Attachment 2-B AMERICAN COLLEGE OF RADIOLOGY: 20 NORTH WACKER DRIVE, CHICAGO, ILLINOIS ILLEGIBLE WASHINGTON OFFICE: 6900 WISCONSIN AVENUE CHEVY CHASE, MARYLAND 20015 ILLEGIBLE January 3, 1972 The Honorable Mike Gravel 1251 New Senate Office Building Washington, D.C. Dear Senator Gravel: This letter represents our response to your request of us to inquire into the whole body radiation therapy project being conducted by Dr. Eugene L. Saenger and his colleagues at the University of Cincinnati. We have made our inquiry and our broad conclusions are as follows: 1. In the normal context of a clinical investigation, the project is validly conceived, stated, executed, controlled and followed up. The appropriate scientific and professional committees of the University of Cincinnati have performed their functions during the course of the project. 2. The process of patient selection based upon clinical considerations conform with good medical practice. 3. The records, publications and patient follow-up are voluminous and commends. 4. The procedure used for obtaining patient consent is valid, thorough and consistent with the recommendations of the National Institutes of Health and with the practice of most cancer centers. 5. Should this project come before the Senate or one of its committees in some fashion, we would urge your support for its continuation. Though physicians do not invariably share with the public the ways in which they reach professional conclusions, we think it appropriate to your inquiry to detail below the way in which we reached these conclusions. Our acceptance of your request was based upon the realization that senators have need of ILLEGIBLE impartial medical and scientific advise in evaluating complex biomedical ILLEGIBLE. The committee As I noted in my earlier letter to you, the College is seldom called ILLEGIBLE ILLEGIBLE to investigate the scientific efforts of any of its matters ILLEGIBLE and a third distinguished physician ILLEGIBLE the inquiry. They are: Page 2 Dr. Henry Kaplan, chairman and professor of radiology at Stanford University Medical School in Palo Alto, California. Dr. Kaplan is internationally know for his pioneering work in several areas of cancer therapy. he has been a member of various cancer study and advisory groups including the Committee of Consultants to Conquer Cancer which recently advised the Senate. His extensive bibliography includes descriptions of his work on Hodgkin's disease involving extensive radiat of patients. Dr. Kaplan is currently chairman of our Commission on Cancer. Dr. Frank R. Henderickson, chairman of the department of radiation therapy at Chicago's Presbyterian-St. Luke's Hospital. Dr. Henderickson is also a faculty member of the University of Illinois College of Medicine and the Rush Medical College as well as a consultant to the Veterans Administration and a member of various national cancer bodies. His bibliography includes reports of his treatment of children afflicted with Ewing's sarcoma with radiation. He is the present chairman of our Commission on Radiation Therapy. Dr. Samuel Taylor, III, a distinguished internist and oncologist at Presbyterian-St. Luke's Hospital in Chicago. He is the founder of the American College of Physicians cancer program. He is a professor of medicine at Rush. Dr. Taylor's wide experience as a senior investigator in the field of cancer provided use with a view from another discipline. He is a long time expert in chemotherapy of disseminated cancer. Mr. Ortha Linton, director of our Washington Office, provided staff support to the group and coordinated their inquiry with Dr. Saenger and his colleagues. Nature of the Inquiry Drs. Kaplan and Henderickson and Mr. Linton met with Dr. Saenger and Dr. Charles M. Barrett, director of radiation therapy at the University of Cincinnati, November 29 in Chicago. The discussion covered the background of the project and the purposes, objectives and achievements of the effort to date. Dr. Saenger then provided the committee with published papers and summary materials about the project. On December 16, Drs. Kaplan, Henderickson and Taylor met in Cincinnati with Dr. Saenger, other members of his team, two members of the University of Cincinnati human investigation committee, and the chairman of the special university committee which was created by the president to review the project. Those interviewed were, from the U.S. Human Research Committee, Dr. Evelyn V. Hess, professor medicine and Dr. Harvey C. Knowles, Jr., professor of medicine, from the special university committee to review the Saenger project, Dr. Raymond R. Suskind, professor of environmental health and medicine, from the department of radiology and the study team, Drs. Charles M. Barrett, Harry Norwitz, Bernard S. Aron and Edward B. Silberstein, physicists, Drs. I-Wen Chen and James G. Neriakes and the psychologist, Mrs. Carolyn N. Winget. Page 3 Dr. Saenger and everyone at the university were willing to recognize our competence and to cooperate fully with our inquiry. The committee members were extended full cooperation and can conclude that they apprised themselves of the situation to the same extent that they would have needed to do as members of an NIH study section or site review team. Each member of the committee has served in such a capacity. The committee viewed the project as it was designed--as a clinical investigation of a modality for the care of cancer patients with extensive and insurable dis ILLEGIBLE Phase One investigations follow basic animal work and always precede randomization clinical trials which may or may not be justified on the basis of the first human applications. In the opinion of the committee, the team at Cincinnati had abundant bases in literature for undertaking its study. The participants are fully qualified to undertake the investigation, both from the viewpoint of good patient care and importantly the possibility that new valuable clinical information could be obtained. Our committee did not concern itself with the implications which have been raised concerning partial funding of the effort by the Department of Defense. We did note that DOD funds were used only to support the laboratory and psychological studies but not the treatment or the care of the patient. The basic costs were borned by the university and its teaching hospitals. Because of the prevalence of cancer which has been noted so recently by the Senate, the House of Representatives and the President, those charged with the care of cancer patients have need for every possible bit of information concerning the methods and modalities which we use to treat these patients. In our opinion this project has the possibility of contributing useful clinical information. It is worth noting that if others have had access only to the reports made to ILLEGIBLE on its part of the project or if they somehow failed to understand that the ILLEGIBLE of extensive followup in no way departed or detracted from fundamental perception of good patient care, then it follows that they might reach conclusions different from those of our committee. The nature of cancer investigations and treatment In clinical investigations of cancer, we are concerned both with the basic ILLEGIBLE process and with its manifestations in humans and specifically in the patients who present themselves for care. The treatment of an individual represents a series of choices for his physicians which are based upon diagnostic findings of their best judgement. Since humans respond to the assault of cancer and to ILLEGIBLE to treat it as uniquely as they do to most other things, generalization here ILLEGIBLE statistical value but limited application to individuals. Page 4 There are many forms of cancer. Each type has in common the loss of intracellular control upon which normal cells depend to regulate their growth. The cancers differ in cellular types and in the site of origin of a primary lesion within the body as well as the bodily pathways through which they may spread. Thus, for example, the problem of defining and treating a solid tumor may differ radically from the approach to a form of leukemia. Physicians have three fundamental modalities which may be used singly or combined to attempt to cure or control cancers. These are extirpative surgery, high energy radiation and chemicals. Hormones also are used to attempt to alter the course of certain cancers involving the endocrine system. The choice of treatment must be decided for each patient. The decision is based upon the type of cancer, its location, its size, its degree of spread and upon the age and general health of the patient. Ideally, the therapeutic decision is made in a cancer conference involving physicians from the different disciplines appropriate to the problem at hand. By the nature of the disease, any cancer therapy must be regarded as heroic. The cancer patient must accept lesser probabilities of success and more stringent side effects of treatment than usually befall sufferers from other diseases. Timing is all important in the treatment of most cancers. A small, early cancer may be removed surgically or destroyed with radiation. But if the cancer has begun to spread beyond its original site and beyond the surgical or radiation field, the destruction of the primary lesion will not suffice to save the patient. Unfortunately, many patients still are diagnosed as having far advanced cancer which must be judged unlikely to respond to any standard curative effort. These patients may have undergone various treatments without success. Or they may have had a "silent" primary cancer which was diagnosed only after it began to spread through the body. The physician having the care of a patient with advanced cancer has three practical choices. One is to do nothing, allowing the disease to take its course. Another is to attempt palliation, an effort to retard the tumor growth and/or to ease the pain of the patient. The third is to attempt drastic or radical treatments not commonly accepted as reliable or efficacious for patients having a greater chance of success. The third approach carries the long- shot possibility of direct patient gain. The doctor and patient must agree that something of benefit to others may be learned from the effort. Thus, the effort to improve cancer treatments has been based upon the first application of now or questionable techniques to those patients having nothing to lose by their failure because there is no known treatment available. Often, the effectiveness of the technique must be measured in time of survival, relief of pain, or from certain body measurements, rather than in terms of overt tumor destruction. Efforts must be made to isolate and measure the specific timing, dosages, procedures and restraints which can be observed to alter the course of the disease. When a form of treatment has bene shown to have some measurable beneficial effect on far advanced patients it can be considered for general use. Page 5 The nature of cancer investigation requires that more than one therapist must undertake a new modality at each stage of its development before it can be accepted for general usage. If an improvement in some tool or resource becomes available such as the advent of supervoltage radiation sources then previous studies may be repeated with profit. Both the high energy radiation and the several chemicals now used in cancer therapy have harmful effects upon patients. So does radical surgery. The choice must be made to refrain from curative efforts when the destruction of the tumor would involve unacceptable side effects of a localized or systemic nature. Thus, efforts to control or relieve side effects are equally significant with those to destroy the tumor. When radiation is used as the tumoricidal agent, the effort is made to limits its effects by tailoring the dose to the suspect area and by using a series of tolerance exposures to destroy the cancer cells without damaging vital organs and adjacent normal tissues. if a cancer is widespread, then a tumoricidal dose of radiation presents problems which, for the most part, remain unsolved. Lesser amount of radiation have been used in various ways as part of efforts to retard tumor growth to relieve pain or to alter the pattern of cancer development. The literature of radiation therapy offers substantial numbers of citations of efforts to use whole or partial body radiation for the palliation of advanced cancers. The conclusion, broadly, must be that the concept has not been sufficing productive to recommend generally nor so lacking in effect to be abandoned as an approach. The Cincinnati project The actual treatment of patients was begun in 1960 by Dr. Saenger and his colleague as a clinical assessment of the use of sublethal whole body radiation for the palliation of patients with a variety of disseminated cancers. The premise was that the level of radiation selected would have a retardant effect upon the growth of the tumor cells throughout the body and that the patient, for the most part, could tolerate the side effects of systemic radiation. The second part of the premise was that patients who were closely followed after their cancer treatments could indicate both the physical and psychological react to the therapeutic effort over a period of several weeks. This clinical assessment provided a new dimension to previous studies of the use of whole body radiation. Beginning in 1964, the group began to use the technique of autologous bone marrow transplants as a means of overcoming the marrow depression otherwise inescapable after whole body radiation. The technique after some modification involves the extraction of 300 to 600 cubic centimeters (about a pint of so) of marrow from the posterior iliac crest just before the radiation exposure. The same day, the marrow is filtered and reinjected into the patient. As a clinical procedure, ILLEGIBLE has succeeded in averting most of the extended radiation syndrome effects previously observed in patients in this series and in other whole body studies. Page 6 Efforts to minimize late effects, such as the drop in which cells and platelets and the decrease in red blood cells which are classic to radiation syndromes, began in 1965. This method using autologous bone marrow immediately after radiation therapy, became practical early in 1969. The concept of whole body radiation as a method of treating cancer is not now with the Cincinnati project. There is voluminous literature reporting controlled animal experiments which are highly useful but not indicative of human responses to human tumors. The literature reporting on human exposures dates back to efforts in 1923. A review of reports to 1942 showed more than 270 patients thus treated with fairly little encouragement. Since these patients in all cases had disseminated tumors and the radiation sources available were in the orthovoltage range, the results were not surprising. The advent of supervoltage generators and particularly cobalt 60 sources prompted additional studies to assess the effect of higher energy radiation and led to a new round of studies. In 1953, V. P. Collins and R. K. Loeffler called the use of 200 roentgens whole body "a useful addition to the management of advanced cancer. A current bibliography contains some 86 scientific articles on the subject, excluding Dr. Saenger's contributions. Whole body projects have been undertaken in more than 42 U. S. medical centers. At present, efforts are underway using whole or partial body radiation for the control of leukemia. Hodgkin's disease, polycythemia vera, multiple myeloma, and disseminated cancers of the breast, thyroid and prostate. In very small groups, whole body radiation has been used successfully in curative efforts against Ewing's sarcoma, a tone tumor primarily of children. The Cincinnati study through the end of 1970 involved a total of 106 patients referred from the Tumor Clinic of the Cincinnati General Hospital. These were patients found by biopsy and clinical examination to have disseminated tumors. They "were chosen because they suffered from advanced and widespread neoplastic disease such that cure could not be anticipated," in Dr. Saenger's words. All of the patient underwent a 7 to 14 day assessment period to reaffirm the diagnosis and to determine whether their disease and their general health would make the radiation attempt feasible. Some 24 patients were rejected and received no radiation on the basis of their clinical assessment. Some of the 82 patients later treated received sham radiation sessions during the assessment period but none actually wee exposed until after a decision by the team which determined the treatment could be beneficial. The patients had a variety of tumors. The largest group was 25 with cancers originating in the colon and rectum. A second group of 14 had tumors of the bronchus. Fifteen women had disseminated breast cancer. There were 25 patients with miscellaneous tumors. Three children had Ewing's sarcoma and were treated for curative effect. One of the 25 patients with miscellaneous tumors had Ewing's sarcoma with metastases too widespread for a curative effort. Page 7 Discussions with the patients and members of their families are standard in any cancer therapy situation and were a part of this project from its beginning. Specific patient consent forms have been used since 1965, when this step was recommended by the National Institutes of Health. Since 1968, patients selected for the study were interviewed on succeeding days by the internist in the project before being asked to sign a consent form for the therapy. When possible and in all cases of children, the interview included one or more members of the family who also consented to the treatment. Except for the three children with Ewing's sarcoma, all were told that their cancers had been defined as incurable and that the treatment would be attempted in an effort to prolong their lives and possibly to retard or shrink the tumors. They were told that the information gained from the study was hoped to be helpful to other patients. In the last few years they were told that the information might have military as well as clinical significance. The patients were told that there could be some side effects from the radiation exposure and that the team would wish to keep in close touch with them for a period of weeks to study their reactions both to the advances in their disease and to the impact of the radiation. The possible side effects were not described in detail nor emphasized to avoid subjective inducement of the symptoms. So far as the side effects were concerned, the team reported that 45 percent had no vomiting or nausea after the radiation. Some 24 percent experienced transient vomiting and nausea within three hours and another 17 percent had the same symptoms within 12 hours of exposure. Another 9 percent continued vomiting up to 24 hours. Only five percent had prolonged and severe vomiting and nausea. It is worth noting that these symptoms are certainly no greater those experienced by patients treated either by surgery or by any of the systemic drugs now being used clinically on disseminated cancers. The patients were selected by clinicians at the Cincinnati General Hospital from the population served by that instruction solely on the basis of their tumor diagnosis. Since CGH is a institution, none of the patients were private patient. The three children with Ewing's sarcoma were referred by physicians at the affili ILLEGIBLE Cincinnati Children's Hospital. Extensive psychological studies wore done on 39 patients. It was possible to establish their IQs. The median on the studied group was 87. The range was from 118 to a low of 68. some 31 of the treated patients were caucasian and 51 were negro. In both race and IQ the group was representative of the patients served by CGH. The three children who were treated definitively for Ewing's sarcoma remained alive from one to four years after treatment. From the other 79, for whom only palliation was expected, five others survived as of October of 1971, the longest by more than six years. Page 8 The clinical assessment of the effort indicated that (with overlapping percentages) 29 percent felt relief of pain, 30 percent showed a measurable decrease in primary tumor size, 11 percent reported an increase in activity on their own part following treatment and 29 percent reported an increase in "well-being." About 29 percent showed no evidence of improvement or change. Four percent were lost to following. A group of 10 percent or eight patients died from 20 to 60 days after the whole body exposure. It is not possible to determine positively that those patients who died within 60 days of the treatment would not have succumbed to their disease within that period, even though the clinical assessment had been that their disease was stable enough to justify their inclusion in the study. However, it was noted from the followup studies that their bone marrow function was subnormal and thus relatable to radiation syndrome. In terms of survival, the Cincinnati group reported results showing an extension of days over untreated patients in each of the tumor categories. However, results were not markedly superior to the survival results reported by other investigators using various chemicals or other combinations. The survival figures are clouded by the fact that many of the patients included in the sample had already undergone one or more types of treatment unsuccessfully, often only a short time before their inclusion in the study. Some of the patients in the study also received extensive followup treatment, sometimes involving further radiation of the primary tumor area. Thus, the patients received a therapeutic regimen which was clinically judged most efficacious for their survival and palliation, however, much the added efforts blurred the observation of the effects of the single whole body exposure. In specific terms of survival, Dr. Saenger was able to draw rough comparisons which indicated the benefit of some treatment over none. He found that his results compared to those gained by other investigators using surgical resections, drugs such as 5- fluorouracil and, for the breast cancer patients, estrogens and androgens. In Dr. Saenger's words, "The relatively small numbers of patients in these groups (his and the ones compared from the literature) preclude any claim to therapeutic superiority. On the other hand, it seems reasonable to continue therapy for this gravely ill individuals since this method of treatment is less elaborate and with no greater risk than many present forms of chemotherapy." In this conclusion, the ACR committee would concur. The committee would also observe that the protocols, reviews by appropriate institutional authorities, attention to patient interests and responsibilities and reporting are all consistent with accepted good clinical and scientific practice. Page 9 Responses to Senator Gravel's questions Some of the points raised in the questions in your letter of November 10 are covered at least in general above. Some are not. Hence, the questions and specific responses are detailed below. 1. ANIMAL DATA: Don't experimental animal trials as a rule precede human trials in the testing of new medical therapies and drugs? What animal trials using partial whole body irradiation to treat cancer were completed before Dr. Saenger began his human experimentation? Did Dr. Saenger begin his special "therapy" before or after Defense Department support? ANSWER: The literature on radiation biology is substantial with regard to animal trials of whole body radiation for a variety of purposes. One bibliography is appended. Almost always, clinical researchers have had the benefit of animal work to test the toxicity of their materials and to develop general patterns of biological response. However, since inter-species differences never allow the total transfer of animal data to human usage, it is necessary to undertake clinical trials under proper conditions to test any new therapy or agent. It is not necessary for a clinical researcher himself to undertake animal work if he has access to and a good understanding of the literature on the subject. This was the case of Dr. Saenger and his colleagues. As an example of the application of animal studies to human uses, the use of autologous bone marrow transplants and the basic understanding of the influence of marrow stem cells on mammalian survival after whole body radiation exposure were worked out in animal experiments. The marrow transplants are a most important part of the Cincinnati investigation. The detailed biochemistry not only permits a more complete analysis of the response of these patients but also could point the way to other researchers who are attempting systemic therapy with radiation and with investigative chemicals. It was a necessary part of the clinical investigation for Dr. Saenger to determine the optimal amount of marrow to extract, the most effective way to handle it and the best timing for its reinjection into the patient. AT the beginning of their work, Dr. Saenger and his group extracted the marrow and froze it to retain it for the 18 to 21 days during which blood white and red cell levels are expected it decline. With subsequent patients, they determined that the prompt reinjection of the marrow the same day the radiation was administered averted much of the blood depleting effect of the radiation. Since Dr. Saenger in this instance applied to the Department of Defense, rather than another funding agency, for the support for the extensive biochemical workup which would provide that "new" element of information from the survey, his preparations preceded the 1980 data at which the actual project was funded by DOD and patient treatment began. As noted, the support for the patient treatment and management was provided by the University of Cincinnati and its hospitals. The DOD funds were applied only to the biochemistry and subsequently the psychological testing which allowed a more complete assessment of the effort. 2. FOLLOWUP STUDIES: How does Dr. Saenger follow up his own patients to find if his "treatment" has been helpful or harmful to them? Does he measure the tumors he hoped to reduce, for instance. ANSWER: As noted, the followup on these patients is considerably more complete than is possible for most tumor clinics. The followup consisted of clinical observations and diagnostic studies and frequent doctor-patient contacts between both the internists and the radiation therapists on the team with the patients who had been treated. In addition, the team psychologist maintained contact, not only for her tests but also as a further supportive measure. The data on biochemical responses and upon psychological reactions is valuable but simply too expensive in terms of manpower and laboratory facilities to be possible for every cancer patient, even in the best of cancer centers. The assessment of results was made by clinical observations of the patient which indicate the elements of well-being and systemic function plus laboratory analyses of blood condition and voiding functions plus x-ray diagnosis to check the size and penetration of solid tumors. In many of the patients, the primary tumor had been excised surgically or treated previously with a prophylactic dose of radiation, leaving management of the metastases as the major clinical concern. It is worth noting that only 4 percent of the 82 patients in the 10-year series were lost to complete followup. A detailed report on these results is cited in the preceding section. 3. CONTROL GROUPS: What control groups does Dr. Saenger have, or has he arranged for at our great cancer research institutes, so that he can determine how his special "treatment" is working? ANSWER: The question of specific control groups and randomized samples does not usually arise until after the completion and evaluation of the type of study currently underway by Dr. Saenger. He advises that planning for a more elaborate phase three study began last June on the basis of assessment of the 10-year results of the present effort. The literature contains sufficient studies of similar patients and comparable sized samples treated by other methods to allow basic comparisons of tumor regression, post-treatment symptoms and survival times after palliation. Again, it is worth noting that the extent of preparations and followup on each patient and the number of cancer patients at CGH who are suitable for an aggressive palliation study have combined to limit the size of the group under investigation. A phase three study appears feasible at Cincinnati but will require a substantial commitment of staffing and financing from some source other than patient care funds. 4. PRIVATE PATIENTS: Does Dr. Saenger treat any private cancer patients, or offer consultation on private cases? Does he recommend or use his partial or whole body radiation "therapy" on paying patients? Does he know any doctor who does? Page 11 ANSWER: Dr. Saenger and his colleagues are full-time faculty members of the University of Cincinnati College of Medicine and have no private practice in the ordinary sense. Their patient care responsibilities are restricted to patients at the city-operated Cincinnati General Hospital and its affiliated institutions. A very few patients were referred to the group from doctors at the Holmes Hospital, a private practice institution affiliated with the university. However, those patients were not charged for the treatment and medical care involved in their participation in the study. At this point, Dr. Saenger does not use his treatment on "paying patients" because he has none. He does not recommend his technique to other physicians because the investigation is not yet complete and the results are not indicative of immediate application to clinical situations apart from a research effort. Dr. Saenger would encourage other qualified researchers to duplicate his project or to modify his techniques on the basis that results to date are sufficiently promising to warrant further investigation both by his group and by others. As noted above, some type of partial or whole body radiation is used in more than 42 different U.S. medical centers. A total list of these is not available but they do include both public institutions like the University of Cincinnati and private ones where most patients are charged for their care and treatments. Thus, it is likely too p8d,X L x @  l 4 [ @mX xX X Z xX M) [ [ (@((D+[ 8@ (8Dሷ [ [ (@((D ([ h@``THIJKLMNO(:ВpВpВp EXPE283.HTM=p=p`8pRCRD V\ S\ (xD,h.% hn%2% U%h% H" h)%$$ P q"@\ \ \ (XD$I30p$I30$I30$I30 $I30L$I30V\ @\ @\ ( Dd D4 D[X        D"X L?X oooo p8d,X L