Attachment 7 University of Cincinnati Cincinnati, Ohio 45229 College of Medicine Department of Internal Medicine Cincinnati General Hospital October 12, 1971 'The Therapeutic Effect of Total Body Irradiation followed by Infusion of Autologous marrow in Humans.' HISTORY: March 1966 - 1st submitted. F.R.C. - Revised and re-submitted in (protection Humans with Stored Autogous Marrow) March 1967 - Therapeutic Effect Total Body ILLEGIBLE by Infusion of ILLEGIBLE Marrow in Humans. May 1967 - Provisional approval. October 1970 - New protocol submitted. March 1971 - Revision submitted. July 1971 - 2nd revision submitted. August 1971 - Dean's Office approval. UNIVERSITY OF CINCINNATI (INTERDEPARTMENTAL CORRESPONDENCE SHEET) To: Dr. E. A. Gall, Pathology From: Dr. Harvey C. Knowles, Jr. Date: April 27, 1966 I have reviewed the proposal by Dr. Ben I. Friedman entitled "Protection of Humans with Stored Autologous Marrow". I approve of the protocol as planned. HCK:ns May 6, 1966 Dr. Clifford G. Grulee, Jr. Dean, Collegee of Medicine University of Cincinnati Cincinnati, Ohio Dear Dr. Grulee: This relates to a request for approval of a research project entitled "Protection of Humans with Stored Autologous Marrow," submitted by Doctors Ben I. Friedman and Eugene L. Saenger. The Faculty Committee on Research is concerned about the implications of this study for several reasons: Consent forms are provided for signature by the patient, but it is not certain from the narrative whether the patient is advised that no specific benefit will derive to him and that there are, indeed, risks involved in the procedure proposed. It is not clearly indicated whether the radiation is admitted as therapy or purely as an experimental maneuver. A more detailed description of the potential hazards involved would be desirable, including some assessment of the effects of the whole body irradiation on the sixteen patients observed to date. Would irradiation influence the morbidity or the mortality in these patients? Indeed, was the course of the patient's disease influenced in any way other than that indicated by the hematologic study? What is meant by "some" hazard from autologous marrow administration? In a study such as this there appears to be a significant potential of hazard to the patient and the committee feels that it has a special obligation to be continued that the date, if collected, will be of benefit to "mankind". How many subjects do the investigators feel will be necessary to complete this project? Sincerely yours, Edward A. Gall, M.D. Director EAG/wh TO: Dr. Edward A. Gall FROM: Dr. George Shields DATE: March 13, 1967 SUBJECT: Protection of Humans with Stored Autologous Marrow I regret that I must withdraw myself from the subcommittee studying this proposals, for reasons of close professional and personal contact with the investigators and with some of the laboratory phases of this project. The following comments are sent to you in confidence, at your request. This protocol is difficult to evaluate. The purpose of the study is obscure, as is the relationship of the experimental groups to the purposes. The significance of the study in relation to the health of the patients under study may be considerable if the investigators succeed in prolonging life of these patients with malignant disease, but the risk of treatment may be very high if the authors' hypothesis (that bone marrow transfusions will ameliorate bone marrow depression due to radiation) is incorrect. The radiation proposed has been documented in the author's own series to cause a 25% mortality. I recommend that this study be disapproved, because of the high risk of this level of radiation. Admittedly it is very difficult, in fact impossible, to balance potential hazard against potential benefit in experiments of this sort. The stakes are high. Our current mandate is that we evaluate the risks on some arbitrary scale. I believe a 25% mortality is too high, (25% of 36 patients is 9 deaths) but this is of course merely an opinion. If it is the consensus of the investigators and the review committee that a 25% mortality risk is not prohibitive, then the experiment could be reconsidered from the standpoint of informed consent - provided the patient is appraised of this risk in a quantative fashion. I believe that the conditions of informed consent will have been observed if the authors change "all patients are informed that a risk exists, but that all precautions to prevent untoward results will be taken" to the equivalent of "all patients are informed that a 1 in 4 chance of death within a few weeks due to treatment exists, etc." Finally, although it is not our concern directly, a comment as to experimental design is indicated in this particular protocol. The authors' stated purposes are vague in the first page of the application, but on the last page three purposes are listed since it would require an untreated group and no reference has been made by the authors to such an untreated group of patients. The second purpose can be fulfilled by this protocol only with the retrospective group (Group 1). The evaluation of bone marrow transfusion in the treatment of bone marrow depression would require a concomitant control group of patients treated only with radiation. It is apparent that the authors feel the radiation risk is too high to re-expose another group to this level of radiation without some effort at radio-protection, and therefore the authors have chosen to use the retrospective group as a control. There is considerable question whether this retrospective group will be entirely similar and therefore whether it will serve the second purpose. The this purpose, "to determine whether autologous bone marrow therapy may play a role in treatment of bone marrow depression following acute radiation exposure in warfare or occupationally induced accidents", is not the subject of this experiment because normal individuals are not being tested. It is problematic whether the information gained in this study will apply to normal individuals following acute radiation exposure. Therefore it is my definite opinion that the third purpose of this experiment would not justify the risk entailed. For these several reasons I feel that the experimental design is inadequate, and because of the high risk inherent in this level of radiation, I think experimental design should be a proper subject for our consideration in this instance. Enclosure: Protocol & DASA-1844 UNIVERSITY OF CINCINNATI (INTERDEPARTMENTAL CORRESPONDENCE SHEET) To: Dr. Edward Gall, Chairman Clinical Research Committee From: Dr.Thomas E. Gaffney, Date: 4/17/67 I cannot recommend approval of the proposed study entitled "The Therapeutic Effect of Total Body Irradiation Followed by Infusion of Stored Autologous Marrow in Humans" for several reasons. The stated goal of the study is to test the hypothesis that total body irradiation at a dose of 200 rad followed by infusion of stored autologous marrow is effective, palliative therapy for metastatic malignancy in human beings. I don't understand the rationale for this study. The applicants have apparently already administered 150-200 rad to some 18 patients with a variety of malignancies and to their satisfaction have not found a beneficial effect. In fact, as I understand it, they found considerable morbidity associated with this high dose radiation. Whey is it now logical to expand this study? Even if the study is expanded, its current design will not yield meaningful date. For instance, the applicants indicate their intention to evaluate the influence of 200 rad total body radiation on survival in patients with a variety of neoplasms. This "variety" or heterogeneity will be present in a sample size of only 16 individuals. It will be difficult if not impossible to observe a beneficial effect in such a small sample containing a variety of diseases all of which share only CANCER in common. This gross deficiency in design will almost certainly prevent making meaningful observations. When this deficiency in experimental method is placed next to their previously observed poor result and high morbidity with this type of treatment in a "variety of neoplasms" I think it is clear that the study as proposed should not be done. I have the uneasy suspicion, shared up by the revised statement of objective, that this revised protocol is a subterfuge to allow the investigators to achieve the purpose described in their original application; manly, to test the ability of autologous marrow to "take" in patients who have received high doses of total body radiation. This letter question may be an important one to answer but I can't justify 200 rad total body radiation simply for this purpose, "even in terminal case material (italics are mine). I think there is sufficient question as to the propriety of these studies to warrant consideration by the entire Research Committee. I recommend therefore that this protocol and the previous one be circulated to all members of the Committee and that a meeting of the entire Committee be held to review this protocol prior to submitting a recommendation to the Dean. Sincerely, Thomas E. Gaffney, M.D. MEMORANDUM Date: 29 April 1967 To: Dr. Edward A. Gall From: Edward P. Radford, M.D. Subject: Application of Dr. Ben I. Friedman and Dr. Eugene L. Saenger The present proposal has been modified to emphasize, at least initially, the potential therapeutic value of the irradiation. I am somewhat concerned, nevertheless, that (page 5) "If it becomes obvious that the results are statistically significant, the study will be terminated." Significant of what ILLEGIBLE increased survival, or just a better hematologic picture? In the previous work cited, there is no mention of the possibility that this dose of whole body irradiation is at all palliative for metastatic cancer. Are no animal experiments available, and if not, why not? The previous work done on Group 1 patients is meaningless with regard to therapy and I think they prejudice their case by even mentioning them. The consent from and procedure for its use is good. Recommendation: Approval, but with the proviso that a further statement concerning the possible therapeutic aims be made, specifically with regard to previous work done with whole body irradiation. UNIVERSITY OF CINCINNATI (INTERDEPARTMENTAL CORRESPONDENCE SHEET) To: Dr. Edward Gall From: Dr. Harvey C. Knowles, Jr. Date: May 5, 1967 I reviewed the study proposal of Drs. Friedman and Saenger entitled "The Therapeutic Effect of Total Body Irradiation Followed by Infusion of Stored Autologous Marrow in Humans." After careful perusal, I approve of the study. I realize that hazards are involved, but I believe that careful monitoring will keep these to a minimum. UNIVERSITY OF CINCINNATI (INTERDEPARTMENTAL CORRESPONDENCE SHEET) To: Dr. E. A. Gall, M.D. From: R. L. Witt, M.D. Date: May 9, 1967 It is not clear to me from the protocol (although if I were to read the references I might learn) whether total body radiation used by others for palliation is in any way effective in man or animals in the palliation of widespread malignancy. I have the feeling from the protocol that the real intent is to work on the problem in infusion of marrow. I do not think I can approve the project until the matter of the likelihood of benefit to the individual patient treated is cleared up. UNIVERSITY OF CINCINNATI (INTERDEPARTMENTAL CORRESPONDENCE SHEET) To: Dr. E. Gall From: Dr. H. C. Knowles, Jr. Date: May 17, 1967 This concerns the research proposal of Drs. Ben Friedman and Eugene Saenger entitled "The Therapeutic Effect of Total Body Irradiation Followed by Infusion of Stored Autologous Marrow in Humans." After study of the proposal and listening to testimony this morning from Drs. Ben Friedman and Harry Horwitz (serving as consultant) I give provisional approval to the proposal. I have to suggestions, however. First, I believe a statement should be inserted to the affect that the radiation therapy to be used in an accepted form of treatment and that beneficial therapy is not being withheld. Second, I believe a statement might be made that means of measurement of dependent variables in question are judged satisfactory to determine a difference between groups II and III. In addition, some statement might be made to the effect that sampling of the population will be at random and that all efforts will be made to reduce the number of independent variables and keep heterogeneity at a minimum. I assume all this is present in the investigators' minds. It would help to have it on paper. I realize that my second request deals with experimental design, a matter which is really not the responsibility of the Committee. Nevertheless, we are balancing the good to come against hazards encountered, and the good to come is related to experimental design. I believe that merely an few sentences can be added to the protocol to clarify those points. I am leaving all of this to your discretion, however. UNIVERSITY OF CINCINNATI (INTERDEPARTMENTAL CORRESPONDENCE SHEET) To: Dr. E. Gall From: R. L. Witt, M.D. Date: May 17, 1967 In regard to the recent committee deliberation on the total body radiation project, the recommendation I would suggest be included with the approval is: A simple sentence or paragraph should be inserted to clarify the therapeutic implications and/or possibilities. UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE May 18, 1967 Dr. E. A. Gall Dept. of Pathology Cincinnati, Ohio 45229 Re: The Friedman Proposal for studies in total body radiation Dear Dr. Gall: The only proviso I would suggest is that the applicants give at least some consideration to the basic rudiments of experimental design which are necessary to the completion of studies of the type contemplated. Sincerely, Thomas E. Gaffney, M.D., Director Division of Clinical Pharmacology TEG:mh May 22, 1967 Dr. Clifford G. Grulee, Jr. Dean, College of Medicine University of Cincinnati Medical Center Dear Dr. Grulee: The Committee on Research has for several months been considering a research project entitled "The Therapeutic Effect of Total Body Irradiation Followed by Infusion of Stored Autologous Marrow in Humans," submitted by Dr. Ben I. Friedman. It is the sense of the Committee that a study directed essentially toward the treatment of widespread metastatic neoplasm by whole body irradiation would have approval with the understanding that the infusion of stored narrow constitutes a supportive measure. Dr. Friedman has partially modified his protocol but has not yet done so to the satisfaction of the Committee. The Committee, therefore, recommends provisional approval of this project. The following requirements, however, ILLEGIBLE. 1. The protocol should be modified to indicate that the exclusive purpose of the study is to determine the therapeutic efficacy of whole body irradiation. 2. The use of stored autologous marrow is intended to be in support of patients so treated. 3. The plan of the investigations should be simplified in order to show: a. its therapeutic purpose b. the range of irradiation to be used and clear indications for its discontinuation c. a delineation of the danger interest in the method and the steps intended to protect the patients. d. how the therapeutic affects (both beneficial and adverse) will be determined and how these already observed will bear upon the continued use of the method. Sincerely yours, Edward A. Gall, M.D. Director May 23, 1967 Dr. Ben I. Friedman Radioisotope Laboratory Cincinnati General Hospital Dear Dr. Friedman: The Research Committee has reported on your protocol entitled, "The Therapeutic Effect of Total Body Irradiation Followed by Infusion of Stored Autologous Marrow in Humans." In meeting its responsibility, it is the sense of the Committee that a study directed essentially toward the treatment of widespread metastatic neoplasm by whole body irradiation would have approval with the understanding that the infusion of stored marrow constitutes a supportive measure. It is, therefore, recommended that provisional approval be granted. The following requirements, however, must be met. 1. The protocol should be modified to indicate that the exclusive purpose of the study is to determine the therapeutic efficacy of whole body irradiation. 2. The use of stored autologous marrow is intended to be in support of patients so treated, 3. The plan of the investigation should be simplified in order to show: a. its therapeutic purpose b. the range of irradiation to be used and clear indications for its discontinuation c. a delineation of the danger inherent in the method and the setups intended to protect the patients d. how the therapeutic effects (both beneficial and adverse) will be determined and how those already observed will bear upon the continued use of the method. Sincerely yours, Clifford G. Grulee, Jr., M.D. Dean UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE April 4, 1972 TO: Evelyn Hess, M.D. FROM: Edward B. Silberstein, M.D. Enclosed is the protocol entitled "Evaluation of the therapeutic effectiveness of total and partial body irradiation as compared to chemotherapy in humans with carcinoma of the lung or colon" for the consideration of the Faculty Committee on Human Research. UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE April 14, 1972 Dr. Evelyn Hess Faculty Committee on Research K-3 Dear Evelyn: On March 21 Ted Silberstein submitted a proposal to the Faculty Research Committee for a Phase III study of cancers of lung and colon in general following the suggestions of the Ad Hoc Faculty Committee. The ad hoc Committee also recommended that we seek outside funding for the work and we are quite anxious to make the June 1, 1972 deadline of the NIH with a new application. Assuming that we would get approval from NIH we could be on the more desirable support basis by January 1, 1973 thus assuring sufficient support for our professional and technical personnel. We have tentatively agreed to withhold further patient treatment under this program until the protocol has been reviewed by your committee. Frankly I am writing this note with considerable trepidation realizing the considerable efforts to which all of you have been put. Nevertheless if the protocol could be reviewed in time for us to make the June 1 deadline of the NIH we would be most grateful. Sincerely, Eugene L. Saenger, M.D. ELS/ml UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE May 22, 1972 TO: Faculty Committee on Research FROM: Edward B. Silberstein, M.D. SUBJECT: Protocol on the Evaluation of the Therapeutic Effectiveness of Wide Field Radiotherapy as Compared to Chemotherapy in Humans with Carcinoma of the Lung or Colon Enclosed is our application for a National Institutes of Health grant for the above study for your consideration. As you know, we must meet a June 1 deadline if we are to be funded by January 1, 1973, so your cooperation in this matter is very deeply appreciated. This grant has been written in accordance with suggestions made by Dr. Hess, who met with us May 3, 1972. I believe that all questions raised have been answered in this protocol. 1. The randomization procedure is described on page 23 employing a table of random numbers. 2. In our proposed budget to the N.I.H., monies have been allotted for a statistical consultant. In the proposed statistical analysis, the expertise of Gustave Bahr, Ph.D., has been employed. 3. The statistical evaluation of treatment is spelled out on page 38 (Actuarial Analysis), a clinical response will be analyzed as noted on page 29 and 30 with conventional contingency tables. Appendix C is a statistical analysis of the number of patients required in this study. 4. Requirements for termination of treatment are noted on page 31. Specifically, the patients with minimal or no response will be terminated in this study. The exact dose of radiation is clearly indicated on pages 26 and 27, 200 rads will be used for the total body and 400 rads for either upper or lower body irradiation. Faculty Committee on Research...-2- May 22, 1972 5. The safety precautions taken in the treatment are noted on page 28 where there is provision for radiation dose reduction. On page 24, indications for excluding patients from the study are all patient safeguards. Page 25 and 26 indicate a complete evaluation that each individual receives prior to randomization. The efficacy of bone marrow transplantation as a safety precaution is found in Appendix B. 6. Objective ways of showing what is to be done on each visit are found in the follow-up sheets in Appendix F. There will be no changes in the dose of irradiation in this protocol. Any changes in irradiation must be placed before the Faculty Committee on Research as part of any entirely new protocol. 7. Measurement of tumor size will be with calipers or with a centimeter ruler applied to roentgenographs or scientistic. 8. Recognition of the problem of objectively noting changes in size of tumors below fifty per cent appears on page 30. 9. Five types of consent forms are included. 10. Studies of the systemic effects of chemotherapy and radiation therapy are found on pages 31 and 32. 11. Appropriate references are made to the toxicity of 5 fluorouracil and chlorambucil on pages 33 and 34. It should be noted that 5 fluorouracil has been in clinical use since 1957 (ILLEGIBLE, F.A. et al. Proc. Am. Assoc. Cancer Research, 2: 230, 1957.). Chlorambucil was developed as a less toxic agent than trimethylene melamine reported on by Altman, S.J. et al in Cancer, 9:512, 1956. There has thus been clinical experience with these two forms of chemotherapy for half a generation. Thank you once again for working with us for the development of this protocol. Very sincerely, Edward B. Silberstein, M.D. EBS/ml Enclosures Re: Total Body Irradiation Project November 19, 1970 Dr. Edward Silberstein Associate Director Radioisotope Laboratory H Basement Dear Dr. Silberstein: Thank you for agreeing to meet with the Faculty Committee on Research on your proposal on Monday, November 30th, approximately 4:45 PM in the K-4 Library. As the committee will be meeting on another proposal earlier, I would appreciate it if you would be available in your department and I will phone you when we are finished with the first proposal so that you do not have to waste time waiting. The committee does have a number of questions and would appreciate it if you could reply to this in writing before the meeting so that it will be available for study and will, therefore, expedite our session. 1) As you may know, this whole study of Therapeutic Effect of Total Body Irradiation was given only Provisional Approval by the Faculty Committee on Research in 1967. It is for this reason then that I think that it should be completely re-evaluated and a full new proposal submitted. This study has been on-going for a number of years now and we are told that 70 patients have received irradiation and that the clinical course has parallel that of comparable patients treated with other agents. The investigators refer to Protocols A and B in this respect. They also refer to Protocol C in regard to the Immune Studies. However, none of these protocols were with ILLEGIBLE application. The Committee requests a full progress report on the date of the 70 patients treated so far. 2) Exactly how will Palliation be measured? Will this be by peripheral blood counts only? 3) When will the stored bone marrow be administered. Times of blood counts are given in detail as well as certain tests, but it is not clear if marrow will be given to all the patients in the group receiving it immediately after irradiation as is implied in the paragraph at the bottom of page 4 or whether it will be given only ILLEGIBLE for a low blood count. Page 2 4) It would appear wiser to make a more definite protocol for the experiments related to stored autologous marrow. What are the experimental risks of pulmonary ILLEGIBLE? Are there any psychological risk for patients in life islands? The possibility of using a ILLEGIBLE air flow unit is mentioned -- is this available at this medical center? 5) There is a brief reference to a serum factum which breaks chromosomes. does the proposal mean that the serum factor may alter the survival of stored marrow to be given to a patient following irradiation? If so, is this a serious detriment to the successful outcome? 6) The details on the voluntary consent statement are inadequate for present-day usage. It is suggested that there should be two (2) consent forms -- one for patients having total body irradiation, and another for those having the bone marrow transplant. On both of these the actual benefits, hazards, etc., should be listed in far more detail and in wording that the patient can fully understand. 7) It is noted that the references are all fairly ancient; it would appear that there must be literature references that are much more up-to-date which would be more appropriate to this 1970 proposal. If we could have a reply in writing to these questions before the meeting, this will expedite that session. Thank you very much for your cooperation. Sincerely, Evelyn V. Hess, M.D. THE CHILDREN'S HOSPITAL RESEARCH FOUNDATION ILLEGIBLE CINCINNATI, OHIO 45229 November 27, 1970 Dr. Evelyn V. Hess Chairman, Faculty Committee on Research Department of Internal Medicine Cincinnati General Hospital Cincinnati, Ohio Dr. Dr. Hess: Enclosed please find the application from Dr. Edward Silberstein concerning autologous marrow infusion in conjunction with total body irradiation. Both the irradiation procedure and the marrow infusion are reasonably standard techniques and the investigators seem to have a good grasp of the limitations and possible dangers of these forms of treatment. The main issue, however, is the effectiveness of marrow transfusion in the irradiated patient. Certainly one would not want to use this procedure which carries some risk unless there were clear benefit to the patient. According to the protocol, this procedure has been attempted in five patients already. No evaluation of these results was included, I would think before final approval could be recommended these data should be reviewed to see if adequate information is already available. If these five patients did not provide adequate information, I should think the committee would be interested in finding out why meaningful information wa snot or could not be collected in those five studies. Certainly the investigators have an obligation to adequately evaluate these procedures if they are to be done. Sincerely, Alvin M. Mauer, M.D. AMM/bp UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE November 30, 1970 Dr. Evelyn V. Hess Chairman Faculty Committee on Research Division of Immunology J-4 Dr. Evelyn: Thanks for your letter of November 19, 1970 and I must again apologize for our inability to meet with your committee on November 3. I am, however, appreciative of the stringent requirements which all human research must fulfill. I have reviewed the protocol which was sent you and I don not consider it satisfactory. I blush that I permitted my name to be substituted for Ben Friedman's when it was sent up to you at your request. It is indeed out of date and I am currently rewriting it totally. This may take a couple of weeks because I am simultaneously preparing an article on our improved technique for marrow transplantation and will do the two concurrently. I am including the survival results of all patients with whom I have works since my arrival here. The fact that two of the first three patients who I treated died indicates only that I selected poor candidates for irradiation whose conditions were terminal at the time of the therapy. The doses given to each weren't sufficient to account for their deaths, for neither will cause life threatening hematogolic depression. The prospectus which you received mentions protocols A and B which I will try to dig out of General Saenger's old files. I'm uncertain as to what they are. Protocol C is yours, of course. Tumor palliation is to be measured by constructing life tables to compare the per cent of those at risk surviving each year with available data on untreated patients. I do not feel that we have enough data to prepare such tables after only two years of work. However, Bernie Aron will concur that a striking number of our patients so treated had a remarkably benign course. Whether this has bene the result of patient selection or our therapy we do not know yet. Dr. Evelyn Hess -2- November 30, 1970 The palliation by bone marrow transplantation of hematopoietic depression induced by radiation is to be measured by peripheral blood counts as you noted. Because storing bone marrow at low temperature decreases the survival of the cells somewhat, and because the techniques employed by my predecessor had given no clear evidence of the successful marrow transplant, I have elected not to store bone marrow at this time. Marrow is removed from the patient under general anesthesia, and when the patient is awake the radiotherapy is given; then about four hours after the marrow is removed it is reinfused intravenously. This gives us optimum cell survival and hence optimum clinical results. Marrow is given the same day as the irradiation rather than waiting until the blood counts have dropped. If one waits, then one can not differentiate natural marrow necessary from the effect of the graft. The psychological problems of patients in Life Islands are well known to both of us. We are still planning to obtain a laminar flow unit at some time in the future but this is not available at this time. There are no risks of clinically or pathologically significant polumonary emboli with the techniques used. In fact, in Ben Friedman;s protocol which you now have he notes on page 7 that the three patients to whom unfiltered marrow was given intravenously had been studied post mortem shortly after the infusion by Drs. Gall and Yamachuchi. According to his report, "no evidence of pulmonary emboli, pulmonary infraction or other disease as a result of marrow infusion was found by microscopic examination. I have been obtaining electrocardiograms, lung scans and arterial gases on our marrow transplant patients before and after infusion of the marrow and there has never been a change. In patients who have been previously irradiated there is some evidence for a serum factor which breaks the chromosomes of normal people but the experiments showing this are flawed. We have done extensive experimentation to confirm these findings and have not been able to do so. I shall rewrite the voluntary consent form to have one for Dr. Evelyn Hess -2- November 30, 1970 total body radiation and one for bone marrow transplantation. Again, let me apologize for allowing the old protocol to be sent you. I permitted my name to replace that of Ben Friedman on what was essentially the old protocol before I had an opportunity to acquaint myself as fully with the field as I have now. The revised protocol, which should be done within two weeks, should reflect a bit better the quality of our work. I really didn't understand the thrust of your letter of November 19 until I had reread the old protocol! It leaves a lot to be desired. Very sincerely, Edward B. Silberstein, M.D. EBS/ml Meeting on Dr. Silberstein's Proposal-- Total Body Irradiation Febr 16, 1971 Recommendations from the Faculty Committee on Research -- 1. To resubmit the proposal excluding references to future work and also excluding the proposed study comparing large field irradiation and 5 fluorouracil for metastatic carcinoma of the large bowel as this is separate proposal and should be submitted on its own merits. 2. That the proposal make reference to autologous marrow transplant only. 3. That references to life islands be omitted as it is not intended to utilize this facility. 4. That the data available to the investigators be much more cogently reviewed and represented. Their report to the Defense Atomic Support Agency says that 64 patients have been in the program to date, but the ILLEGIBLE submitted with the most recent revision of the proposal lists 27 patients and it is not clear who did and who did not receive marrow treatment, how survival times have bene influenced by the treatment, and lastly, what parameters are actually being followed to determine the quality of the response and whether or not it is effective. Data are therefore requested on the patients who have been treated to date. 5. It is suggested that the tumor registry data which are available for all investigators in Cincinnati might be utilized as a baseline for comparison for treatments. This is particularly appropriate for carcinoma of the colon. 6. It is suggested that data be obtained from the two other centers where total body irradiation is being used for the treatment of Ewing's tumors -- Chicago and the University of Toronto Medical Center. In summary, the Committee felt that it required: 1. More specific information relating to all the investigations that have been done to date so that this large amount of work can provide good and valuable data. 2. They request clearer guidelines from the investigators as to their method of evaluating the results in these cancer patients with metastatic disease. it is agreed that this is a most difficult area to evaluate and yet philosophically, without evaluation there really is no data and therefore probably little justification for the great amount of work and effort which goes into this study such as this. Page 2 Dr. Silberstein's protocol The committee is in complete agreement with the attempts of the Department of Radiotherapy to provide appropriate treatment for patients with metastatic carcinoma, a constantly difficult and challenging area of therapeutic medicine. Evelyn V. Hess, M.D. Chairman, Faculty Committee on Research EVH:js University of Cincinnati Cincinnati, Ohio 45229 College of Medicine Department of Internal Medicine Cincinnati General Hospital February 16, 1971 RE: Revised Protocol - "The therapeutic effect of total body irradiation followed by infusion autologous or isologous marrow in humans." E. Silberstein, M.D. Reviewers Comments and Questions Some explanation of the first protocol would be appropriate for the section on potential hazards on page 8. Why did one patient develop severe thrombocytopenia and leukopenia whereas it has been demonstrated that marrow transplantation prevents this? On page 9, what is the psychologic performance decrement? Should not this protocol be explicit on each of the first four items in this list which are not covered by a protocol? What is the significance of the future work planned? There is no rationale given for the sequence of events described. Will these things be done without submission fop another protocol? The protocol entitled, "An evaluation of the therapeutic effect of total body irradiation in humans" cannot be judged because it is incomplete. No information is given concerning the therapeutic effectiveness of 5-fluorouracil as compared to irradiation. Before judging regimen was chosen for study. As far as this reviewer is concerned mud-packs could be given to the controls; he has as much information about their effectiveness as that of 5-fluorouracil. I am still not clear however, about past experience. I would be interested in knowing how the survival rates with body radiation conducted so far compare with patients given in the literature with out treatment and those of patients receiving kemo therapy. Twenty fives cases are listed in the appended table. Have they been set the life table system? We recognize that the investigators are aware of the emotional problems arising in "life islands". The question was not directed towards their information, but rather to the mechanism used to inform the patient of complications of this sort of protection from his environment. Possibly, they are not actually going to use the life island, or never have. If they are to use one, I think one needs to consider the possibility of gaining informed consent for such a procedure, difficult though it be. What is the risk of embolism associated with the infusion of the patient's marrow? What procedures have been used to define the presence or absence of intravascular clotting and/or embolism associated with this procedures? Rather than take myself to the library to read the long list of references given, I would appreciate it if the investigators would summarize the experience of other groups with this procedure with regard to: a) marrow "takes" b) complications of infusion of marrow, such as embolism c) the survival data obtained by others using such procedures - Is the information they with to obtain already available? I note that in the voluntary consent statement, there is a statement with regard to risk that the "only cells affected which would cause any risk to you are those in your bone marrow." This is an exclusion of fact, and perhaps should be modified. University of Cincinnati Medical Center Inter-Office Memo To: Dr. Clark West From: Evelyn V. Hess, M.D. Dr. Harvey Knowles Chairman Dr. Virginia Donaldson Faculty Committee Dr. Alvin Mauer on Research Date: 9 March 1971 A subcommittee of the Faculty Committee on Research met on K-3 on February 16, 1971. Those present were Drs. Clark West, Harvey Knowles, Evelyn Hess and the special consultant, Dr. Alvin Mauer. Dr. Virginia Donaldson could not be present as she was out of town. Drs. Eugene Saenger and Edward Silberstein were scheduled to attend but at the last moment Dr. Silberstein was unable to attend. All the reviewers were fully conversant with the first proposal, the rewritten proposal and the investigators' replies to the various questions. These were reviewed prior to Dr. Saenger's arrival and it was decided to evaluate the following points with the investigator: 1. More information on which patients get total, partial body irradiation. 2. Whether or note isologous marrow transplant is intended. 3. The estimated number of patients in the various components of the study and whether these would be sufficient to provide data. 4. To obtain more of the result data from the studies undertaken during the previous few years. When Dr. Saenger arrived, there was a very full and open discussion of all aspects of the proposal. Dr. Saenger was a little unfamiliar with some of the details and these will be supplied in the investigator's written reply. Dr. Saenger made it clear that the data for the study was essential as their are in fact very few ongoing studies of this type of therapy in the United States. It was his impression that the benefits of irradiation were definite and that the original 200 rad dose had given better results than the 100 rad dose. He also stated that it is difficult to estimate the number of patients for the study because there are many other therapeutic trials for which these patients are required and they have to compete with other groups. Also the patients may have various complications of infections and entry into the study has to be postponed. Many of the results of these studies are in the Annual Report which the department makes to the Defense Atomic Support Agency which funds the radiation study. Dr. Saenger obtained 6 copies of this report and the subcommittee reviewed parts of it at the meeting. Dr. Saenger agreed that the proposal should not include any references to life islands, in fact these will not be utilized. He also agreed with the committee that the inclusion of other studies and suggestions for future work were not appropriate to the proposals. Page 2 - Faculty Committee on Research Minutes of Meeting The subcommittee makes the following suggesting to the investigators before making final recommendations to the Dean: 1. To resubmit the proposal excluding references to future work and also excluding the proposed study comparing large field irradiation and 5 fluorouracil for metastatic carcinoma of the large bowel as this is a separate proposal and should be submitted on its own merits. 2. That the proposal make reference to autologous marrow transplant only. 3. That references to life islands be omitted as it is not intended to utilize this facility. 4. That the data available to the investigators be much more cogently reviewed and represented. There report to the Defense Atomic Support Agency says that 64 patients have been in the program to date but the table submitted with the most recent revision of the proposal lists 27 patients and it is not clear who did and who did not receive marrow transplants, through survival times have been influenced by the treatment, and lastly, what parameters are actually being followed to determined the quality of the response and whether or not it is effective. Data is therefore requested on the patients who have been treated to date. 5. It is suggested that the tumor registry data which is available for all investigators in Cincinnati might be utilized as a baseline for carcinoma of the colon. 6. It is suggested that data be obtained from the two other centers where total body irradiation is being used for the treatment of Ewing's tumors - Chicago and the University of Toronto Medical Center. In summary, the committee felt that it required: 1. More specific information relating to all the investigations that have been done to date so that this large amount of work can provide good and valuable data. 2. They request clearer guidelines from the investigators as to their method of evaluating the results in these cancer patients with metastatic disease; it is agreed that this is a most difficult area to evaluate and yet philosophically without evaluation, there really is no data and therefore probably little justification for the great amount of work and effort which goes into a study as this. The committee is in complete agreement with the attempts of the Department of Radiotherapy to provide appropriate treatment for patients with metastatic carcinoma, a constantly difficult and challenging area of therapeutic medicine. Evelyn V. Hess, M.D. Chairman, Faculty Committee on Research March 26, 1971 Dr. Edward Silberstein Associate Director Radioisotope laboratory H Basement Dear Dr. Silberstein: Enclosed are the recommendations of the Faculty Committee on Research following the meeting with Dr. Gene Saenger on February 16 last. The minutes of the meeting and the discussion have been circulated to the members of the committee for final approval and these recommendations are enclosed for your perusal. If you can reply to these suggestions and questions in writing as soon as possible, this will expedite the handling of your proposal. Thank you for all your cooperation. Yours sincerely, Evelyn V. Hess, MD. Chairman, Faculty Committee on Research ILLEGIBLE Meeting on Dr. Silberstein's Proposal -- Total Body Irradiation Feb. 16, 1971 Recommendations from the Faculty Committee on Research -- 1. To resubmit the proposal excluding references to future work and also excluding the proposed study comparing large field irradiation and 5 fluorouracil for metastatic carcinoma of the large bowel as this is a separate proposal and should be submitted on its own merits. 2. That the proposal make reference to autologous marrow transplant only. 3. That references to life islands be omitted as it is not intended to utilize this facility. 4. That the data available to the investigators be much more cogently reviewed and represented. Their report to the Defense Atomic Support Agency says that 64 patients have been in the program to date, but the table submitted with the most recent revision of the proposal lists 27 patients and it is not clear who did and who did not receive marrow transplants, how survival times have been influenced by the treatment, and lastly, what parameters are actually being followed to determine the quality of the response and whether or not it is effective. Data are therefore requested on the patients who have been treated to date. 5. It is suggested that the tumor registry data which are available for all investigators in Cincinnati might be utilized as a baseline for comparison for treatments. This is particularly appropriate for carcinoma of the colon. 6. It is suggested that data be obtained from the two other centers where total body irradiation is begin used for the treatment of Ewing's tumors -- Chicago and the University of Toronto Medical Center. In summary, the committee felt that it required: 1. More specific information relating to all the investigations that have been done to date so that this large amount of work can provide good and valuable data. 2. They request clearer guidelines from the investigators as to their method of evaluating the results in these cancer patients with metastatic disease. It is agreed that this is a most difficult area to evaluate and yet philosophically, without evaluation there really is not data and therefore probably little justification for the great amount of work and effort which goes into a study such as this. Page 2 Dr. Silberstein's protocol The committee is in complete agreement with the attempts of the Department of Radiotherapy to provide appropriate treatment for patients with metastatic carcinoma, a constantly difficult and challenging area of therapeutic medicine. Evelyn V. Hess, M.D. Chairman, Faculty Committee on Research EVH:js UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE April 6, 1971 Evelyn V. Hess, M.D. Chairman Faculty Committee on Research Division of Immunology Dear Evelyn: Thank you for your letter of March 26 concerning your meeting on our total body radiation proposal of February 16, 1971. We will follow your suggestions in omitting certain references to areas of future work and to the life island facility. Nevertheless, we are currently investigating the cost of laminar flow units for future research. We will continue to employ autologous and isologous marrow transplantation but not allotransplantation at this time. However, it is difficult to understand your Committee requesting that we exclude the proposed study comparing large fields of radiation with five fluoro-ILLEGIBLE for metastatic carcinoma of the large bowel, because at the same time the Committee is asking for evaluation of results of therapy. The whole purpose of the five fluoro-uracil-total body radiation combined study is to compare the results of a mode of therapy which has a fairly well accepted incidence of response with this experimental mode of therapy. Our report to the Defense Atomic Support Agency does not contain the total number of patients in the study presently, as you can note from the date appearing on that report. The table submitted with the most recent revision of the proposal lists 27 patients studied since I have been here. I shall clarify which patients did and did not receive marrow transplantations in this table when it is resubmitted. I believe that the first paragraph, page 2 of the proposal which you initially received indicates what parameters are being followed to determine response. We are specifically employing a life table technique as well as comparing days of survival post-irradiation with data obtained in references 7 and 9 of our proposal, as well as with the results of the upcoming five flouro-uracil total body radiation joint study. Dr. Evelyn Hess -2- April 6, 1971 In addition to survival we are looking specifically at shrinkage of measurable tumor by more than 50% and relief of pain as well as reduction of liver enzyme levels towards normal post irradiation. However, these data are not significant for many patients who have metastatic disease but are free of pain and have normal live enzymes. It is for this reason that survival has been our basic variable to follow. I jointed Dr. William Rider at a meeting on the effects of whole body irradiation sponsored by Oak Ridge Associated Universities and the Defense Atomic Support Agency last week. We are continuing to compare our results on patients treated with Ewing's tumor of those of Dr. Hendrickson of Chicago and those of Dr. Rider from Toronto. Enclosed are some abstracts from this meeting. You will shortly receive the second revision of the total body irradiation protocol. Please accept our thanks for the time you have spent in helping us to write a more precise and acceptable protocol. Very sincerely, Edward E. Silberstein, M.D. EBS/ml Enclosure July 22, 1971 Dr. Edward B. Silverstein Dr. Eugene L. Saenger RE: THE THERAPEUTIC EFFECT OF TOTAL BODY IRRADIATION FOLLOWED BY INFUSION OF AUTOLOGOUS MARROW IN HUMANS Dear Drs. Silverstein and Saenger: Recommendation regarding approval or disapproval of this proposal is deferred pending answers to the following questions: We are not much further ahead after reading the revision that after seeing the original. We cannot decide whether the proposal concerns whole body radiation, bone marrow transplantation or a combination of the two. If whole body radiation is to be carried out as a study, the proposal is too skimpy for a project of such magnitude. Furthermore, the authors state that a protocol for this is "under consideration". If the proposal concerns mainly bone ILLEGIBLE, the methodology is given very completely, but no experimental design is stated. The whole problem concerns the lace of understanding of just what is to be done. If evaluation of whole body radiation is the main point, then the proposal should so indicate. If the main point is to survey the natural history of patients receiving bone marrow transplantation, then this should be stated. We wish these authors could meet with us and simply outline (perhaps on a blackboard) what they want to do. On the first page, Dr. Silberstein refers to the Table I summary of the number of patients and types of irradiation lused by their group. Unfortunately, Table I is so brief and so poorly defined that we do not know what these numbers mean. It would be helpful if he could elaborate on this table. On page two, he says that preliminary results published by Dr. Saenger have suggested an effect on prolonging life. However, upon reviewing Table 2, we do not find any evidence of prolongation of survival. Furthermore, without a careful description of the kinds of patients involved in these various groups, the extend of their tumor, and the subsequent clinical courses, it is impossible to evaluate this information. For instance, it might be possible that those patients who were clinically in better condition would be selected for the higher dose rates. However, even with the dose as they stand, we do not find any evidence of prolongation of survival and we are not provided with any statistical evaluation to substantiate this claim. We have no further comments concerning the technique to be used for marrow harvesting, handling and infusion. However, there still seem to be problems in how these patients will be evaluated. We had asked specifically for a review of those patients who have already received marrow transfusion. We do not find this review in the current application. On page 8, it mentioned that in patients in whom marrow is given on the day of radiotherapy, severe ILLEGIBLE is not found on the day on which it would have been expected if the patient had not received the transfusion. However, no support for this claim is found. Thus, the first consideration would be - does in fact the marrow transfusion prevent the development of ILLEGIBLE and the consequent clinical complication? The second problem of evaluation, of course, is whether or not these patients will do better having had irradiation than patients who are treated either symptomatically or patients in whom chemotherapy is used. For proper evaluation, all available patients should be entered on the study. A method for staging these patients should be devised. Patients should then be randomly allocated to one form or another of treatment. After a suitable number of patients have been studied, the data should then be evaluated according to a set of criteria to determine which method of treatment is best. We do not find adequate methods of evaluation in this study protocol. In our minds, this new protocol has still not answered the questions raised initially. The technical aspects of marrow transplantation do not seem to be the problem. The real problem seems to be how are we going to evaluate the effectiveness of marry transplants in protesting against the side effect of total body irradiation. Secondly, how are we going to evaluate the effectiveness of total body irradiation. Thank you for your cooperation. Sincerely, Evelyn V. Hess, M.D. Chairman Faculty Committee on Research EVH/jre August 3, 1971 Eugene Saenger, M.D. Director, Radioisotope Laboratory RE: THE THERAPEUTIC EFFECT OF TOTAL BODY IRRADIATION FOLLOWED BY INFUSION OF AUTOLOGOUS MARROW IN HUMANS. Dear Dr. Saenger: Thank you for so quickly submitting revision number three of your research protocol. Following Dr. Silberstein's meeting with Dr. Knowles, and the review of the new protocol by other member of the committee, all questions now appear to be answered. Accordingly, the committee will recommend approval of this protocol to Dean Grulee. We would like to thank you for your most complete cooperation with the committee. I'm sure at times that we appear to be very illegible indeed. However, I think for all our sakes, that good, clear protocols will benefit all of us and our patients. Again, thank you for your cooperation and all your work that you put into this proposal. Sincerely, Evelyn V. Hess, M.D. Chairman, Faculty Committee on Research EVH/jrc SILBERSTEIN/SAENGER: THE THERAPEUTIC EFFECT OF TOTAL BODY IRRADIATION FOLLOWED BY INFUSION OF AUTOLOGOUS MARROW IN HUMANS. Following the meetings of the Faculty committee and the investigators in March, 1971, it was suggested that the investigators resubmit their proposal on this study. This they did, and the second revision was sent to Drs. Donaldson, West, Knowles, and special consultant, Dr. Mauer, in May of 1971. Following this, Drs West and Donaldson approved this revision, although Dr. Donaldson had some questions. Drs. Mauer and Knowles, however, were unable to give their full approval. Accordingly, a meeting of the sub-committee of the Faculty Research Committee was held on July 23, 1971, with Drs. Hess, Mauer and Knowles. The major problem appeared to be that the protocol, as designed, did not really allow for valid statistical data to be obtained over the follow-up period of the study. Dr. Knowles, in particular, had difficulty in following the scientific methodology. Accordingly, on July 26, 1971, Dr. Knowles met with Dr. Silberstein to go over the protocol in detail and, resulting from this, revision #3 was submitted to the committee. The third revision is a much clearer one than the previous submissions, and appears to satisfy all members of the committee. Drs. Hess and Mauer reviewed it on July 28, 1971, and as it now stands, it meets fully with the approval of Drs. Knowles and Mauer. Therefore, the committee will recommend approval of this protocol to Dean Grulee. August 9, 1971 Dr. Edward B. Silberstein Dr. Eugene L. Saenger Department of Radiology Radioisotope Laboratory Cincinnati General Hospital Dear Drs. Silberstein and Saenger: The project entitled THERAPEUTIC EFFECT OF TOTAL BODY IRRADIATION FOLLOWED BY INFUSION OF AUTOLOGOUS MARROW IN HUMANS has been reviewed and approved by the illegible Committee on Research. Sincerely, Clifford G. Grulee, Jr., M.D. Dean August 28, 1971 Clifford G. Grulee, Jr., M.D. Dean College of Medicine Illegible and Bethesda Avenues Cincinnati, Ohio RE: Evaluation of the Therapeutic Effectiveness of Wide-Field Radiotherapy as Compared to Chemotherapy in Humans with Carcinoma of the Lung or Colon. Dear Dr. Grulee: The Faculty Committee of Research has reviewed the above captioned protocol submitted by Dr. Eugene L. Saenger, Professor of Radiology, Edward B. Silberstein, M.D., Assistant Professor of Radiology and Medicine and Bernard S. Aron, M.D., Associate Professor of Radiology, Department of Radiology, Cincinnati General Hospital. The Faculty Committee on Research after long, exhaustive (and occasionally exhausting) review has recommended for approval the radiation project in its present form as a grant application to the National Cancer Institute. Yours sincerely, Evelyn V. Hess, M.D. Chairman Faculty Committee on Research evh/vrh FACULTY RESEARCH COMMITTEE Five members - Five years with staggered rotation 1964 Dr. Edward A. Gall, Chmn Dr. Harvey C. Knowles Dr. Herman C. Lichstein Dr. Edward L. Pratt Dr. Thomas Gaffney 1965 Dr. E.A. Gall, Chmn Dr. Harvey Knowles Dr. Edward L. Pratt Dr. Thomas Gaffney Dr. Edward P. Radford Dr. Harry D. Bouman Dr. George Shields Dr. Burce G. Macmillan Dr. Clark West Dr. John Will Dr. Richard Witt 1966 - See Attached 1967 Dr. E.A. Gall, Chmn Dr. Harry Bouman Dr. Thomas Gaffney Dr. Samuel Kaplan Dr. Harvey Knowles Dr. Bruce MacMillan Dr. Edward Radford Dr. George Sheilds Dr. Clark West Dr. John Will D. Richard Witt 1968 Dr. Thomas Gaffney, Chmn Dr. Richard Bosian Dr. Edward Gall Dr. Samuel Kaplan Dr. Harvey Knowles Dr. Edward Radford Dr. George Shields Dr. Clark West Dr. Richard Witt Dr. John Wulsin 1969 Dr. Gaffney, Chairman Dr. R.C. Bosian Dr. E.A. Gall Dr. Evelyn Hess Dr. Sam Kaplan Dr. Harvey Knowles Dr. George Shields Dr. Stander Dr. Clark West Dr. Tom Barden 1970 Dr. Evelyn Hess, Chmn Dr. Thomas Barden Dr. Saul Bloomfield Dr. Richard Bozian Dr. Virginia Donaldson Dr. Noble Fowler Dr. Thomas Gaffney Dr. Sam Kaplan Dr. Harvey Knowles Dr. Clark West Dr. Richard Witt Dr. John Wulsin 1971 Dr. Evelyn Hess, Chmn Dr. J. Wesley Alexander Dr. Thomas Barden Dr. sAul Bloomfield Dr. Richard Bozian Dr. Gene Conway Dr. Virginia Donaldson Dr. Noble Fowler Dr. Thomas E. Gaffney Dr. Samuel Kaplan Dr. Leslie Lkevay Dr. Harvey C. Knowles Dr. Clark West Robert L. Katz, Rabbi Alvin E. White 1972 Dr. James Schieve, Chmn Dr. Wesley Alexander Dr. Tom Bardin Dr. Saul Bloomfield Dr. Richard Bozian Dr. Gene Conway Dr. Noble Fowler Dr. Samual Kaplan Dr. Clark West Dr. John Wulsin Dr. John McDonough Dr. Ray Lipicky Dr. Barry Blackwell Rabbi Robert Katz Dr. Alvin White 1973 Dr. James F. Schieve, Chmn Dr. J. Wesley Alexander Dr. Tom Barden Dr. Barry Blackwell Dr. Saul Bloomfield Dr. Richard Bozian Dr. Stuart Brooks Dr. Gene Conway Dr. Irwin Hanenson Dr. Samual Kaplan Milton Kramer Dr. R.J. Lipicky Dr. John McDonough Dr. Clark West Dr. John H. Wulsin Mr. Alvin E. White