A Chronology of the Clinical Studies Program at the Oak Ridge Institute of Nuclear Studies/Orau

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A chronology of the clinical studies program at the Oak Ridge Institute of Nuclear Studiedoak Ridge Associated Universities * Partially excerpted from testimony before the Subcommittee on Investigations and Oversight Committee on Science and Technology U.S. House of Representatives Prepared by the Oak Ridge Institute for Science and Education Oak Ridge Associated Universities

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Shortly after the Atomic Energy Commission (AEC)was created in 1947, the Advisory Committee on Biology and Medicine was formed by the Commission to advise them on organizing the AEC‘s Division of Biology and Medicine. The Advisory Committee subsequently reviewed periodically the biomedical program of AEC and reported to the Commission on the quality of these research projects. As the new Division’s initial major program, the Advisory Committee recommended establishing three clinical research facilities to take advantage of the unique radioactive material in diagnosing and treating cancer. The primary facility was to be the Argome Cancer Research Hospital as an adjunct to the School ofMedicine of the University of Chicago, with smaller hospitals at Oak Ridge and Brookhaven National Laboratory. Early in 1948, the AEC moved to implement the The AEC already had a contract with the Oak Ridge Institute of Nuclear Studies (ORINS), a nonprofit, educational corporation whose membership was composed of universities and colleges in the Southern Region (See Attachment 1). Under the existing contract, ORINS was training scientific personnel from institutions throughout the country in the use of radioisotopes and was arranging for graduate students and university faculty members to come to Oak Ridge to participate in research programs. Following approval of the ORINS proposed operating plan by AEC, construction of a laboratory building and renovation of an adjacent &sting hospital wing was begun. ORINS appointed Dr. Marshall H. Brucer as Chairman of the Medical Division. In May 1950, the first patient was admitted to the hospital operated by the Medical Division. During the early fifties, the ORINS Medical Division developed methods of synthesizing radiolabelled compounds and preparing them for clinical trials. ORINS was also conducting an active program to develop external radioisotope sources to be used in place of x-rays to produce an external beam that could be directed into the body as a treatment of cancer. By late 1951, an efficient cobalt40 teletherapy machine had been designed and placed in a specially built room at ORINS. After testing, it was moved to M. D. Anderson Hospital in Houston for clinical trials. Early in 1952, the ORINS Medical Division began a teletherapy evaluation program to determine which of several potentially useful radioisotopes would prove most useful in teletherapy. Cobalt-60 became the most widely used teletherapy source and before long this form of therapy was common all over the world. The Medical Division also devoted a major effort to human total body irradiation studies to improve the treatment for certain types of leukemia and lymphoma. Prior to 1960, the total body irradiation was given to the patients using a cobalt40 teletherapy unit.

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In June 1958, eight workers at the AEC Y-12plant in Oak Ridge were involved in a radiation accident. Their doses ranged from 23 to 365 rads, with five of the men receiving more than 225 rads. All of the men were treated at the ORINS Medical Division and subsequently recovered uneventfully and returned to work at Y-12. As a result of the Y-12accident, it became clear that more information on the response of the human to radiation was needed. The teletherapy machines available in the late 1950's did not give uniform radiation fields such as one would prefer for total body radiation therapy. During irradiation treatment using teletherapy, the patient bad to change positions t o achieve a fairly uniform exposure. To solve this problem, ORINS designed and constructed a new facility which was a concrete shielded room containing eight radiation sources and delivered a uniform dose to the patient. This facility, called Medium Exposure Total Body Irradiator (METBI), was completed in 1959 and began operation in 1960. In 1960, an immunology program was started at ORINS to study the effects of radiation on immune responses and the immunology of bone marrow transplantation. In order to study the types of infections that w u r in patients with bone marrow damage from radiation and chemotherapy, a research program in microbiology was also initiated in 1960. In 1%3, NASA approached AEC for assistance in determining biological risks astronauts might encounter during space travel. Such data were needed by NASA in order to determine the amount of shielding required to protect the astronauts. Following a feasibility study in which medical records were examined to determine if useful data could be obtained from patients' charts, ORINS studied data from 45 hospitals that had radiobiologic information from over 2,500 previous therapeutic exposures. The results of this initial study were made available to the National Academy of Sciences and were published in 1967 in "Radiobiological Factors in Manned Spaceflight". As a result of animal studies on repair mechanisms, it appeared obvious that radiation delivered at a slower rate had the potential for providing the same therapeutic benefit to the patient without causing the undesirable side effects observed at faster delivery rates. However, to get the same dose, the patient would need to be exposed for much longer periods of time. Such a facility to be known as the Low Exposure Total Body Irradiator (LETBI) to test this idea in a clinical environment was proposed by ORINS to AEC in 1965.

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LETBI was intended to provide information on the possible benefit of lowdose rate total body irradiation as opposed to the more conventional higher dose rate facilities. The construction of LETBI was funded by AEC to provide this information in a one-of-a-kind facility. Should LETBI prove more beneficial than conventional methods, this concept would have been expected to be picked up by other clinical centers using whole body irradiation for cancer therapy. Since LETBI did not prove to be more beneficial than conventional means, only one such facility was constructed by AEC. By the early 197O's, it was becoming clear that while the treatment of patients at the ORAU Medical Division was excellent, the number of cases treated was too small to be statistically significant in evaluating various modalities of therapy. Moreover, since all c o s t s related to patient care were borne by AEC, it was becoming increasingly difficult to justify the continued operation of this, and other AEC hospitals. In the early fifties and sixties, these AEC hospitals were responsible for developing the whole new field of nuclear medicine; by the late sixties, their influence had spread and nuclear medicine was well advanced at most major medical centers. Physicians who had been trained at these AEC hospitals had returned to their universities and were now conducting the training. The AEC hospitals had, in effect, put themselves out of business. The ORAU clinical cancer research program was terminated in 1974 with the closing by AEC of the inpatient care facility. From the outset of the clinical studies program at ORINS (1950) informed consent was routinely obtained from patients consistent with contemporary standards and the more recent formal guidelines of the NIH and DOE. In addition, no proposed treatment protocol by an individual physician could be used without approval of all the clinical staff. In 1967 coincident with the development of form;:! guidelines (initially by National Institutes of Health and more recently by Department of Energy) for obtaining informed consent, ORAU established an Institutional Review Board (IRB). This board has continued to provide review of all ORAU's protocols involving human subjects to assure their protection.

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ORINS Member Institutions - 1948 University of Alabama University of Arkansas Catholic University of America University of Florida University of Georgia Georgia Institute of Technology University of Kentucky Louisiana State University University of Mississippi University of North Carolina University of Tennessee University of Texas at Austin University of Virginia