Appendices (Mostly Concerning the Faculty Committee on Research Involvement in Total Body Irradiation Project).

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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. The opinions and judgments which the statements reflect are the result of careful deliberation and consideration of all of the evidence. At the end of each section there is a short summary statement of findings and recommendations for the In the Committee's judgment, the circumstances vihich 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 judgment in the planning of research programs, particularly those involving

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Is there such work in proqress at other institutions? committee has no knowledge of such work. What was the rationale for qivinq whole bodv irradiation to humans with cancer in relation to the state of knowledqe at the time the study was beinq planned In answering this question, three categories of patients should 5. Patients with widespread tumors which are relatively These tumors include % the malignancies of blood cells (leukemia, lymphoma)8 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 be- 'cause 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 I11 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

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and are in a Phase I1 stage of therapeutic evaluation currently. -B. Patients with widespread tumors which are relatively These tumors include those malignancies such as lung and breast cancer which disseminated widely to bone. is manifested by widespread bone pain, symptoms of bone marrow failure, and other systemic side effects for advanced metastatic cancer. A well designed Phase I1 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 b e widely disseminated from the primary site. The rationale for using whole body radiation involves the potentiating factors ascribed to this form of treatment found only in the animal experiments of Hollcroft and co-workers . An argument could also b e made in these cases to spare the extremities or other noninvolved 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 11 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 5 and and questionable for patients in category c.

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Two (2) of the three (3) patients with colon cancer survived 4to9 months, and the patient surviving9 months i s 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 t o the radio sensitive, widespread malignancies rather than the results i n the 16 patients with radio resistant cancers. . I n summary, from the articles reviewed, the criteria for a Phase I study have been fulfilled. The Phase I1 criteria for whole body radiation were not adequately satisfied at the time the original protocol was designed i n 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 11 study at that time was indicated. Ra a i ation Research 8:150-165, 1958. 9) Are any other medical centers currently us in q whole body irradiation for treatment of cancer? Yes. There are3papers in the literature since 1968 (1,2,3) reporting the results of whole body irradiation. One of these

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reports (1) deals with treatment of radiosensitive hematopoietic malignancies 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. progress report from Oak Ridge National Laboratories indicates whole body irradiation is being used for hematopoietic malignancies. Whole body irradiation is used in many centers for immunosuppression to prevent graft rejection in preparation for marrow 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. Although whole body radiation is widely used 10) Why is it important to know the bioloqical 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

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SUMMARY AND RECOMMENDATIONS 1. The knowledge and experience developed through Phase I1 and Phase 111 studies for generalized radiosensitive malignancies 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 radioresistent tumors which are spread widely from the primary site, such as cancer of the bronchus and breast, the the development of a Phase I1 therapy program. With regard to radioresistent 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, and the human data develing except for data on colon cancer of the U . C . study itself, evidence of effectiveness, it would justify the mounting of a Phase I11 study of whole body radiation in colon cancer.

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a final revision was approved i n August 1971 (Appendix II**). **Dr. Clifford G. Gru lee ' s letter of August 9, 1971. 2) Why was the project not reviewed i n 1960 when the work The first formal declaration in the United States of the rights of the individual in human experimentation was set forth i n the Declaration of Helsinki in 1964. The American Association of Medical Colleges ' drafted its first code of ethics i n 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 (AppenIt should be noted that the investigators submitted their proposals as soon as the Medical College machinery for such review was made available.Prior to 1966, the investigators had utilized the general consent forms used a t the Cincinnati General 3 ) How is the Fa cult v 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 invest iga - tion.The committee originally had eleven menibers (see page 3

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interested and knowledgeable i n medical matters, and are pre - sent at ive of religion interested and knowledgeable inthe moral and ethical aspects of medical affairs. 5 ) What qui de lines do the committee follow? The committee i s guided by the statement of principles issued by the committee i n 1967 (see Appendix 111) and by the guidelines published as a pamphlet by theU.S. Department of Health, Education and Welfare i n May, 1969 (see Appendix IV). The DHEW isin 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 t h e committee review? A faculty member submits a research protocol to his Departmerit Chairman for review and approval. After departmental review, three copies of the Proposal, which 'must follow the guidelines suggested by the committee and w i t h the accepted type of consent form, are sent to the Faculty Committee Chairman (see Appendix V). The chairman selects three members of the committee with expertise relevant to the submitted protocol and each are senta copy. These reviewers submit their comments and decision regarding appro val,in writing. The chairman forwards these questions and'comments to the investigator who then replies in writing.This typed

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Work on the total body irradiation project began in 1960, Fiftyprior to the advent of Faculty Committees on Research. 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. the study plan and investigators, the protocol was re-submitted in 1970 and a final revision covering the eighty-two patients treated from 1960-1971 was approved in August of 1971. Because of changes in 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 compl.ex 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

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111. 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. Twenty-four (24) patients were not treated because either(a) another method of treatment was considered preferable,or (b) the pre treatment evaluation revealed a sign if - i cant risk of radiation therapy (e.g.8 poor bone marrow reserve due t o previous chemotherapy or radiation therapy) o r advanced stage of malignancy. 2) What types of cancer patients were treated ? Ofthe 82 treated patients, 56 had widespread dissemination . of cancer which was generalized. Twenty (20) patients had extensive regional spread in vol v irq the whole abdomen orthe whole chest and three(3)patients had advanced primary malignancies. All of these patients with the exceptign of three patients with Ewing's sarcoma were not treatable by standard anti - cancer methods. The three latter patients were treated with whole body radiation along with local radiation therapy i n an attempt to cure the 3 ) Were there other cancer treatment methods beinq used in the period 1960-1971? During the time period covered by the whole body radiation study, there were other concomitant studies evaluating thera - pe u tic modalities which restricted the number of patients that could be entered in the whole body radiation study. Two studies

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( a ) chemotherapy i n advanced lung carcinoma (b) surgery and chemotherapy i n colon carcinoma 4 ) How were the Patients selected for the whole body The patients were selected from two sources: .(a)Patients were referred for treatment from the Cincinnati General Hospital Out-Patient Tumor (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 malignancy. The treatment was usually given as indicated before whole body radiation. Following whole body radiation, the patients received further appropriate therapy as indicated by their clinical condition. In some

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cases this was chemotherapy, and in others palliative local 6) Did all similar patients with advanced cancer atthe Cincinnati General Hospital receive whole body radi - ation as a routine form of treatment ? No. The only patients to receive whole body radiation or partial body radiation were those in this study and occasionally patients with leukemia or generalized neuroblastoma. 7 ) What other forms of supportive care were qiven t o 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 December3, 1971 - Appendix VI - and the Report of Winget and KUnkel, which i s found a t the end of this section). Post-treatment evaluation was similarly comprehensive and was carried atleast over a 6-7 week period. Even after discharge from the hbs pital,the patients were seen atleast 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 o f Winget patient is impressive. The attention given to the problems o f the dying 8 ) Fifty-one (62%) of the 82 patients treated in this study were black. Most of the patients treated were in d iq ent. Some of the patients had relatively low in tell iq ent quotients. What is the explanation for This distribution reflects the patient population of the Cinc in nat i General …