Attachment 4 How Can the Quality of Life and the Length of Life of a Cancer Patient be Determined? Frequently family members will be concerned that a relative suffering from cancer has suffered too much or died too soon as a result of too much or too little treatment. These two questions are discussed in regard to the patients who were part of our study to total body irradiation and partial body irradiation. In this group there were 88 patients receiving radiation therapy and 27 patients who were evaluated and then treated by other methods. In the period 1960 through 1971, patients were offered wide field radiation treatment only for palliation to relieve symptoms by shrinking tumors and hence increase patient comfort. Palliation is any treatment offered to patients for whom a curative attempt is not thought possible. In all cases, the tumor had spread (metastasized) from the initial site. Thus, a curative attempt of treatment was not possible based on the judgement of the attending physicians and consultants. The goals of this palliative treatment were in large part realized1. The steady and rapid progress of the tumor could only be stopped for relatively short periods of time and the same was true of relief of symptoms. Thus patient symptoms (except for short-term nausea and vomiting) were due to progression of tumor rather than the result of the treatment and were seen in both the treated and untreated patients. Relief of pain and other symptoms are very difficult to measure and the interpretation of the natural progression of tumor as compared to effect of therapy is complex. As compared to the patients evaluated but not treated by total body or partial body irradiation, we found that their treatment was comparable in the degree of palliation and simpler for the patient than many of the chemotherapy treatment regimens used in the period 1960-1970. The frequency of symptoms and signs such as nausea, vomiting, weakness, and weight loss was to greater with the irradiated patients than in patients treated with other agents. It is important to realize that in any given patient it is not possible to determine objectively whether death occurred too soon or was prolonged as a consequence of treatment. The only way E.L. Saenger, M.D. October 20, 1994 that an estimate can be made is to compare the length of survival of a group of patients with the same tumor and extent of tumor treated by radiation to a group of patients with the same tumor and extent of tumor treated by different methods. This comparison was performed for three tumors in our original paper in 19731. We found that for cancers of the lung, colon and breast that survival times were not different when compared to similar patients treated by different methods both at our hospital (Cincinnati General Hospital) or as reported in the medical literature. As has been emphasized repeatedly, the patients treated by radiation at Cincinnati General Hospital did not differ from other patients in this hospital when compared by race, IQ, age or gender. Reference 1. E.L. Saenger, MD, E.B. Silberstein, MD, B. Aron, MD, H. Horwitz, MD, J.G. Kereiakes, PhD, G.K. Barh, PhD, H. Perry, MD, and B.I. Friedman, MD. Whole Body and Partial Body Radiotherapy of Advanced Cancer. Am. J. Roentgenol. 117(3):670-685. 1973. E.L. Saenger, M.D. October 20, 1994 Informed Consent The valid use of Informed Consent in the total body irradiation/partial body irradiation project has been of particular interest due to the charges and assumptions that information was kept from the patients. When and how was Informed Consent applied? How could Informed Consent be documented? These questions can be answered in two ways - first, the actual experience with patients rom 1960 through 971 and second, a brief discussion of the background of directives by government and academia then. 1. The us of Informed Consent at Cincinnati General Hospital in the Radiaton Project between 10 and 1971. a) How were patients recommended for total body irradiation/partial body irradiation? Patients were recommended total body irradiation/partial body irradiation by several experienced radiation oncologists and medical oncologists who would evaluate each patient individually and make a recommendation as to treatment. This recommendation was made solely on clinical grounds. If total body irradiation/partial body irradiation was agreed to, the patient was placed on a protocol that was completed in 1-2 weeks prior to the actual treatment. Not all patients entered in the study were irradiated. There were 115 patients entered and 88 were treated with total body irradiation/partial body irradiation. b) Lack of normal advice from DOD regarding Informed Consent At the time of negotiation of the contract between DOD (DASA) and UC, no advice, specific statement or caution was given by DOD personnel to the principal investigator, E.L. Saenger, M.D., concerning Informed Consent and, during the life of the contract, no official statement of DOD policy was provided or sent UC. E.L. Saenger, M.D. October 20, 1994 c) Informed Consent for total body irradiation/partial body irradiation at UC prior to April 1965 At the outset of the project, it was agreed by the UC physicians that each patient was to be advised of the treatment, its goals and risks in relation to the stage and progress of the cancer. During the period from 1960 to 1965, there was no requirement of Cincinnati General Hospital concerning written Informed Consent. It was the policy of the physicians on this project to inform the patient orally (Informed Consent). The several physicians differed somewhat in methodology but their written statements indicate that Informed Consent was carried out for each patient. The University of Cincinnati had no specific policies at that point; the then "IRB" committee was evaluating the situation but did not make any specific recommendations until 1966. At that time these recommendations were made primarily for projects supported by the NIH. d) Use of written Informed Consent beginning in April 1965 In 1964, Dr. Saenger received a copy of the May 12, 1964 DOD Instruction; Subject Investigational Use of Drugs by the DOD4, which detailed the steps to be taken for research with drugs to be in compliance with the Federal Food, Drug and Cosmetic Act5. Although total body irradiation/partial body irradiation had been used clinically and was not considered an "investigational drug", nevertheless Dr. Saenger considered that total body irradiation/partial body irradiation could be so considered. Therefore he drafted a written consent form dated April 1965 and used thereafter. This written Informed Consent preceded any F.D.A. requirement by approximately two years. This form underwent several modifications in the next several years on the active of the UC IRB and its predecessors. 2. Documents of Informed Consent of he DOD A recent review of DOD policy regarding Informed Consent revealed that on 26 February, 1953, The Secretary of DOD issued a memorandum marked Top Secret concerning Informed Consent and E.L. Saenger, M.D. October 20, 1994 the rights of subjects of experimentation1. This document was released to the public on 22 August, 1975, well after the completion of the UC project. The Department of the Army issued regulations for written Informed Consent on the use of volunteers as subjects of research - AR 70-25, 26 March 19623; this regulation was not sent to UC. All Informed Consent at the UC Medical Center was in conformity with the Declaration of Helsinki, derived from the Nuremburg Code. In order to clarify the various rulings of the Federal Government attached are the major regulations of DHEW and DOD concerning Informed Consent. References 1. Memorandum for the Secretary of the Army, Secretary of the Navy, Secretary of the Air Force, 26 February 1953. Downgraded to Unclassified 22 August 1975. 3. Use of Volunteers as Subjects of Research, AR 70-25, Department of the Army, USA, 1962. 4. May 12, 1964 - Department of Defense Instruction: Subject: Investigational Use of Drugs by the Department of Defense; Reference: (a) Drugs regulations published by Department of Health, Education and Welfare (21 CFR 130.3). 5. Drug Amendments Act of 1962 E.L. Saenger, M.D. October 20, 1994 Notes on Regulations affecting Clinical Investigations from Federal Agencies: DHEW (FDA, NIH, PHS) & DOD FDA1 1962 - Drug Amendments Act of 1952: The law would probably not been enacted without the tragedy of phocomelia caused by thalidomide in 1961 and 1962. Sen. Javits offered the "patient consent" amendment to the bill in its last stages before enactment. It required that "patients be 'appropriately advised that such drug had not been determined to be safe in use for human beings.' "The only major area where clarification of the law was not provided in the new regulations was in regard to the subject-consent provision...[as] there was no legislative - hearing material...and only sparse floor debate on the meaning of the terms." Dr. Kelsey, then Chief of the FDA's Investigational Drug Branch, Division of New Drugs made a few authoritative comments on the consent provisions. She asserted "that the consent requirement applied to all normal subjects, such as medical students, prisoners, laboratory personnel, or volunteer religious groups." Additional, she "wrote that the consent requirement would not bar either "blind" or "double-blind" studies. She asserted that the law does not require that the subject be informed as to which preparation he receives...so long as he is told that he is engaged in an experiment involving an experimental drug." These two areas became codified in The Patient-Consent Regulations of 1966. The definition for consent is given in the last Subsection and reads as follows: "(h) "Consent" or "Informed consent" means that the person involved has legal capacity to given consent, is so situated as to be able to exercise free power of choice, and is provided with a fair explanation of material information concerning the administration of the investigational drug or his possible use as a control, as to enable him to make an understanding decision as to his willingness to receive said investigational drug. This latter element requires that before the acceptance of an affirmative decision by such person the investigator should make known to him the nature, duration, and purpose of the administration of said investigation drug; the method and means by which it is to be administered; all inconveniences and hazards reasonably to be expected of alternative forms of therapy, if any; and the effects upon his health or person that may possibly come from the administration of the investigational drug. Said patient's consent shall be obtained in writing by the investigator." NIH2 1966 - Group Consideration and Informed Consent in Clinical Research at the National Institutes of Health: "The policy of the National Institutes of Health for the conduct of clinical research and medical care places primary responsibility on the principal investigators designated by each institute...The National Institutes of Health recognizes that the main principles guiding clinical research are: (1) group consideration, including peer judgement; (2) informed consent of the patient or normal volunteer; and (3) the right of the patient or E.L. Saenger, M.D. October 20, 1994 Page 1 normal volunteer to withdraw from participation in a clinical research project at any time. The form of obtaining and recording of both group consideration and informed consent may vary among the several Institutes and in dealing with patients as opposed to normal volunteers, but the substance of informed consent and group consideration is not to be altered materially by any such differences in procedures." The following are excerpts from the statement of principles that the NIH believes must govern clinical research: "II. Medical Care and Clinical Research: In the are of patients every medical procedures is modified or adapted to accommodated the individual patient. It is recognized that every medical procedure carries some element of risk. In the formulation of clinical research projects, the determination as to which clinical procedures are considered as not being "established" or as involving unusual hazard should be on an individual basis, in the light of experience developed in institutions recognized by the profession for their excellence in conducting medical are and research." "III. Principles Governing Physician-Patient Relationship: 1. Information for the Patient: Each patient and each normal volunteer shall be given an oral explanation in terms suited to this comprehension of this role in the Clinical Center, the nature of the proposed studies and, particularly, any hazards. This information should be given to the patient on a continuing basis. A summary of this information and a record of its communication to the patient shall be placed in the patient's medical record over the signature of the principal investigator. For normal volunteers a specific consent form [NIH-658-1 (formerly PHS-4573-1)] containing this information must be signed by normal volunteer and the principal investigator. 2. Patient Understanding and Agreement and Consent: The Director of the National Institutes of Health has indicated the type of procedures which require specific informed consent. For those procedures and studies not covered, voluntary agreement by the patient to participate, or when appropriate by next to kin, based upon informed consent, shall be obtained and recorded by the principal investigator. 3. Responsibility: The principal investigation shall be responsible for providing information to the patient, to the referring physician and next of kin, and for obtaining consent when it is required." PHS3 Public Health Service Policy and Procedure No. 129, Revised July 1, 1966: Requirements for Review to insure the Rights and Welfare of individuals; Background: The first resolution regarding the use of human subjects in experiments was passed by the National Advisory Health Council on December 3, 1965. Regarding such use, the policy states: "...the judgement of the investigator is subject to prior review by his institutional associates to assure an independent determination of the protection of the rights and welfare of the individual or individuals involved, of the appropriateness of the methods used to secure informed consent, and of the risks and potential medical benefits of the investigation." E.L. Saenger, M.D. October 20, 1994 Page 2 "Policy: The Surgeon General accepted the resolution and on February 8, 1966 decreed a more detailed policy statement. With regards to human subjects, the policy states: "...the grantee institution will provide prior review...This review should assure an independent determination: (1) of the rights and welfare of the individual or individuals involved, (2) of the appropriateness of the methods used to secure informed consent, and (3) of the risks of potential medical benefits of the investigation." "Revised Policy: The policy applies to all investigations involving human subjects, including clinical research. A. Assignment of Responsibility Safeguarding the rights and welfare of human subjects involved in research supported by PHS grants is the responsibility of the institution to which the grant is awarded...The grantee is required to make and keep written records of the group reviews and decisions on the use of human subjects and to obtain and keep documentary evidence of informed consent relating to investigations carried out with the assistance of PHS financial support." December 12, 1966 - Requirements for review to Insure the Rights and Welfare of Individuals; Clarification "The principles of this policy apply most directly and comprehensively in those instances of social, behavioral, and medical science investigations where a procedure may induce the subject an altered state or condition potentially harmful to his personal welfare. Surgical procedures, the administration of drugs, the requirement of strenuous physical exertion, and participation in psychologically or socially harmful activities are examples of experimental arrangements which require continuing overview and full documentation for the record...issues of concern are the fully voluntary nature of the participation of the subject, the maintenance of confidentiality of information obtained from the subject, and the protection of the subject from misuse of the findings." HEW4 March 13, 1975 - Code of Federal Regulations, Title 46; Part 46 Protection of Human Subjects - Redesignated August 8, 1975 "Policy: (a)...it is the policy of DHEW that no activity involving human subjects to be supported by DHEW grants shall be undertaken unless an Institutional Review Board has reviewed and approved such activity... (b) This review shall determine whether these subjects will be placed at risk, and, if risk is involved, whether: (1) The risks to the subject are so outweighed by the sum of the benefit to the subject and the importance of the knowledge to be gained as to warrant a decision to allow the subject to accept these risks; (2) The rights and welfare of any such subjects will be adequately protected; and (3) Legally effective informed consent will be adequately protected; and methods in accordance with the provisions of this part... E.L. Saenger, M.D. October 20, 1994 Page 3 Definitions: ...(b) "Subject at risk" means any individual who may be exposed to the possibility of injury, including physical, psychological, or social injury, as a consequences of participation as a subject in any research, development, or related activity which departs for the application of those established and accepted methods necessary to meet his need... (c) "Informed consent" means the knowing consent of an individual or his legally authorized representative, so situated as to be able to exercise free power of choice without undue inducement or any element of force, fraud, deceit, duress, or other form of constraint or coercion. The basis elements of information necessary to such consent include: (1) A fair explanation of the procedures to be followed, and their purposes, including identification of any procedures which are experimental; (2) A description of any attendant discomforts and risks reasonably to be expected; (3) A description of any benefits reasonably to be expected; (4) A disclosure of any appropriate alternative procedures that might be advantageous for the subject; (5) An offer to answer any inquiries concerning the procedures; and (6) An instruction that the person is free to withdraw his consent and to discontinue participation in the project or activity at any time without prejudice to the subject... Obligation to Obtain Informed Consent: Prohibition of Exculpatory Clauses: Any institution proposing to place any subject at risk is obligated to obtain and document legally effective informed consent. No such informed consent, oral or written, obtained under an assurance provided pursuant to this part shall include any exculpatory language through which the subject is made to waive, or to appear to waive, any of his legal rights, including any release of the institution or its agents from liability for negligence." DOD 26 February 1953 - Memorandum for the Secretary of the Army, Secretary of the Navy, Secretary of the Air Force [TOP SECRET] Downgraded to UNCLASSIFIED 22 August, 1975 Subject: Use of Human Volunteers in Experimental Research. It recognizes that "...human subjects be employed under recognized safeguards, as the only feasible means for realistic evaluation and/or development of effective preventive measures of defense against atomic, biological or chemical aspects..." Required were the following: a. The voluntary consent of the human subject is absolutely essential. (1) This means that the person involved should have legal capacity to give consent; should be constituted as to be to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, overreaching or other ulterior form of constraint or coercion and should have sufficient knowledge and understanding of the elements of the subject matter E.L. Saenger, M.D. October 20, 1994 Page 4 involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be known to him the nature, duration, and purpose of the experiment, the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the affect upon his health or person which may possibly come from his participation in the experiment. (2) The concept of the human subject shall be in writing, his signature shall be affixed to a written instrument setting forth substantially the aforementioned requirements and shall be signed in the presence of at least one witness who shall attest to such signature in writing. (a) In experiments where personnel from more than one Service are involved the Secretary of the Service which is exercising primary responsibility for conducting the experiment is designated to prepare such an instrument and coordinate it for use by all the Services having human volunteers involved in the experiment. (3) The duty and responsibility of ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity. b. The experiment should be such as to fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature. c. The number of volunteers used shall be kept at a minimum consistent with item b., above. d. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment. e. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury. f. No experiment should be so conducted where there is an priori reason to believe that death or disabling injury will occur. g. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment. E.L. Saenger, M.D. October 20, 1994 Page 5 h. Proper preparation should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability or death. i. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment. j. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible. k. During the course of the experiment, the scientist in charge must be prepared to terminate the experiment at any stage if he has probable cause to believe, in the exercise of the good faith, superior skill and careful judgment required of him that a continuation of the experiment is likely to result in injury, disability or death to the experimental subject. l. The established policy, which prohibits the use of prisoners of war in human experimentation, is continued and they will not be used under any circumstances. 30 June 1953 - Memorandum thru: Assistant Chief of Staff, G-4 Form: Chief General officer The Surgeon General [CLASSIFIED] NOTE: This memorandum of 30 June 1953 was brought to the attention of Dr. Saenger only in September 1994. Subject: Use of Volunteers in Research Copies furnished: Asst. Chief of Staff; Chief Chemical Officer, the Surgeon General, The Judge Advocate General, and Chief of Research and Development, OCS This document incorporated, with little change or omission, the consents of the above cited document. It also expands to include several additional sections. "3. a. Legality of accepting volunteers. The authority of the Secretary of the Army to conduct research and development activities is contained in section 104 of the act of 10 July 1950 (64 Stat. 322; 5 U.S.C. 235a) which provides: ...and to procure, or contract for the use of such facilities, equipment, services, and supplies as may be required to effectuate such programs." E.L. Saenger, M.D. October 20, 1994 Page 6 "3. b. Military Personnel and Department of the Army Civilian Employees. Compensation for the disability or death of a civilian employee resulting from personal injury or disease proximately caused by his employment is payable under the Federal Employees Compensation Act (39 Stat. 742 et seq.)..." "3. c. Contractors' employees. (1) Legality of employment...There appears to be no provision of law which would prevent a contractor from employing his personnel upon experiments of the nature contemplated...It devolves upon the contracting officer to ascertain whether the terms are sufficiently broad to permit the participation of contractor employees in the experiment. The terms of the contract must insure that the contractor will observe the conditions and safeguards set forth in this directive". The directive also addresses the issue of "Claims against the Government," the "Purchase of Life Insurance", and states that "As a general rule, volunteer subjects should be males under 35 years of age, with no physical or mental diseases". "5. Agents used in research must have the following limiting characteristics: a. Controllable lethality. b. No serious chronicity anticipated. c. Effective therapy available. d. Adequate background of animal experimentation." November 5, 1953 - Memorandum from the Secretary of the Army to the Chief of Staff [SECRET] 8 Jan 54 NOTE: "This memo was originally classified Secret, regarded confidential when separate from classified inclosure [sic]." Subject: Use of Volunteers in Research "1. Approval is granted for the conduct of research investigations utilizing volunteers, in defense against chemical warfare, as outlined in the proposed plan, subject as above, dated 16 September 1953... 2. Special care and attention will be given to those portions of the approved investigations which are to be accomplished by contract, to insure that the same basic principles and safeguards applicable to department of the Army laboratories are observed by the contractor". [Emboldment mine] E.L. Saenger, M.D. October 20, 1994 Page 7 26 March 1962 - AR 70-25 Research and Development; Use of Volunteers as Subjects of Research "1. Purpose. The regulations prescribe policies and procedures governing the use of volunteers as subjects in Department of the Army research, including research in nuclear, biological, and chemical warfare, wherein human beings are deliberately exposed to unusual or potential hazardous conditions... 3. Exemptions. b. That portion of human factors research which involves normal training or other military duties as part of an experiment, wherein disclosure of experimental conditions to participating personnel would reveal the artificial nature of such conditions and defeat the purpose of the investigation [italics mine]. c. Ethical medical and clinical investigations involving the basic disease process or new treatment procedures conducted by the Army Medical Service for the benefit of patients [italics mine]." The section of "Voluntary consent" incorporated the ideas of the above cited memos from 1953. Here, section 4.b.-1. dealt mainly with parameters of the experiment and with minimizing risk to study subjects. As opposed to previous memos regarding compensation of volunteers due to proximate cause of injury, this AR is terse. May 12, 1964 - Department of Defense Instruction: Subject; Investigational Use of Drugs by the Department of Defense; Reference (a) Drug regulations published by Department of Health, Education and Welfare (21 CFR 130.3) "I. Purpose: This Instruction specifies the manner in which the regulations cited in reference (a) will be applied to the investigational use of drugs by the Department of Defense" "II. Applicability: The provisions of this Instruction apply to all DOD Components and their contractors or grantees engaged in the investigational use of drugs." "III. Responsibilities: A. The Department of Defense assumes full responsibility for the protection of humans involved in research under its sponsorship whether this involves investigational drugs or other hazards. B. Each Military Department will establish within the office of its Surgeon General a formal Review Board of professional personnel to consider each research proposal from within that Military Department or from its contractors or grantees which may involve the use of human subjects in the clinical investigation of new drugs. Before a clinical test with an investigational drug may be performed under the sponsorship of a Military Department. E.L. Saenger, M.D. October 20, 1994 Page 8 1. the plan of the test and other pertinent details must be submitted to the appropriate Review Board, 2. the Board must indicate its approval, and 3. the approval must be confirmed by the respective Surgeon General." May 12, 64 - Memorandum of Understanding between the Department of Health, Education and Welfare, and the Department of Defense concerning Investigational Use of Drugs by the Department of Defense (Cyrus Vance - The Secretary of Defense; Anthony Celebrezze - The Secretary of Health, Education and Welfare) "Purpose: The purpose of this Memorandum of Understanding is to state the procedures that will be followed by the Departments of Defense and Health, Education, and Welfare to insure that the requirements of the Federal Food, Drug, and Cosmetic Act and the investigational drug regulations issues under that Act are fully met without jeopardizing or impeding the requirements of national security or the requirements of Federal laws and regulations relating to such use of drugs". "Agreement: "Under these circumstances, the Departments of Defense, and Health, Education, and Welfare agree that the following procedure meets the requirements of the Food, Drug and Cosmetic Act:... 2. In the case of non-classified security research programs sponsored by the Department of Defense and conducted within its research facilities or for the Department upon contract, copies of the request for approval submitted to the appropriate DOD Review Board, the Review Board's evaluation and approval, and notice of approval by the appropriate Surgeon General will be filed with the FDA as the claim for exemption for the investigational drug." REFERENCES 1. W.J. Curran, "Governmental Regulation of the Use of Human Subjects in Medical Research: The Approach of Two Federal Agencies," Daedalus, (Spring, 1969), pp. 542-594. 2. H.K. Beecher, M.D., "Group Consideration and Informed Consent in Clinical Research at the National Institutes of Health, 1966," In Research and the Individual: Human Studies, Little, Brown and Company, Boston, (1970), pp. 285-288. 3. H.K. Beecher, M.D., "Requirements for Review to Insure the Rights and Welfare of Individuals" In Research and the Individual: Human Studies, Little, Brown and Company, Boston, (1970), pp. 293- 298. 4. G.J. Annas, L.H. Glantz and B.F. Katz, "H.E.W. Regulations on the Protection of Human Subjects, In Informed Consent to Human Experimentation: The Subject's Dilemma, Ballinger Publishing Company, Cambridge, MA, (1977), pp. 289-303. E.L. Saenger, M.D. October 20, 1994 Page 9 Was the Treatment Meant Therapeutically? The treatment of patients with far-advanced cancer has been and continues to be quite difficult. One is presented with a person in whom the cancer has escaped i.e. metastasized beyond the initial site and is spread widely through the body. The metastases are often very small, even microscopic in size, thus being impossible to identify. Therefore the treatment must involve the entire body using chemotherapeutic drugs and/or ionizing radiation in an effort to control the downward progress of the cancer. It is this set of circumstances that determined our therapeutic interest as discussed below. One of the issues that has been raised some three decades after termination of our study is whether the treatments given to the patients were to investigate the effectiveness of the treatment in decreasing suffering of cancer or only in studying radiation effects. One reviewer in 1958 indicates the dual purposes of our study with the following comment: "Any correlation of tumor response total dose of irradiation by such means as proposed in this project would be of great value in the field of cancer. In addition if by some means such as those proposed accurate knowledge of the total dose of radiation received could be determined it would be of inestimable value in case of atomic disaster of nuclear warfare.1" In the late 50's and 60's there were many attempts at relieving suffering in cancer patients by attempting radiotherapy methods and schedules on a relatively informal schedule as compared to the rigorous experimental designs that have steadily become more common since the eighties. During the period of our studies, the hypothesis was that whole body or partial body radiation might well be as effective or more effective treatment as compared to the than current chemotherapeutic anticancer drugs. We were particularly interested in evaluating this E.L. Saenger, M.D. October 20, 1994 Page 1 hypothesis for the so-called radioresistant tumors - breast, lung, colon - since some favorable responses were found in treating those cancers with drugs. Another desirable feature of whole body or partial body radiation was the possibility of symptomatic improvement, especially relief of pain, with only a single treatment as compared to multiple treatments with drugs. From our viewpoint and that of DOD was the possibility that some changes in biochemical indicators would be found after exposure to radiation. There was a considerable basis in the animal literature for several of these hypotheses. Also, if changes in various indicators (e.g. deoxycytidine, amino acids, immune systems) could be elicited, the information would be of equal value for understanding of cancer and its treatment as well as being of value to DOD. We investigated some 13 potential indicators of radiation effects. In our attempts to detect changes of a biochemical nature, we were measuring chemical abnormalities at the cellular level. In the 90's, in retrospect, one could consider these forays as a beginning attempt at molecular biology. Some critics of this study have stated that, based on earlier reports of TBI, there was no point in pursuing this investigation beyond 1960. We, have, identified 23 papers published between 1942 and 1991 dealing with clinical application of total body irradiation/partial body irradiation for diseases other than leukemia, lymphoma and Hodgkins disease. These reports show that these treatments using total body irradiation/partial body irradiation with increasing doses and varying dose schedules continue through the 1980's and to 1991. Radiation is now combined with various chemotherapeutic regimens and autologous marrow transplantation. These reports suggest that this method continues to be of clinical importance especially for stage IV (far-advanced) cancers. E.L. Saenger, M.D. October 20, 1994 Page 2 In March 1994, the US Department of Heath and Human Services issued a quick reference guide for clinicians, #9, entitled Management of Cancer Pain Adults. On page 20, under the heading of Radiation Therapy, the following statement is made, "Local or whole body radiation enhances the effectiveness of analgesic drug and other non-invasive therapy by directly affecting the cause of pain (i.e. reducing primary and metastatic tumor bulk). Dosage must be chosen to achieve a balance between the amount of radiation required to kill tumor cells and that which would adversely affect normal cells or allow the repair of damaged tissue. The current application of total body irradiation to non- hematological neoplasms bears similarities to our work e.g. the use of autologous marrow to sustain patients with disseminated neoplasms, e.g., breast. Autologous marrow consists in the removal of the patients' own marrow which is then stored and retransfused intravenously. Now such patients also undergo intensive chemotherapy as well. In our research, we were concerned at to the safety of doses greater than 200 rad for total body irradiation and 300 rad for partial body irradiation because of the possibility of bone marrow depression. These levels which we chose not to exceed in our therapy are low by today's standards. Attempts to use autologous marrow effectively began in 1964 and we were able to use this method effectively in patients by 1968. Successful autologous marrow administered immediately following radiation treatment resulted in definite improvement by minimizing the characteristic fall in depression of bone marrow. This method has been widely developed by many others together with the administration of much larger doses of TBI and PBI ranging from 600-1000 rad. At doses of 1000 rad and higher, the doses are fractionated over several days of minimize the radiation effect on the lungs. E.L. Saenger, M.D. October 20, 1994 Page 3 In current oncologic practice the availability of autologous marrow therapy has permitted the administration of very large doses of otherwise potentially lethal drugs and radiation, resulting in increased survival and quality of life. 1. J.A. Isherwood, MD for the Army Medical Research and Development Command, 1958. E.L. Saenger, M.D. October 20, 1994 Page 4