in Section II-A and B, and Appendix I. This review assures: (1) that the rights and welfare of the individual involved are adequately protected; (2) that the methods used to obtain informed consent are adequate and appropriate; and (3) that the risks to the individual are outweighed by the potential benefit to him or by the importance of the knowledge to be gained. 3) Describe the consent forms utilized in the partial and whole body radiation study. The use of partial and whole body radiation for the treatment of far advanced and terminal cancer was considered in the late 1950's and begun in 1960. Initially, informed consent was obtained in exactly the same way and with the same form as used by the Cincinnati General Hospital for all medical and surgical treatment and procedures. From 1960 through 1964, consent was obtained verbally (see p. 50, Question 5). Beginning in 1965 and extending to date, there have been several additional consent forms used, each reflecting increasing detail in the information provided for the patient and/or his family. The sequence of forms used is available in Appendix VII. The modifications in consent forms paralleled the changes in consent going on throughout the Cincinnati General Hospital, the University of Cincinnati, and the remainder of the country. The 1960's were a time during which the protection of the rights of the individual as a research subject was being reexamined and - 48 - re-evaluated. As a result, improved and more stringent policies about the protection of the individual's rights were instituted. In most academic and medical institutions the change provided the patient and his family with more complete information about the study procedure and anticipated effects, thereby improving the "informed consent." The evaluation in methods and the forms used in this project reflects general changes occurring throughout the country. 4) How was informed consent obtained? Were patients sufficiently informed about possible benefits and possible complications? Since 1968, the following procedure has been used: Initially the patient is informed about the procedure and its possible effects, both palliative and adverse. The discussion is then repeated completely on a subsequent day and the patient's signature requested on a consent form. When the patient is a minor, signed consent is obtained from the responsible guardian. According to Dr. Silberstein, since 1968 no patients were treated who were incapable of comprehending adequately the procedure or its effects. In six (6) patients during this period, members of the family were available and the procedure explained to them. The patients and their families were informed in writing and verbally that the treatment was not a cure but there were possible palliative effects. They were informed about the research goals. (See page 13, Question No. 13.) During the initial explanation, they were informed about the possible need for bone marrow transfusion. That procedure was subsequently dealt with separately in another consent form and with another verbal explanation (Appendix VII). - 49 - Patients and families were not informed about the possibility of transient nausea and vomiting since such symptoms may be induced by suggestion. Typically, such side effects can occur a few days after treatment. The presence of this symptom, however, is highly variable. According to the present principal investigator, Dr. Silberstein, the charts of the 33 patients who were involved in the study during the period 1960 through 1964, which he reviewed, do not contain consent forms. In six (6) of these, there are notations indicating that the patient was informed about the nature of the treatment and its possible benefits. It should be noted that in this period the signing of consent forms was not required for any project or procedure, and verbal consent was considered adequate. 5) Were patients and/or families informed about the source of the funding for the project? The sources of funding for this study were usually not discussed with the patients and/or their families. This information was not withheld if the patient asked about this matter. The procedure follows the custom of every other research project in this University. 6) Describe the procedure for the patient to withdraw his informed consent. Withdrawal of consent could be initiated verbally and subsequently documented in writing. This is the standard procedure in most hospitals. There have been no suggestions that consent was given under duress. - 50 - 7) Were there patients, whose I.Q. was subsequently determined to be 75 or below, who signed the consent form themselves? Yes, there were ten patients. There was no reason to believe that they did not understand the conditions of the project. The Committee also questions the significance of the scores of intelligence tests in this group of patients who were dying of far advanced cancer. 8) Were the privacy or the confidences of the patients and/or their families violated? From the information originally made available to the Committee, privacy of the patient and confidentiality were maintained. In only one instance have we found an exception. In September 1971, two members of the staff and one patient from the study were interviewed separately by a group from National Education Television. Consent for interviewing was obtained from three patients and their families by Dr. Silberstein, but only one of the patients was visited at home. Although no one from the University staff was present, the patient later told Dr. Silberstein that she became so upset with the questioning that she said she knew nothing about the radiation study and the interview was terminated. We are told that the N.E.T. group discontinued the filming and left the city without completing their task. This experience provides an important lesson. Interviews such as this one or those by any other investigating group may constitute embarrassment and harassment, and may be in violation of the patient rights. The staff of the radiation study group was in error in permitting the interviews to take place under these circumstances - 51 - 9) Would current interviews of patients and/or families by an outside reviewing group violate the privacy or confidence of the patient? The Committee wishes to be on record as opposed to any outside investigating body interviewing a patient and/or his family because it believes that such interviews would violate the patients' rights and would be in violation of the guidelines provided by the United States Public Health Service of the Department of Health, Education, and Welfare. 10) Was the quality of care adequate for the patients who were involved in this study? In the opinion of the Committee, the care delivered during the course of the patient's illness was of high quality. Care was provided by an interdisciplinary team which took a broad approach to the illness, its course, and its outcome. Its obligations were to provide social and psychological support when indicated. Frequent and thorough out-patient follow up was provided for six weeks after irradiation. Home visits by professional personnel to provide care and advice were common. In a trying and difficult time, the patient and his family were aided by the staff to respond to the threat of death and the actual death of the patient in as constructive a fashion as possible. The presence of psychiatrists and psychologists as an integral part of the clinical care and research teams increased the interest of the teams in the sociological and psychological problems faced by their patients and families. There were increased opportunities for the involved individuals on the staff to discuss their - 52 - concerns about death and about patient care, and to improve their patient care capacities. Social problems about finances, food, housing, etc., were responded to promptly and effectively. The patients and families obtained counseling advice to an extent which is usually not available on medical, surgical, or cancer treatment units. 11) What was the rationale for conducting the studies on the cognitive and emotional effects of radiation? This group of patients and their treatment modality provided an opportunity to study two classes of problems about which there is currently limited information in the scientific literature. Three classes of problems are: (1) the effect of whole or part body radiation on the cognitive and emotional functioning of individuals; and (2) the cognitive and emotional impact of threatened or impending death on the individual. In the first instance, the opportunity for such investigations was potentially of great value because of the many uses of ionizing radiation in industry, the possibility of its use against civilian populations, and the conventional therapeutic use of this modality. Until the last few years, very few people hue studied the complex socio-psychological responses to dying and death. Some investigators would contend that this area is extremely important and has been too long neglected. - 53 - 12) What was the method of investigating the cognitive and emotional aspects, as well as other psychological phenomena? The method of investigation is outlined in the report of Winget and Kunkel (Section III). The investigation revealed that there was loss of cognitive capacity immediately after radiation for all three groups of patients: those receiving total body radiation > 150 rads, total body radiation _>_ 150 rads, and partial body radiation. The effect was transient and decreased markedly by day three. Just as with other measures of intellectual impairment, those with high levels of basic intelligence respond with less dysfunction than do those with basic intellectual deficits. These findings must be interpreted within the context of other variables which are specific to this particular patient group: (a) high anxiety levels; (b) evidence of moderate depression throughout the period of the study; and (c) the confounding effect of impending death for some patients. - 54 - SUMMARY The informed consent for the partial and whole body radiation project reflected the processes characteristic of the University of Cincinnati and the nation. Prior to the mid-1960's, documentation of informed consent tended to be brief and non-specific. Subsequent to that time, the written documentation of informed consent has been improved for all University investigative projects including this one. Personnel have taken precautions to avoid embarrassment, discomfort or harassment to the patient and his family. The patients' rights have been safeguarded in appropriate fashion except for the instance in September 1971, involving interviews for an N.E.T. film. The general and specific medical care of the patients involved in the study was of a high order. The presence of professionals interested in psychological and social phenomena enhanced those aspects of care. The cognitive and emotional psychological investigation was based on the opportunity to learn more about responses in two poorly understood circumstances: (1) to dying and death, and (2) to partial or whole body radiation. The positive findings include: (1) transient loss of some cognitive capacities occurred for three days after radiation, (2) those losses were more marked in those individuals who already demonstrated some basic intellectual deficits, and (3) these findings were complicated by high anxiety levels, moderate depression, and the effects of impending death. - 55 - RECOMMENDATIONS Informed consent should be obtained as it is now. Revisions of the consent forms should be considered in relation to the use of the phrase "sound mind and body". The procedure for withdrawal from the project should be improved. 2. The Committee wishes to be on record as opposed to any outside investigating body interviewing a patient and/or his family because it believes that such interviews would violate the patient's rights and would be in violation of the guidelines provided by the United States Public Health Service of the Department of Health, Education and Welfare. 3. Improved guidelines should be developed by the University for handling publicity involving patients, medical care, or research. - 56 - VI. EXPERIMENTAL DESIGN Consideration of the experimental design needs to be separated into multiple parts for both Phase I (toxicity level) and Phase II (beneficial effects on the course of the illness). The analysis of the experimental design is complex because in 1960 when the study was begun it was customary and necessary to provide written protocols for only limited portions of the investigations. Therefore, in many instances the experimental design must be inferred from the evidence available, particularly Dr. Saenger's statement dated December 3, 1971 (Appendix VI), the report of Winget and Kunkel (Section III), Silberstein's revised protocol to the Faculty Research Committee, dated July 26, 1971 (Appendix VIII, and the DASA Report, February 1960 through April 30, 1966 Appendix IX). 1) In Phase I, was the experimental design inadequate to determine toxicity? Yes, the design was adequate to determine the toxicity of whole body radiation and partial body radiation over tide range of 16-300 Rads. Sufficient clinical observations, appropriate hematological and biochemical determinations (cf. Saenger's statement, Appendix VI, p. 46), (DASA report, Appendix IX, pp. 8-17 and Table X) were incorporated and, after 1965, psychologic support and testing (DASA report pp. 9-15), (Winget and Kunkel Report, List of Procedures) to define the immediate post-irradiation effects and the delayed acute radiation syndrome clinically, hematologically and with respect to fluctuating depression, anxiety relief and changes in hope (DASA pp. 11-14). The design was adequate to - 57 - reveal a dose-response relationship for the clinical and hematological effects with whole body radiation. 2) Was there a design to improve the clinical management of the patients from the inception of the study? The plan of the study with respect to caring for the needs of the terminally ill patient resulted in the development of a coordinated team approach wherein all members of the team were psychologically adjusted to dealing with this difficult clinical situation, and were appropriately attuned to recognize the medical, psychological, and social needs of the patients. The design successfully provided a warm, personal and supportive team who were continually available to the patients in the hospital or at home (cf. Winget-Kunkel pp. 1-3), (Saenger report of December 3, 1971, pp. 11-12). Communications about the patients were maintained with the team throughout the patient's life by reports from the Tumor Clinic physicians, or in some cases, by the patients contacting members of the team directly weeks or months later. 3) What was the design to search for a biological indicator of the amount of radiation and for alterations of metabolism induced by radiation? The design of the survey to achieve these secondary goals was that of a survey program devoted to following up leads that were derived from studies of irradiated animals done by members of Dr. Saenger's group (Radiol. 9:343, 1968; Radiat. Res. 39:490, 1969) and by others. Later a study to elucidate the basis of irradiation injury and processes in repair was instigated through an investigation of DNA metabolism. Here the design is vague as to the exact hypothesis being tested, and what biochemical changes - 58 - are expected. For the most part this is a survey program which is searching for a few DNA precursors and metabolites. 4) What was the design of the study to show an effect on survival? (Phase II) The design of the study incorporates sufficient clinical data and adequate follow-up procedures so that life-tables have been constructed. These have been used to assess the effects of whole body radiation and partial body radiation on the course of individual patients and subgroups of patients. It is uncertain whether this study and similar studies reported in the medical literature are truly comparable in all major factors that influence survival such as selection of patients and ancillary medical management. Therefore, the significance of comparisons of survival rates is doubtful, unless related differences are found. However, matched populations are not an essential element for a Phase II study in this type of illness. 5) What was the plan to evaluate palliative effects? Before 1966, the design of the study to measure the palliative effects of whole body radiation or partial body radiation was unstructured and not uniformly applied, particularly as regards uniform definitions and methods of reporting. Beginning in 1966 the design incorporated clinical observations in the in-patient and out-patient records to evaluate changes in tumor size, alterations in liver enzymes, changes in x-ray findings, or the appearance of tumor masses, if such alterations occur. The records of the various members of the team, resulting from their close association with the patients during the first six weeks following irradiation, permit some assessment of relief of pain, sense of well-being versus malaise, and changes in certain emotional states. It is likely that alterations in these factors are more closely related to the overall care and supportive management of the patients, as well as happenings in their life situation, so that they cannot be related specifically to the radiation therapy. Structured protocols for the evaluation of certain emotional and intellectual functions have been used since 1965. A structured protocol for Performance Status Rating is proposed (Silberstein, July 26, 1971). 6) Did the design of the study from 1966 on, incorporate additional measures to improve the clinical management of the patient with advanced cancer? The supportive measure, autologous bone marrow transplantation, is designed to improve the well-being of the patients receiving whole body radiation by shortening their hospital stay and ameliorating the radiation sickness syndrome due to bone depression. 7) Was the design of the experiment for evaluating the safety and efficacy of autologous bone marrow transplantation adequate? Yes, the appropriate clinical procedures, safeguards, and observations plus the hematological data collected are described in the protocol to the Faculty Research Committee by Dr. Silberstein, July 26, 1971 (Appendix VIII). - 60 - SUMMARY The design of the experiment, from the beginning, did incorporate measures to improve the care of the patients. During the progress of the investigations, procedures that reduced the physical and emotional stress of the patients were added, for example: the psychological support and the use of bone marrow transplantation. The design of the experiment was adequate to define the toxicity of the radiation used and to indicate the safety and efficacy of the use of autologous bone marrow transplantation. It is not adequate to evaluate the effect of the treatment on survival rates. The design of the experiment lacked carefully selected measures to evaluate palliation. No rigid criteria of palliation were laid down. A defined set of observations to be made at each visit were not selected prior to 1966 except for some of the biochemical hematological determinations. Thus, comparisons of palliation within the group over the years or with similar patients treated by other methods are difficult; all the bore so because the reports of other studies that we received were likewise weak in their measures of palliation. No systematic approach based on prior biological knowledge of the effects of radiation was utilized in the plan to find an indicator of radiation or to elucidate metabolic changes. Survey techniques were used. RECOMMENDATIONS At the present time it is generally accepted that biostatistical guidance can improve clinical investigations. We urge that - 61 - biostatisticians, competent and experienced in medical investigations involving patients, be brought in at the conception of clinical studies, such as these reviewed here, particularly to aid in the design of the experiment, rather than be called in at the delivery, merely to analyze the data. The College of Medicine must support biostatisticians familiar with clinical investigation. - 62 - VII. RESULTS OF STUDY AND EVALUATION OF DATA 1) What was the effect of whole body radiation on survival rate? The crude comparisons of survival with the findings in studies using other modalities suggest an increase in survival rate as compared with untreated patients. There is absolutely no evidence that whole body radiation shortened the period of survival of the treated patients. From April 1960 through December 1970, 82 patients were treated. The largest individual groups of patients were those with cancer of the colon, bronchus, or breast. Seventeen (17) patients with cancer of the colon and metastases to the liver had a median survival time (after diagnosis of metastases) of 327 days. The cumulative survival rate was similar to that reported by Rapoport and Burleson1, wherein 61 patients were treated with fluorouracil. The median survival time in this latter study was 255 days. The survival rates of the present study and of Rapoport's study appear more favorable than that of an untreated similar group of 177 patients described by Jaffe et al2. In this last study, the median survival time was 146 days. Survival comparisons are shown in Fig. 1. Fourteen (14) patients with cancer of the bronchus and distant metastases who received whole body radiation had a median survival time of 178 days. This rate was more favorable than those of 12 patients with local or distant metastases treated - 63 - with chlorambucil (median survival 90 days) and 11 similar non- treated patients (median survival 67 days) by Horwitz et al3. This latter study was conducted at the Cincinnati General Hospital with patients drawn from the same source as used in the present study. Fifteen (15) patients with disseminated breast cancer treated with whole body radiation had a median survival time of 479 days after diagnosis. Comparison with other treatment regimens suggests a better survival rate than that obtained from treatment with hormonal alteration and local radiation4 (378 days) and possibly a less beneficial effect than in treatment with fluorouracil (522 days)5. Survival comparisons are shown in Fig. 2. 2) What evidence was there of palliation from whole body radiation? No plan for a systematic study of palliative effects was made. In a retrospective review of the charts, the following data were elicited: twenty-nine (29%) percent had some degree of pain relief as judged by "say so" and decrease in required pain medication; thirty (30%) percent had a decrease in tumor size of 50% or greater; eleven (11%) percent had increase in activity, in that they returned to work; twenty-nine (29%) percent said they "felt better"; twenty-nine (29%) percent gave no evidence of any change. 3) Were there any deaths attributable to radiation? The doses of radiation administered could initiate the hematological form of acute radiation syndrome. Many of the patients received much radiation and/or chemotherapy prior to total or - 64 - partial body radiation, and in many cases this treatment was followed by local therapy to various portions of the body. Of the 82 cases treated, 19 died within 20-60 days and possibly could have died from radiation alone. Of these, however, in only eight (8) cases was the bone marrow found to be acellular or hypocellular near death or at autopsy. 4) How many autopsies were done? Of the 74 patients who died as of October 10, 1971, autopsies were performed on eight (8) of them. Many patients died either at home or in other hospitals. 5) How many patients received autologous bone marrow transplants? Thirteen (13) patients received transplants. The nadir of the white blood cell count was 3100 in transplant patients, in contrast to 900 in patients receiving whole body radiation without marrow transplant. 6) What is the current status of the whole body radiation study? The Committee agrees with Dr. Saenger's evaluation, which is as follows: "The current status can be regarded as an incomplete Phase II study. In the relatively small categories, we have shown survival which is approximately the same as has been found with other methods even though the controls are not rigorous nor are the methods of measurement entirely satisfactory." - 65 - SUMMARY The data provided to the Committee regarding the effectiveness of whole body radiation suggests that survival of the patients in this study does not appear to differ from survival with the use of chemotherapy as reported in the literature. There were only three types of cancer for which the number of patients was sufficient for any kind of analysis: colon, breast and bronchus. Since the manner in which the data on palliative effects was developed was inadequate, no conclusions can be drawn from them. RECOMMENDATIONS Since the Committee cannot at this time rule out a positive effect of whole body radiation, a well-designed study to compare whole body radiation with other forms of therapy is recommended. The specific tumor groups which appear most likely to show significant results are those of the colon and lung. Adequate populations of patients with these tumors are available at this Medical Center. These tumors afford the best opportunity for objectively measuring effects. Randomization with another treatment modality should be an integral part of any future study. - 66 - FIGURE 1 Survival Comparisons Cancer of Colon Metastatic to Liver FOR REFERENCE SEE (2bb15) GRAPHIC FIGURE 2 Survival Comparisons Cancer of Breast with Metastases FOR REFERENCE SEE (2bb16) GRAPHIC REFERENCES 1. Rapoport, A.H., and Burleson, R.L.: Survival of patients treated with systemic fluorouracil for hepatic metastases. Surg. Gynecol. Obstet. 130:773, 1970. 2. Jaffe, B.N., Donegan, W.L., Watson, F., and Spratt, J.S., Jr.: Factors influencing survival in patients with untreated hepatic metastases. Surg. Gynecol. Obstet. 127:1, 1968. 3. Horwitz, H., Wright, T.L., Perry, H., and Barrett, C.M.: "Suppressive" chemotherapy in bronchogenic carcinoma; a randomized prospective clinical trial. Am. J. Roentgenol. Radium Ther. Nucl. Med. 93:615, 1965. 4. American Medical Association, Council on Drugs: Androgens and estrogens in the treatment of disseminated mammary carcinoma; retrospective study of nine hundred forty-four patients. J.A.M.A. 172:1271, 1960. 5. Samp, R.J., and Ansfield, F.J.: Breast cancer treated with fluorouracil; survival studies in advanced cases. J.A.M.A. 198:724, 1966. - 69 - APPENDIX IV BOOKLET "Protection of the Individual as a Research Subject", Grants, Awards & Contracts Available through the U.S. Department of Health, Education and Welfare, PHS University of Cincinnati Medical Center Faculty Committee of Research Format of Research Proposal Appendix V _____ of investigations to be carried out in the University of Cincinnati Medical Center in which human subjects are to be used necessitates prior approval by the Faculty Committee on Research. In submitting request for approval, use of the following format will provide the Committee with adequate information to arrive at a decision. Submit all material in triplicate. TO: FACULTY COMMITTEE ON RESEARCH FROM: Principal Investigator; list other investigators on project. SUBJECT: (Title of Investigation) department head signature is required on your final protocol before submission to committee I. PURPOSE OF STUDY II. INDICATE SIGNIFICANCE OF STUDY IN RELATION TO HUMAN HEALTH (patients under study and patients in general) III. RESEARCH PLAN. If a new manipulation is involved, brief detail should be given. If any drug or agent is to be under investigation, detailed information of its nature, structural formula, class, etc. should be given. Please give IND number when appropriate. Please indicate which components of the Medical Center will be utilized in the study. IV. POTENTIAL HAZARDS a. known and suspected hazards b. Precautions to avoid hazards, including methods for detecting adverse reactions. V. PREVIOUS WORK DONE IN THIS AREA. Please include that by present or other investigators. If an investigational new drug (IND) is involved, a summary of the results of previous pertinent animal, and if available, human (phase I and II) toxicity studies must be included. VI. METHOD TO BE USED IN PROCURING CONSENT OF SUBJECTS. (Written consent is legal requirement for all FDA Phase I and II studies.) There are four (4) types of consent forma: a. Investigational Drug Consent Form b. Experimental Procedure Consent Form c. Organ Transplantation (donor) Consent Form d. Organ Transplantation (recipient) consent Form Please select the appropriate form for your use and use it as a guideline. You can particularize wording you will use to your research subject, remembering that it should be in easily understood lay terms. Please enclose three (3) copies of the appropriate forms. Always state if patient or normal volunteer. VII. PERIOD OF TIME ESTIMATED TO COMPLETE PROJECT AS DESCRIBED Approval by the Faculty Committee on Research is limited to the projects as described herein. Send completed material to: Dr. Evelyn Hess, Division of Immunology, K-3 *the same format may be used for submission to the Central Clinical Research Center Committee (C.C.R.C.) UNIVERSITY OF CINCINNATI MEDICAL CENTER FACULTY COMMITTEE ON RESEARCH PERMISSION FOR ORGAN TRANSPLANTATION (RECIPIENT FORM) I, (name), do hereby consent to the transplantation of (organ) to (name or myself) by (Drs.) (Dr.) as(his) (their) assistants, and whomever (they) (he) may designate. In doing so, I also consent to the performance of splenectomy, appendectomy, (UNREADABLE) and other operations incident to the transplantation procedure, including any operation or procedure not initially contemplated, but deemed medically advisable by the responsible physicians because of an unforeseen condition arising in the course of any portion of the operative procedure. I also consent to the administration of any anesthetics, drugs,biological materials, including antilymphocyte globulin, or treatments which the physician responsible for (my, his, her) care may be of benefit to (my, his, her), including those of an investigational or unproven nature and to the performance of any studies which they feel are necessary to evaluate (my, his, her) condition, both preoperatively and postoperatively. I fully understand that the transplantation of organs is, in itself, of an experimental nature, and the numerous serious complications can result therefrom, and I acknowledge the following risks and possible benefits of this undertaking have been clearly explain to me: Rises of infection, rejection; or lack of function of the transplanted organ, bleeding, drug toxicity, and risks associated with any major operative procedure; benefits and likelihood of possible normal organ function. In consideration for the administration of the medical services referred to herein, I hereby waive any and all claims for liability, except negligence, on the part of the medical personnel involved, the University of Cincinnati, its Hospital and its assigns as a result of the administration of these services. I certify that I have read and fully understand this consent and that the explanations listed above, were, in fact, made and that I am competent to understand these explanations WITNESS: Signature Date Relationship to Patient, if a Minor NOTE: Copy to Recipient, Research File and Patient's Chart. [ILLEGIBLE FORM] UNREADABLE TEXT UNIVERSITY OF CINCINNATI MEDICAL CENTER FACULTY COMMITTEE ON RESEARCH REQUEST TO USE INVESTIGATIONAL DRUG AND AGREEMENT TO SERVE IN STUDY *I _________ of _______ request treatment for my condition with _________________________________________________ (name or designation of drug) and agree to serve in a study. I am of the age of majority. The purpose of the dedication and the study, as well as the risks and inconvenience have been explained to me, and also the fact that this medication is new or investigational. I understand that it was developed to improve conditions such as mine and has been given to other people, but has not yet been fully tested. I further understand that thc investigation has been approved, compares alternative methods of treatment, and that I may receive standard, investigational or supportive treatment. Also, I am aware of how the drug must be taken and that appropriate protection is available and satisfactory to me. All my questions have been satisfactorily answered Patient ______________________________________________ Date _____________________ Investigator___________________________________________ Date __________________________ Date ________________________ Witness________________________________________________ * In case of subject under age, the parent or guardian should be the responsible party and should sign on his behalf. **Please state how you will describe the drug to the patient.