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Radiobiology in clinical radiation therapy
Proceedings of the 35th Annual ASTRO Meeting
97
ASTRO REFRESHER COURSE DESCRIPTION MONDAY,
OCTOBER
11, 1993
7:15 a.m. - 8:45 a.m.
1OlC RADIOBIOLOGY IN CLINICAL RADIATION THERAPY - PART I - SYSTEMS AND PRINCIPLES Eric J. Hall, D.Sc. Center for Radiological Research, College of Physicians & Surgeons of Columbia University, New York, NY 10032 Objective: This course is designed for residents in radiation oncology, preparing for their boards. It includes the physics and chemistry of the absorption of radiation, a description of the biological systems used to obtain a quantitative relationship between dose and biological effect, as well as a review of the basic principles in radiation biology that have been established. The Biological effects of radiation may result from the direct action, which refers to ionizations in the DNA itself, or the indirect action which is mediated by free radicals. For x or gamma rays, about 70% of the damage is by the indirect action, which can be modified by oxygen and various chemical agents. Radiation-induced DNA damage may lead to carcinogenesis and hereditary effects, which are important in personnel protection, or to cell lethality which is the basis of radiotherapy. Chromosome aberrations and cell lethality appear to result from the interaction of two lesions (probably double strand breaks) which leads to the linear-quadratic relationship. This refers to mitotic &&I, which is the most common form of radiation induced death. Programmed cell death or &ootosis can also occur and is particularly important in more radiosensitive tumors. A number of quantitative biological test systems have been developed to quantify the effects of radiation as a function of dose. Cells may be cultured & yltm, of normal and neoplastic origin, and survival curves produced with reproductive integrity plotted as a function of dose. Normal tissue systems where reproductive integrity can be scored as an endpoint include skin, gut, colony forming units in the bone marrow, as well as breast, thyroid and testis. Other normal tissue systems have been developed where a functional endpoint is scored. The response of some normal tissues depends, not only on the fraction of cells killed, but on the tissue architecture in terms of functional subunits. A range of transplantable tumors have been studied with endpoints of tumor cure, growth delay, or cell survival. In addition, many human tumor cells grow as multicellular spheroids, or as xenografts in immunodeficient nude mice. Based on laboratory data, the basic principles of radiation biology have been established, these include: (1) The shape. of the cell survival curve for sparsely and densely ionizing radiations. (2) The difference in the shapes of the dose response relationships for early and late responding tissues. (3) The variation of cellular response with the quality of the radiation; the relation between RBE and LET. (4) The age-response func:tion, i.e., the variation of cellular radiosensitivity with the phase of the cell cycle. (5) Fractionation, the repair of sublethal damage and potentially lethal damage and the dose rate effect. (6) The effect of the presence or absence of molecular oxygen on radiation response, and the wider question of the chemical modification of radiation injury by sensitizers and protectors. (7) The kinetics of cells, tissues and tumors; cell cycle, growth fraction, cell loss factor and the process or reoxygenation. Multifraction radiotherapy protocols were developed empirically, but can now be understood in terms of principles derived from laboratory data. The importance of fraction size and overall time as separate variables has been made clear from experiments with cells and animals. Many of the new initiatives to be discussed in Part II are also a development of ideas that originated in the laboratory.
102 BRACHYTHERAPY FOR SARCOMAS Louis B. Harrison, M.D. Memorial Sloan-Kettering Cancer Center, New York, NY 10021
Brachytherapy is a method of delivering radiation therapy directly into a tumor volume, with maximal sparing of adjacent normal structures. Due to the potential for an improved therapeutic ratio, this modality has gained increasing importance in clinical oncology. The role of brachytherapy in the treatment of soft tissue sarcomas has expanded. A large body of retrospective data has accumulated, demonstrating the results of this modality as a surgical adjuvant. A recently completed prospective randomized trial from the Memorial Sloan-Kettering Cancer Center will be discussed in detail. This study sheds considerable light on patient selection, treatment ttihnique. and long-term outcome. Discussion will include high grade and low grade sarcomas, lesions involving neurovascular structures., desmoid tumors, and pediatric tumors. Selection of isotopes (Ir-192 vs. I-125) will be addressed. Future directions will also be discussed, with special emphasis on intraoperative radiation therapy. A discussion of retroperitoneal sarcomas and the potential for brachytherapy in this area will also b e included. There will be extensive use of clinical examples to illustrate both brachytherapy technique and outcome.
97
ASTRO REFRESHER COURSE DESCRIPTION MONDAY,
OCTOBER
11, 1993
7:15 a.m. - 8:45 a.m.
1OlC RADIOBIOLOGY IN CLINICAL RADIATION THERAPY - PART I - SYSTEMS AND PRINCIPLES Eric J. Hall, D.Sc. Center for Radiological Research, College of Physicians & Surgeons of Columbia University, New York, NY 10032 Objective: This course is designed for residents in radiation oncology, preparing for their boards. It includes the physics and chemistry of the absorption of radiation, a description of the biological systems used to obtain a quantitative relationship between dose and biological effect, as well as a review of the basic principles in radiation biology that have been established. The Biological effects of radiation may result from the direct action, which refers to ionizations in the DNA itself, or the indirect action which is mediated by free radicals. For x or gamma rays, about 70% of the damage is by the indirect action, which can be modified by oxygen and various chemical agents. Radiation-induced DNA damage may lead to carcinogenesis and hereditary effects, which are important in personnel protection, or to cell lethality which is the basis of radiotherapy. Chromosome aberrations and cell lethality appear to result from the interaction of two lesions (probably double strand breaks) which leads to the linear-quadratic relationship. This refers to mitotic &&I, which is the most common form of radiation induced death. Programmed cell death or &ootosis can also occur and is particularly important in more radiosensitive tumors. A number of quantitative biological test systems have been developed to quantify the effects of radiation as a function of dose. Cells may be cultured & yltm, of normal and neoplastic origin, and survival curves produced with reproductive integrity plotted as a function of dose. Normal tissue systems where reproductive integrity can be scored as an endpoint include skin, gut, colony forming units in the bone marrow, as well as breast, thyroid and testis. Other normal tissue systems have been developed where a functional endpoint is scored. The response of some normal tissues depends, not only on the fraction of cells killed, but on the tissue architecture in terms of functional subunits. A range of transplantable tumors have been studied with endpoints of tumor cure, growth delay, or cell survival. In addition, many human tumor cells grow as multicellular spheroids, or as xenografts in immunodeficient nude mice. Based on laboratory data, the basic principles of radiation biology have been established, these include: (1) The shape. of the cell survival curve for sparsely and densely ionizing radiations. (2) The difference in the shapes of the dose response relationships for early and late responding tissues. (3) The variation of cellular response with the quality of the radiation; the relation between RBE and LET. (4) The age-response func:tion, i.e., the variation of cellular radiosensitivity with the phase of the cell cycle. (5) Fractionation, the repair of sublethal damage and potentially lethal damage and the dose rate effect. (6) The effect of the presence or absence of molecular oxygen on radiation response, and the wider question of the chemical modification of radiation injury by sensitizers and protectors. (7) The kinetics of cells, tissues and tumors; cell cycle, growth fraction, cell loss factor and the process or reoxygenation. Multifraction radiotherapy protocols were developed empirically, but can now be understood in terms of principles derived from laboratory data. The importance of fraction size and overall time as separate variables has been made clear from experiments with cells and animals. Many of the new initiatives to be discussed in Part II are also a development of ideas that originated in the laboratory.
102 BRACHYTHERAPY FOR SARCOMAS Louis B. Harrison, M.D. Memorial Sloan-Kettering Cancer Center, New York, NY 10021
Brachytherapy is a method of delivering radiation therapy directly into a tumor volume, with maximal sparing of adjacent normal structures. Due to the potential for an improved therapeutic ratio, this modality has gained increasing importance in clinical oncology. The role of brachytherapy in the treatment of soft tissue sarcomas has expanded. A large body of retrospective data has accumulated, demonstrating the results of this modality as a surgical adjuvant. A recently completed prospective randomized trial from the Memorial Sloan-Kettering Cancer Center will be discussed in detail. This study sheds considerable light on patient selection, treatment ttihnique. and long-term outcome. Discussion will include high grade and low grade sarcomas, lesions involving neurovascular structures., desmoid tumors, and pediatric tumors. Selection of isotopes (Ir-192 vs. I-125) will be addressed. Future directions will also be discussed, with special emphasis on intraoperative radiation therapy. A discussion of retroperitoneal sarcomas and the potential for brachytherapy in this area will also b e included. There will be extensive use of clinical examples to illustrate both brachytherapy technique and outcome.