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Keynote addresses
Proceedings of the 24th Annual ASTR Meeting
61
KEYNOTE ADDRESSES
Tuesday October 26, 9:15 am, SELECTIVE IMMUNOSUPPRESSION BY TOTAL LYMPHOID IRRADIATION: TRANSPLANTATION
APPLICATIONS IN AUTOIMMUNE DISEASE AND ORGAN
Henry S. Kaplan Division of Radiation Therapy, Department of Radiology, Stanford University Medical Center, Stanford, CA 94305 The technique of total lymphoid irradiation (TLI) was developed at Stanford in 1962 for the treatment of patients with Stage III Hodgkin's disease and other malignant lymphomas (1,2). Long term observations are now available on hundreds of patients treated by this technique to essentially all of the lymphoid tissues of the human body. The only clinically overt immunologic effects of TLI have been an increase in susceptibility to herpes zoster-varicella virus infection (3) and one well-documented case of radiation-induced splenic atrophy, complicated by fatal pneumococcal sepsis (4). In vitro studies revealed that TLI induces a profound T-lymphocytopenia which may persist for 10 yearS-or more after successful radiotherapy for Hodgkin's disease (5). The T-lymphocytopenia is accompanied by profound abnormalities of T-lymphocyte reaction which may persist for 2-5 years and an impairment of responses to PHA and other lectins which may persist for 10 or more years (5). These observations suggested that TLI might be useful as an immunosuppressive regimen for patients undergoing organ and tissue transplantation, as well as in patients with severe autoimmune disease. Laboratory investigations in mice (6), rats (7), dogs (8), and monkeys (9) have confirmed the remarkable efficacy of TLI as a conditioning regimen in organ and tissue recipients. The cellular mechanisms underlying these immunosuppressive effects of TLI have been extensively investigated and point strongly to the induction of populations of suppressor cells which block both host-vs.-graft and graft-vs.-host reactions (10). Preliminary clinical investigations are now in progress to assess the efficacy of TLI in the treatment of patients with refractory rheumatoid arthritis and with systemic lupus erythematosus and impaired renal function, as well as in patients undergoing organ transplantation. The present status of these investigations will be reviewed. (1) (2) (3) (4) (5) (6) (7) (8) (9) (10)
Kaplan,H.D., and Rosenberg,S.A. Cancer Res.26:1268,1966. Kaplan,H.S. "Hodgkin's Disease", 2nd ed., Harvard University Press, Cambridge, 1980. Goffinet,D.R., et al. Natl.Cancer Inst.Monogr.36:439,1973. Dailey,M.O., et al. New Engl.J.Med.302:215,1980. Fuks,Z., et al. J.Clin.lnvest.58:803,1976. Slavin,S., et al. J.Exp.Med.146:34,1977. Slavin,S., et al. J.Exp.Med.147:700,1978. Gottlieb,M., et al. Transplantation 29:487,1980 Bieber,D.P., et al. Transplantation 28:347,1979. King,D.P., et al . J. Immunol.126:1140,1981.
Wednesday October 27,9:15 a.m. MODIFICATION OF RADIATION RESPONSE OF TISSUES Herman D. Suit, M.D.,D.Phil. Department of Radiation Medicine, Massachusetts General Hospital - Harvard Medical School, Boston, MA 02114 Research in basic radiation biology has provided the tissue radiation biologist and radiation therapist with a rich variety of agents which when combined with radiation (not necessarily concurrently) modifies the response. The major preclinical and clinical goal has been to develop radiation response modifiers which differentially increase response of tumor tissue and decrease response of normal tissue. Mechanisms by which response is modified have been quite varied. A major practical concern of the clinician is the impact of the modifier on the shape and position on the dose response curve. For normal tissue response, the subject tissues in the population of patients to be irradiated are close to uniform and hence the effect of a modifier would be approximately constant on all patients. Hence, the dose response curve would be shifted along the dose axis, but the shape affected little
62
Radiation Oncology. Biology. Physics October 1982, Volume 8, Sup. 1
if at all (plotted on a probability of response - log dose grid). This differs from the situation for tumor response because a clinical study would be performed on a population of spontaneous autochthonous tumors each of which has a unique set of values for the various values of the parameters of radiation sensitivity, cell proliferation kinetics, number of c1onogens, etc. This non-uniformity of tumor tissue means that there might be a change in shape as well as a shift in position. The clinical gain resulting from use of a response modifier will be considered with reference to the magnitude of the enhancement ratio and the proportion of subjects in whom the response would be modified in order to be detected in trials based upon reasonable patient numbers. For illustration of several of these principles, consideration will be given to laboratory and clinical studies directed toward overcoming the impact of hypoxic cells .
Thursday October 28, 9:15 am, SCIENTIFIC BASIS OF THE PRESENT AND FUTURE CLINICAL RADIOTHERAPY Gilbert H. Fletcher, M.D. Division of Radiotherapy, The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, Houston, Texas 77030 At mid-century radiotherapy was more an art than a science, but is presently based on radiobiological parameters and cell kinetics. This close interaction between basic scientific principles and clinical practice has been made possible because one can correlate quantitatively doses of irradiation with observed responses. First, a short historical review will be made because it gives a perspective for the understanding both of progress made and prevailing misconceptions. The important radiobiological parameters and cell kinetics will then be discussed in some detail to demonstrate that they should be thoroughly understood in their relationship to radiotherapy. The isoeffect formulae will be critically evaluated in the light of these parameters. The overall treatment planning must be based on the clinical applications of the main radiobiological parameters. The combined treatment with surgery, either preoperatively or postoperatively, and multiple daily fractionations will be used as examples. The teaching of radiobiology should be considerably expanded, not only for its own scientific merit but also to show how it applies to clinical situations. This should be reflected in the expansion of the Board Examination.
Friday October 29, 9:15 a.m. THE NATIONAL CANCER PROGRAM:
CONTRASTS AND CHANGING OPPORTUNITIES OVER A DECADE OF DISCOVERY
Vincent T. DeVita, Jr ., M.D. National Cancer Institute A more appropriate topic for this discussion might be "You Can't See The Forest For The Trees." In truth, since the passage of the National Cancer Act, there have been so many important scientific discoveries that the technology of science in 1982 is extraordinarily different than that was available to us in 1970. Today, we are able to talk about genes that appear in normal cells that are homologous to known viral oncogenes; restriction mapping of genetic materials allows us to follow gene rearrangement required for immunoglobulin production by lymphatic tissue; new information on the influence of anti-promotors and antioxidants, coupled with vital epidemiologic data is allowing us to develop a strategy to interfere with late stages of carcinogenesis and prevent cancer in ways we could not consider in 1970. Application of the result of research in the treatment area has made surgery less radical, radiotherapy more sophisticated and given us a greater understanding of the reasons for the .failure of chemotherapy to be more effective leading to new directions for future promising clinical research. A major public program facing the staff of the Cancer Institute and sc~ent~sts supported by _Cancer rrQ9ram is the articulation of this progress in a way understandable not only to sClentlsts who operate at extreme ends of a widely diverse program but to the lay public .
61
KEYNOTE ADDRESSES
Tuesday October 26, 9:15 am, SELECTIVE IMMUNOSUPPRESSION BY TOTAL LYMPHOID IRRADIATION: TRANSPLANTATION
APPLICATIONS IN AUTOIMMUNE DISEASE AND ORGAN
Henry S. Kaplan Division of Radiation Therapy, Department of Radiology, Stanford University Medical Center, Stanford, CA 94305 The technique of total lymphoid irradiation (TLI) was developed at Stanford in 1962 for the treatment of patients with Stage III Hodgkin's disease and other malignant lymphomas (1,2). Long term observations are now available on hundreds of patients treated by this technique to essentially all of the lymphoid tissues of the human body. The only clinically overt immunologic effects of TLI have been an increase in susceptibility to herpes zoster-varicella virus infection (3) and one well-documented case of radiation-induced splenic atrophy, complicated by fatal pneumococcal sepsis (4). In vitro studies revealed that TLI induces a profound T-lymphocytopenia which may persist for 10 yearS-or more after successful radiotherapy for Hodgkin's disease (5). The T-lymphocytopenia is accompanied by profound abnormalities of T-lymphocyte reaction which may persist for 2-5 years and an impairment of responses to PHA and other lectins which may persist for 10 or more years (5). These observations suggested that TLI might be useful as an immunosuppressive regimen for patients undergoing organ and tissue transplantation, as well as in patients with severe autoimmune disease. Laboratory investigations in mice (6), rats (7), dogs (8), and monkeys (9) have confirmed the remarkable efficacy of TLI as a conditioning regimen in organ and tissue recipients. The cellular mechanisms underlying these immunosuppressive effects of TLI have been extensively investigated and point strongly to the induction of populations of suppressor cells which block both host-vs.-graft and graft-vs.-host reactions (10). Preliminary clinical investigations are now in progress to assess the efficacy of TLI in the treatment of patients with refractory rheumatoid arthritis and with systemic lupus erythematosus and impaired renal function, as well as in patients undergoing organ transplantation. The present status of these investigations will be reviewed. (1) (2) (3) (4) (5) (6) (7) (8) (9) (10)
Kaplan,H.D., and Rosenberg,S.A. Cancer Res.26:1268,1966. Kaplan,H.S. "Hodgkin's Disease", 2nd ed., Harvard University Press, Cambridge, 1980. Goffinet,D.R., et al. Natl.Cancer Inst.Monogr.36:439,1973. Dailey,M.O., et al. New Engl.J.Med.302:215,1980. Fuks,Z., et al. J.Clin.lnvest.58:803,1976. Slavin,S., et al. J.Exp.Med.146:34,1977. Slavin,S., et al. J.Exp.Med.147:700,1978. Gottlieb,M., et al. Transplantation 29:487,1980 Bieber,D.P., et al. Transplantation 28:347,1979. King,D.P., et al . J. Immunol.126:1140,1981.
Wednesday October 27,9:15 a.m. MODIFICATION OF RADIATION RESPONSE OF TISSUES Herman D. Suit, M.D.,D.Phil. Department of Radiation Medicine, Massachusetts General Hospital - Harvard Medical School, Boston, MA 02114 Research in basic radiation biology has provided the tissue radiation biologist and radiation therapist with a rich variety of agents which when combined with radiation (not necessarily concurrently) modifies the response. The major preclinical and clinical goal has been to develop radiation response modifiers which differentially increase response of tumor tissue and decrease response of normal tissue. Mechanisms by which response is modified have been quite varied. A major practical concern of the clinician is the impact of the modifier on the shape and position on the dose response curve. For normal tissue response, the subject tissues in the population of patients to be irradiated are close to uniform and hence the effect of a modifier would be approximately constant on all patients. Hence, the dose response curve would be shifted along the dose axis, but the shape affected little
62
Radiation Oncology. Biology. Physics October 1982, Volume 8, Sup. 1
if at all (plotted on a probability of response - log dose grid). This differs from the situation for tumor response because a clinical study would be performed on a population of spontaneous autochthonous tumors each of which has a unique set of values for the various values of the parameters of radiation sensitivity, cell proliferation kinetics, number of c1onogens, etc. This non-uniformity of tumor tissue means that there might be a change in shape as well as a shift in position. The clinical gain resulting from use of a response modifier will be considered with reference to the magnitude of the enhancement ratio and the proportion of subjects in whom the response would be modified in order to be detected in trials based upon reasonable patient numbers. For illustration of several of these principles, consideration will be given to laboratory and clinical studies directed toward overcoming the impact of hypoxic cells .
Thursday October 28, 9:15 am, SCIENTIFIC BASIS OF THE PRESENT AND FUTURE CLINICAL RADIOTHERAPY Gilbert H. Fletcher, M.D. Division of Radiotherapy, The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, Houston, Texas 77030 At mid-century radiotherapy was more an art than a science, but is presently based on radiobiological parameters and cell kinetics. This close interaction between basic scientific principles and clinical practice has been made possible because one can correlate quantitatively doses of irradiation with observed responses. First, a short historical review will be made because it gives a perspective for the understanding both of progress made and prevailing misconceptions. The important radiobiological parameters and cell kinetics will then be discussed in some detail to demonstrate that they should be thoroughly understood in their relationship to radiotherapy. The isoeffect formulae will be critically evaluated in the light of these parameters. The overall treatment planning must be based on the clinical applications of the main radiobiological parameters. The combined treatment with surgery, either preoperatively or postoperatively, and multiple daily fractionations will be used as examples. The teaching of radiobiology should be considerably expanded, not only for its own scientific merit but also to show how it applies to clinical situations. This should be reflected in the expansion of the Board Examination.
Friday October 29, 9:15 a.m. THE NATIONAL CANCER PROGRAM:
CONTRASTS AND CHANGING OPPORTUNITIES OVER A DECADE OF DISCOVERY
Vincent T. DeVita, Jr ., M.D. National Cancer Institute A more appropriate topic for this discussion might be "You Can't See The Forest For The Trees." In truth, since the passage of the National Cancer Act, there have been so many important scientific discoveries that the technology of science in 1982 is extraordinarily different than that was available to us in 1970. Today, we are able to talk about genes that appear in normal cells that are homologous to known viral oncogenes; restriction mapping of genetic materials allows us to follow gene rearrangement required for immunoglobulin production by lymphatic tissue; new information on the influence of anti-promotors and antioxidants, coupled with vital epidemiologic data is allowing us to develop a strategy to interfere with late stages of carcinogenesis and prevent cancer in ways we could not consider in 1970. Application of the result of research in the treatment area has made surgery less radical, radiotherapy more sophisticated and given us a greater understanding of the reasons for the .failure of chemotherapy to be more effective leading to new directions for future promising clinical research. A major public program facing the staff of the Cancer Institute and sc~ent~sts supported by _Cancer rrQ9ram is the articulation of this progress in a way understandable not only to sClentlsts who operate at extreme ends of a widely diverse program but to the lay public .