In!. J Radrarm Oncolo,gy RioI Phvs Vol. Pnnted in the U.S.A. All tights reserved.

24. pp.

0360.3016/92 $5.00 + .oO Copyright 6 1992 Pergamon Press Ltd.

847-849

??Svecial Feature

RESIDENCY TRAINING IN RADIATION ONCOLOGY, RADIATION BIOLOGY AND CANCER BIOLOGY ERICJ. HALL, D.PHIL., ‘Center for

D.S.C.,’

AND JULIANA DENEKEMP,

D.S.C.2

Radiological Research, College of Physicians and Surgeons, Columbia *CRC Gray Laboratory,

Mt. Vernon

Hospital,

To attain the objective of educating physicians to be skillfull in the practice of radiation oncology, a solid grounding in radiation biology and cancer biology is essential. Without the inclusion of the basic sciences, the clinical practice of radiation oncology would be sterile and could not move forward. There are three essential components to a training program in radiation biology. A didactic course of lectures covering established basic principles of radiation biology, tumor response, normal tissue damage and the newer areas of molecular genetics. Laboratory electives of at least 3 months, preferably 6 months, to allow hands-on laboratory research experience. A variety of research opportunities should be available involving topics relevant to the practice and support of radiation therapy. This may lead in some cases to a fellowship year of full-time research following the completion of the residency. A seminar series at which new and ongoing research is discussed, with speakers from other countries and other institutions.

S_vllabus.for radiation biology

I. Interaction of radiation with matter: (A) Types of ionizing radiations; (B) Excitation and ionization; (C) Absorption of x-rays; (D) Absorption of neutrons; (E) Free radical production; (F) Direct and indirect effects; (G) Free radical scavengers and antioxidants; (1) Chain of events between absorption of energy and expression of biological consequences. Il. DNA damage: Single and double strand DNA breaks. Mechanisms of DNA repair. Genes controlling DNA repair. Biochemical and biophysical models related to DNA repair. Ill. Mammalian cell radiosensitivity: (A) Interphase, reproductive death, and apopposis; (B) Cell survival curves

DISCUSSION Current problems

There are many differences between the U.S., U.K., and Europe in the way in which radiation biology is taught to residents in radiation oncology. In the U.K., for example, the Royal College of Radiology sets the qualifying examination, organizes weekend courses, and publishes a syllabus of material that should be covered. In the U.S. by contrast, the examination is set by the American Board of Radiology, while extensive refresher

for publication

University, 630 W. 168 St., NY, NY 10032; Northwood, Middlesex, UK

courses are organized by national societies such as ASTRO and RSNA,-however, there is no immediate connection between the material covered in the courses and the questions set for the examination. There is no syllabus available at all. This is clearly less than optimal. Another significant difference concerns the attitude toward the need for radiation oncology centers to employ a radiation biologist. Clearly the ideal situation involves the close interaction at all levels of clinical oncology and an active research group large enough to constitute a critical mass. In the U.S., a residency program cannot be accredited unless the institution employs a radiation biologist full-time on staff. In smaller institutions this often leads to departments having a young unexperienced radiation biologist to satisfy the requirement by teaching a course. Meaningful research can hardly be conducted under these circumstances. In other countries, residents from smaller centers receive instruction in radiation biology by attending a centrally organized course. In the U.K., for example, Manchester and the Gray Lab each offer a week long course attended by residents from all over the country.

INTRODUCTION

Accepted

PH.D.,

30 June 1992. 847

848

1. J. Radiation Oncology 0 Biology0 Physics

in vitro; (C) Characterizations of cell survival curves; (D) Critical sites and target theory; (E) Chromosomal aberrations; (F) Dose response curves in vivo (clonogenic): (1) Skin clones, (2) Surviving crypts, (3) Bone marrow colonies growing in the spleen; (G) Quantitative normal tissue systems that are not clonogenic: (1) Pig skin, (2) Rodent skin, (3) Lung, (4) Esophagus, (5) Kidney, (6) Bladder. IV. Factors that modify radiation response: (A) The oxygen effect: (1) Effect of oxygen concentration, (2) Time of action of oxygen, (3) Mechanism of the oxygen effect, (4) Implications for radiotherapy, (5) Methods to overcome problems of hypoxic cells; (B) The age response function: (1) The cell cycle, (2) Age response for cells cultured in vitro, (3) Age response for tissues in vivo, (4) Age response and LET, (5) The oxygen effect through the cell cycle, (6) Implications for radiotherapy; (C) Potentially lethal damage: (1) Repair in vitro, (2) Repair in vivo, (3) PLD and high LET radiations, (4) Implications in radiotherapy; (D) Sublethal damage: (1) Split-dose experiments with cells in vitro, (2) Sublethal damage repair in normal tissues, (3) Sublethal damage repair in tumors, (4) Sublethal damage and hypoxia, (5) Sublethal damage and high LET radiations; (E) Dose-rate: (1) Dose-rate effect in cells in vitro, (2) Dose-rate effect in normal tissues, (3) Doserate effect in tumors, (4) Interstitial and intracavitary therapy, (5) Beam therapy at low dose rate, (6) Radiolabeled immunoglobulin therapy; (F) Radiosensitizers: (1) The halogenated pyrimidines, (2) Hypoxic cell radiosensitizers: (a) Structure and mode of action, (b) Enhancement ratio, (c) Pharmokinetics in the human, (d) Clinical limitations, (3) Antibiotics, (4) Bioreductive drugs; (G) Radioprotectors: ( 1) Free radical scavengers. V. Solid tumor systems: A. Experiment models: (1) Tumor regrowth measurements, (2) Tumor cureTCDSO, (3) Dilution assay technique, (4) Lung colony assay system, (5) In situ treatment/in vitro assay, (6) Spheroids; (B) Demonstration of hypoxic cells in tumors; (C) Proportion of hypoxic cells in tumors; (D) Reoxygenation; (E) Implications for radiotherapy. VI. Linear energy transfer: (A) Definition; (B) Track and energy average; (C) LET of different radiations; (D) OER as a function of LET. VII. Relative biological effectiveness: (A) Definition; (B) RBE as a function of dose; (C) RBE and fractionation; (D) RBE for different cells and tissues; (E) RBE as a function of LET; (F) Q factor. VIII. Cell and tissue kinetics: (A) The cell cycle: (B) Autoradiography/BUdR; (C) Constituent parts of the cell cycle; (D) Percent labelled mitoses technique; (E) Growth fraction; (F) Cell loss factor; (G) Flow and in situ cytometry; (H) Growth kinetics of human tumors; (I) Measurement of Tpot; (J) Latency between irradiation and appearance of tissue damage. IX. Tissue radiosensitivity: (A) Classification based on radiation pathology: (B) Types of cell populations: (1) Self renewal, (2) Conditional renewal, (3) Stem cell, (4) Differentiated.

Volume 24. Number 5, 1992

X. Time-dose and fractionation: (A) The 4 R’s of radiobiology; (B) The basis of fractionation; (C) The stranquist plot; (D) Nominal standard dose; (E) al/B model; (F) Early and late responding tissues; (G) Proliferation in normal tissues; (H) Accelerated repopulation; (I) Hyperfractionation; (J) Accelerated treatment. XI. New radiation modalities: (A) Protons: (1) Production, (2) Processes of absorption, (3) Depth dose patterns, (4) Advantages compared with x-rays, (5) Facilities available; (B) Neutrons: (1) Production, (2) Processes of absorption, (3) Depth dose patterns, (4) Advantages compared with x-rays: (C) High energy heavy ions: (1) Production, (2) Processes of absorption, (3) Depth dose patterns, (4) Advantages compared with x-rays, (5) Facilities available. XII. Chemotherapeutic agents used as adjuvants with radiation: (A) Classes of agents; (B) Cycling and non-cycling cells; (C) The oxygen effect for chemotherapy agents; (D) Combination with radiation; (E) Additivity and synergy; (F) Spatial cooperation; (G) Drug resistance; (H) Second malignancies from chemotherapy agents. XIII. Hyperthermia: (A) Methods of heating: (1) RF microwaves, (2) Ultrasound, (3) Water baths; (B) Systemic hyperthermia; (C) Localized heating; (D) Cellular response to heat; (E) Repair of thermal damage; (F) Thermotolerance; (G) Hyperthermia combined with irradiation: (H) Time sequence of heat and irradiation; (I) Hypoxic cells and heat: (J) Effect of pH on the response to hyperthermia; (K) Hyperthermic effects on tumor vasculature; (L) Response of transplanted tumors to heat; (M) Response of spontaneous tumors to heat; (N) Response of normal tissues to heat; (0) Heat and the therapeutic gain factor; (P) Hyperthermia and chemotherapy; (Q) Thermal dose: (R) Hyperthermia and low dose-rate irradiation. XIV. Total body irradiation-acute effects: (A) Prodromal radiation syndrome; (B) Cerebrovascular syndrome; (C) Gastrointestinal syndrome; (D) Hematopoietic syndrome; (E) Mean lethal dose (LD,o); (F) Treatment of radiation accidents. XV. Late effects: (A) Carcinogenesis: (1) The latent period, (2) Dose response curve in animals, (3) Leukemia, (4) Breast cancer, (5) Thyroid cancer, (6) Bone cancer, (7) Skin cancer, (8) Lung cancer, (9) Other tumors, ( 10) Malignancies in prenatally exposed children, (11) Mechanisms of radiation carcinogenesis. (12) Risk estimates in the human, ( 13) Oncogenic transformation in vitro, (14) Transfection, ( 15) Southern/Northern/Western blots, ( 16) Oncogenes, (17) Suppressor genes, (18) Multistep processes in carcinogenesis; (B) Heritable effects of radiation: (1) Single gene mutations, (2) Relationship to dose, (3) Chromosome aberrations, (4) Relationship to dose, (5) Relative vs. absolute mutation risk, (6) Doubling dose, (7) Genetically significant dose (GSD), (8) Genetic effect in humans, (9) Background radiation in relation to the GSD, (10) Risk estimates for heritable effects; (1 1) Malignancies from preconceptual irradiation (The Gardner report).

Residency training in radiation oncology 0

XVI. Radiation effects in the developing embryo and fetus: (A) Intrauterine death; (B) Congenital abnormalities and neonatal death; (C) Growth retardation; (D) Microcephaly; (E) Mental retardation; (F) Dependence of the above effects on dose, dose-rate and stage in gestation; (G) Carcinogenesis following in utero exposure; (H) Human experience of pregnant women exposed to therapeutic doses; (I) The “practical threshold” for therapeutic abortion. XVII. Radiation protection: (A) Quality factor; (B) Dose equivalent; (C) Effective dose equivalent; (D) Collective dose; (E) Committed dose; (F) Stochastic and deterministic effects; (G) Doses from natural sources; (H) Radon; (I) Doses from man-made sources; (J) ICRP, NCRP, UNSCEAR, BEIR; (K) Regulation of dose. XVIII. Radiophysiology of human tissues: (A) Effects of irradiation of the skin: (1) Clinical manifestations, (2) Histological substratum of effects, (3) Repair, (4) Degrees of sequelae, (5) Injurious effects; (B) Effects of irradiation of bone and cartilage: (1) Effects of growing bones and cartilage, (2) Effects on adult bones and cartilage, (3) Clinical manifestations, (4) Histological substratum of effects, (5) Functional consequences and sequelae; (C) Effects of irradiation of the kidney: (I) Clinical manifestations, (2) Histological substratum of effects, (3) Acute and chronic functional repercussions, (4) Permanent sequelae; (D) Effects of irradiation of the lung: (1) Acute clinical effects, (2) Ultimate effects, (3) Histologic substratum of effects, (4) Measures to reduce final effects, (5) Sequelae; (E) Effects of irradiation of nervous tissues: (I) Effects on the brain, (2) Effects on spinal cord, (3) Effects on peripheral nerves, (4) Clinical manifestations, (5) Histological substratum, (6) Sequelae; (F) Effects of irradiation of the ovary: (1) Clinical manifestations, (2) Histological substratum, (3) Reversibility of effects, (4) Therapeutic implications; (G) Effects of irradiation of the testis: (1) Clinical consequences, (2) Histological substratum, (3) Reversibility, (4) Protective measures; (H) Effects of (2) Hisirradiation of the eye: (I) Clinical consequences,

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tological substratum, (3) Cataract as a late effect, (4) Protective measures, (5) Time-dose connotations, (6) Sequelae-therapy; (I) Effects of irradiation of lymphoid tissue: (1) Clinical manifestations, (2) Histological substratum, (3) Reversibility; (J) Effects of irradiation of the bone marrow: (1) Clinical and laboratory manifestations, (2) Chronology of effects, (3) Histologic substratum, (4) Recovery, (5) Therapeutic applications: (K) Effects of irradiation of the oral, pharyngolaryngeal and esophageal mucuous membrane: (1) Clinical manifestations, (2) Histological substratum, (3) Repair. (4) Sequelae; (L) Effects of irradiation of the salivary glands: (1) Acute manifestations, (2) Histological substratum, (3) Dental consequences, (4) Prophylaxis: (M) Untoward effects observable in clinical radiotherapy: (1) Role of total dose, (2) Role of fractionation, (3) Measures of prevention. (4) Therapeutic measures; (N) Parenchymal versus stroma injury. ( 1) Relative importance of damage to both types of cells. (2) Latency between depletion of clonogenic cells and tissue injury.

CONCLUSION

AND

ACKNOWLEDGEMENT

The origins of this suggested syllabus can be traced to an International Symposium on the education of residents in radiation oncology held in Philadelphia in April 199 1. The initial plan was to devise an outline for a course of study in radiation biology that could be accepted internationally. However, it was soon obvious that this laudable aim was unattainable since radiation oncology is taught in such different ways in various countries. Consequently, this syllabus must be regarded as the personal opinion of the authors, but is nevertheless fairly representative of what is commonly taught in institutions across the United States and in Great Britain. It does not necessarily reflect so closely the situation in Continental Europe. With pleasure the author acknowledges much useful discussion with Dr. Jens Overgaard.

Residency training in radiation oncology; radiation biology and cancer biology.

In!. J Radrarm Oncolo,gy RioI Phvs Vol. Pnnted in the U.S.A. All tights reserved. 24. pp. 0360.3016/92 $5.00 + .oO Copyright 6 1992 Pergamon Press L...
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