intent or to retard progression of uniformly fatal diseases. The drugs available to treat widespread cancer in patients in the 1960's were minimally effective by current standards. Cancer of the bronchus or the colon infrequently responded to the available drugs, and breast cancer was only slightly more responsive. Virtually all standard cancer treatment in the 1960's evolved by clinical applications of best known therapies without formal clinical trials. Standard surgical procedures for cancer such as radical mastectomy, laryngectomy, resections of the large bowel, stomach and esophagus had not been tested in formal clinical trials. Similarly, radiation therapy considered standard, such as that for cervical cancer, had not been studied in clinical trials, but had proven to be curative over several decades. Patients whose tumors had spread beyond local-regional means of treatment (surgery and radiation therapy) were considered incurable. The aim of treatment of such patients was to alleviate symptoms such as pain, bleeding and obstruction of natural passages. Such palliative treatments were not undertaken with an expectation of prolonging the patient's life. Faced with the choices of doing nothing, administering local palliative treatment, or attempting highly experimental unproven treatments, the patient would frequently express a desire to do something unproven rather than doing nothing. Prepared Statement of James D. Cox, M.D. Page 2. Total Body Irradiation in Cancer Treatment The responsiveness of tumors to ionizing radiations demonstrated soon after the discovery of x-rays by Roentgen in 1895 resulted in a steady increase in the use of such treatments. By the early 1950's, high-energy photons became available for cancer treatment with Cobalt 60 teletherapy units, betatrons, and linear accelerators, and the use of radiation therapy expanded rapidly. Radiation therapy was known to produce predictable responses in most forms of cancer and was often curative for Hodgkin's disease, cervical cancer, advanced cancer of the mouth, pharynx (throat) and larynx (voice box), etc. Its limitation was that it could be applied only to local or regionally advanced tumors. Total body irradiation had been used with some success in the treatment of patients with strikingly radioresponsive diseases such as chronic and acute leukemias and lymphomas. It was reasonable to hypothesize that total body irradiation might have some benefit in widely disseminated cancer. Even greater enthusiasm for total body irradiation as a component of cancer treatment developed as the technology to remove, store and reinfuse bone marrow to overcome the potentially lethal effects of high-dose systemic treatment was explored. E. Donnall Thomas, M.D., of the University of Washington, was awarded the Nobel Prize in Physiology and Medicine in 1990 for pioneering treatments which included total body irradiation with doses so high as to Prepared Statement of James D. Cox, M.D. be lethal were it not for bone marrow transplantation. Published data from the University of Cincinnati indicate that the total body irradiation trials were undertaken as phase I (to determine maximum tolerated dose) and phase II (to determine anti-tumor effect with specific diseases). The total body irradiation doses delivered ranged from 100 to 200 rads and were carefully calculated and measured. The trials involved three major forms of cancer--carcinoma of the colon, bronchus and breast. All but three patients had advanced cancer not curable by local-regional treatments. Total body irradiation was given as an adjuvant to local irradiation for three children with Ewing's sarcoma of the bone (considered at extremely high risk for the presence of distant metastasis). The treatment team consisted of radiation oncologists, two specialists in internal medicine and a medical physicist. The University of Cincinnati project underwent several levels of peer review. In addition to concurrence with the protocol by the participating members of the team, the studies were reviewed by the Faculty Research Committee of the University of Cincinnati College of Medicine. They also underwent review by the National Institutes of Health, editors of scientific journals, and a special review by Drs. Henry Kaplan of Stanford University, Frank Hendrickson of Chicago's Presbyterian St. Luke's Hospital, and Samuel Taylor, III, of the Presbyterian St. Luke's Hospital at the request of Robert W. McConnell, President, American College of Radiology, in response to a request by Senator Mike Gravel in 1972. Prepared Statement of James D. Cox, M.D. Page 4. Cancer Clinical Trials and Informed Consent The history of medicine is filled with clinical experiments undertaken with the intent to benefit individual patients or all mankind. Clinical trials which compared experimental treatments to standard treatments for patients with cancer were begun in England in the 1940's and in the mid to late 1950's in the United States. Seventeen clinical cooperative groups were established in 1956 with funding from the National Cancer Institute. The conceptual framework leading from phase I (toxicity) to phase II (efficacy) to phase III (comparisons with standard treatment) was first formalized in the early 1960's at the National Cancer Institute. As studies in these cancer clinical cooperative groups evolved, the concept of informed consent evolved. Prior to 1965, patients enrolled in clinical trials were obviously asked to consent and such consent was usually documented in the medical record; formalization of this process began in the 1960's and has continued to evolve to the present time. Current standards include a description to the patient of the experimental treatment offered, specifics risks that such treatment might entail, statements to the effect that all risks are not fully understood and unexpected effects might occur, the possible benefits to the patients and society as a whole, and the express willingness of the physicians to treat the patient outside the protocol with the best standard treatments if the patient declines participation. It is now customary to provide the patient written information (usually two or three pages long); to let the patient keep a copy of this information Prepared Statement of James D. Cox, M.D. Page 5. so he or she may discuss it with family or friends; and, after opportunities for questions, to ask the patient to sign a consent form. The patient always has the right to withdraw from investigational treatment at any time, and to receive the best standard care. In a 1973 publication of the Cincinnati studies by Eugene L. Sanger, et al ("Whole Body and Partial Body Radiotherapy of Advanced Cancer", American Journal of Roentgenology. Radium Therapy, and Nuclear Medicine. Vol 117; 670-685), the following statement is included: All patients gave informed consent in accordance with the directives of the Faculty Research Committee of the University of Cincinnati College of Medicine and those of the National Institutes of Health. The use of formal, informed consent forms in this study antedated the above requirements by two years. Summary Radiation therapy is an important part of the armamentarium of physicians in the care of patients with cancer. Because of its effectiveness in the treatment of local-regional tumors, whole body irradiation has been a subject of research for decades. At present, total body irradiation followed by bone marrow transplantation is considered a standard part of treatment of many patients with leukemia, lymphoma, and Hodgkin's disease, and is under investigation for myeloma and cancer of the breast. In the era prior to the establishment of bone marrow transplantation to support such treatment, lower (sublethal) doses of total body irradiation were Prepared Statement of James D. Cox, M.D. Page 6. |