Principles and Practice of Radiation Therapy

Name: Principles and Practice of Radiation Therapy
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Description: Principles and Practice of Radiation Therapy

Principles and Practice of Radiation Therapy
Chapter 4 Overview of Radiobiology Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.
Review of Cell Biology Cytology is the study of the structure and function of the cell The human body contains both somatic and sex cells Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Review of Cell Biology Inorganic components HOH 70%-80% Salts Potassium inside cell Sodium outside cell Organic components Proteins 15% Monomers vs. polymers Amino acids Carbohydrates 1% Nucleic Acid RNA and DNA Lipids Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Radiobiology The study of the sequence of events following the absorption of energy from ionizing radiation, the efforts of the organism to compensate, and the damage to the organism that may be produced Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Interactions of Radiation and Matter
Direct action Radiation interacts with the target Indirect action Radiation interacts with something else that eventually causes an interaction with the target Typically HOH More common than direct Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Free Radical Production
HOH + ionizing radiation HOH+ + e- Can rejoin without damage e- can bond with HOH HOH + e- HOH- Both products disassociate HOH+  H+ + OHl HOH-  OH- + Hl l represents a free radical Typically the H+ and OH- rejoin to form HOH with no damage Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Free Radical Production
Interactions of free radicals Possible results Hl + OHl HOH Hl + Hl H2 OHl + OHl  H2O2 Join with other normal molecule Hl + O2 HO2 Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Linear Energy Transfer (LET)
A measure of the energy transferred or deposited into a material as an ionizing particle travels through the material Low LET X and gamma rays Moderate LET Neutrons High LET Alpha particles Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Relative Biologic Effectiveness (RBE)
A comparison of doses between a standard radiation (250 kV, x-rays) and a test radiation (R) that yield the same biologic result RBE = D250/DR As LET increases, RBE increases Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Oxygen Enhancement Ratio (OER)
A numeric representation of the dose comparison for a given biologic effect in anoxic and aerobic conditions OER = Danoxic/Daerobic As LET and RBE increase, OER decreases Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Radiation Effects on DNA
Repair Base damage Loss or change of a base Single-strand break Double-strand break Cross-linking An abnormal bond between DNA strands or proteins Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Radiation Effects on Chromosomes
Any change is considered an aberration, lesion, or anomaly Chromosome aberration vs. chromatid aberration Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Radiation Effects on Chromosomes
Acentric fragment Two broken ends without a centromere Dicentric chromatid Two chromosomes with broken ends join, resulting in one chromosome with two centromeres Ring Translocation Inversion Deletion Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Radiation Effects on Other Cell Components
Cell membrane Changes in the permeability Mitochondria Lysosome Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Cellular Response to Radiation
In vivo means in the organism Can observe the effects of radiation only on skin and hematopoietic system In vitro means in glassware Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Fate of Irradiated Cells
No damage Division delay or mitotic delay Cell is held in G2 before entering mitosis Mitotic overshoot Interphase death Dose dependent Reproductive failure Cell fails to enter mitosis Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Cell Survival Curve Describes the relationship between dose and the percentage of surviving cells Based on experimental data Suggests that there are two mechanisms for cell death Lethal single-hit killing Accumulation of multiple sublethal hits resulting in death Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Semilogarithmic Graphing Paper
Vertical axis Logarithmic portion Represents percent survival Horizontal axis Nonlogarithmic Represents dose Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Cell Survival Curve Straight line portion As dose doubles, the percentage surviving decreases by half Occurs at higher doses Shoulder The initial portion of the survival curve (low dose) does not behave like the straight line portion Initial slope is much more shallow Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Target Theory Dq Quasithreshold dose Extrapolation of D0 to the 100% line N Extrapolation number or target number Extrapolation of D0 back to the vertical axis Thought to represent the number of targets in the cell D1 Sometimes called 1D0 Represents the initial slope of the curve D0 Represents the terminal slope or straight line portion D37 Dose required to kill all but 37% of the cells Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Linear Quadratic Model
Dual radiation action theory a: Lethal single-hit kills b: Accumulation of sublethal dose kills D: Dose SF = aD +bD2 aD is the linear component bD2 is the quadratic component Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Linear Quadratic Model
Can be rewritten to account for fractionation SF = aD[1 + d/(a/b)] d is the fraction dose [1 + d/(a/b)] is the relative effectiveness a/b is the dose at which single-hit and multihit killing are equal SF/a is the biologic effective dose Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Law of Bergonié and Tribondeau
Cells are most radiosensitive when Actively proliferating Highly metabolic Undifferentiated Well nourished Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Law of Ancel and Vitemberger
Describes biologic stress and sensitivity to radiation Postulates that all cells have the same inherent radiosensitivity because all have the same target “Radiosensitive” cells are those under biologic stress, such as the need to divide Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Cell Populations Categories based on radiosensitivity Vegetative intermitotic (VIM) cells Differentiating intermitotic (DIM) cells Multipotential connective tissue (MPCT) cells Reverting postmitotic (RPM) cells Fixed postmitotic (FPM) cells Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Clonogenic Assay Investigate the cell’s ability to divide In situ assay Example: Intestinal crypt cells Measure the number of cell colonies after various doses Transplantation assay Example: Bone marrow Transplant irradiated cells into a new host Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Functional Assays Used to assess cells that do not rapidly divide by measuring function after irradiation Measure late effects Results in dose-response curves rather than cell survival curves Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Lethality Assays Measure the number of dead organisms after a specific dose of radiation to a specific organ LD50 Dose required to kill 50% of the population Also known as median lethal dose LD50/30 Dose required to kill 50% of population in 30 days TD5/5 Dose that will cause 5% of the population to have effect after 5 years Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Physical Factors Affecting Cellular Response
LET and RBE Higher LET and RBE leads to a decrease in SF High LET and RBE result in steeper shoulder and slope Dose rate Slower dose rates lead to increase in SF Slow dose rates result in a more shallow shoulder and slope High LET radiation is not affected by changes in dose rate Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Chemical Factors Affecting Cellular Response
Radiosensitizers Increase the effect of ionizing radiation Presence of oxygen Not well understood Theorized to increase the production of free radicals or prevent the repair of chemical damage following radiation Radioresisters Also known as radioprotectors Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Biologic Factors Affecting Cellular Response
Cell cycle Most radiosensitive in G2 and M phases Least radiosensitive in S Cell cycle is less important as dose increases Intracellular repair Basis for fractionation Most repair completed within 24 hours Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Nominal Standard Dose Derived from isoeffect curves D = NSD × T0.11 × N0.24 D = total dose NSD = nominal standard dose 1800 rets was considered standard T = overall treatment time in days N = number of fractions Limitations Not useful for late-responding normal tissues Does not account for volume irradiated Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Acute vs. Late Changes Acute effects The result of the depletion of parenchymal cells Chronic (late) effects Primary chronic effects The result of the depletion of nonparenchymal cells Secondary chronic effects Consequence of irreversible early changes Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Tissue Healing Regeneration Replacement of a dead cell with a cell with the same function Repair Replacement of a dead cell with a different cell type Example: Scar Both are tissue type and dose specific Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Organ-Specific Effects
Bone marrow Reduction in number of stem cells Principle of TBI Blood Cell type specific Circulating RBCs are radioresistant Lymphocytes are the most sensitive Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Skin High doses may lead to atrophy, fibrosis, pigmentation changes, and/or necrosis Hair follicles are radiosensitive Sweat glands are somewhat radioresistant Skin-sparing effects of high-energy radiation Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Gastrointestinal tract Moderate doses cause mucositis and esophagitis Small bowel is the most radiosensitive GI organ Intestinal crypt cells or cells of Lieberkühn Replaced daily Extremely high doses lead to intestinal denuding Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Male reproductive system Most tissue is radioresistant, except testes Reduction in spermatogonin Also known as maturation depletion Mature sperm is radioresistant Temporary sterility occurs after 2.5 Gy Permanent sterility occurs with doses greater than 6 Gy Any dose may lead to inheritable chromosome aberrations Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Female reproductive system Sterility is age dependent Temporary sterility may occur after 6.25 Gy Radiation-induced permanent sterility will result in early-onset menopause Any dose may lead to inheritable chromosome aberrations Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Normal Tissue Tolerance Doses
Refer to Table 4-9 on page 82 of the textbook for tolerance doses. Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Total-Body Response Conditions for radiation syndromes Acute exposure Seconds to minutes Total- or near-total-body exposure External source of radiation Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Survival Time Life span shortening is the major effect of total-body exposure Measured by LD50/30 Actual doses will vary by species and individuals within the species Small percentage of mammals will die after 2 Gy Between 2 and 10 Gy, survival decreases as dose increases Between 10 and 100 Gy, there is little effect on survival Above 100 Gy, survival decreases as dose increases Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Radiation Syndromes Stages of response All patients, regardless of syndrome, experience the same stages Length of stage varies Prodromal Nausea, vomiting, diarrhea Latent Patient appears to be healthy Manifest illness Specific syndrome presents Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Hematopoietic Syndrome
Doses between 1 and 10 Gy Prodromal stage Begins hours after exposure and persists for days to weeks (3 weeks) Pancytopenia can result in infection or hemorrhage Death After 2 Gy in 6-8 weeks in sensitive individuals After 4-6 Gy is the range of LD50/30 After 10 Gy, all die within 2 weeks unless given bone marrow transplant Rarely successful Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Gastrointestinal Syndrome
Doses between 10 and 100 Gy Death is independent of dose All die at same time 3-10 days without medical intervention 2 weeks with medical intervention Death is the result of intestinal denuding Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Central Nervous System Syndrome
May occur at doses as low as 50 Gy Latent period ends 5-6 hours postexposure Death occurs in 2-3 days Individual experiences nervousness and confusion Cause of death is not well understood Autopsies reveal little cellular damage Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Embryologic Effects Most sensitive during first few weeks of development Divisions of pregnancy Preimplantation First 8-10 days Major organogenesis Second week to seventh week Fetus Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Embryologic Animal Studies
Preimplantation exposure 200 R leads to an embryonic death rate of 80% and a 5% abnormality rate Major organogenesis exposure 200 R leads to an embryonic death rate of 25% and a 100% abnormality rate Most abnormalities are skeletal or CNS Fetal exposure 200 R yields negligible side effects Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Embryologic Human Studies
Pregnant survivors of the atomic bomb Doses greater than 2 Gy resulted in 36% of children born with mental retardation Doses between 0.5 and 1 Gy yielded a mental retardation rate of 4.55% Incidence of mental retardation in general population is less than 1% Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Somatic Effects Effects of radiation that occur in the irradiated individual and cannot be passed on to future generations May occur months to years postexposure A probability of developing effect exists with all doses Probability increases as exposure increases Example: Smoking and lung cancer Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Carcinogenesis Risk associated with doses lower than 1 Gy is not known Case studies Radium dial painters Thymus irradiation in infants Early medical radiation personnel Uranium mine workers Survivors of the atomic bombs Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Risk Absolute risk Associated with a latent period and a period of increased risk followed by a return to normal risk Example: Leukemia Relative risk Continuous risk throughout life Population must be followed until death Methods of estimating risk Linear: Assume all doses have same potential for effect Linear quadratic: Assume that dose and risk are proportional Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Cataractogenesis Normal lens fibers are transparent Radiation damages lens cells, resulting in cataract formation Dose is species dependent Dose is patient specific May be as low as 2 Gy but all after 7 Gy Fractionated dose threshold is 12 Gy Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Life Span Shortening Decrease in average life span documented in irradiated animal populations No unique diseases Earlier onset Retrospective studies of early radiologists Life span shortening of 5 years on average Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Mutations Spontaneous mutations Changes in DNA that are not the result of outside stimuli Permanent and possibly inheritable Examples: Down syndrome, hydrocephalus Mutation frequency Number of spontaneous mutations in a generation Mutagens Source of mutation Examples: Viruses, chemicals, radiation Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Measuring Risk Doubling dose Unit of measurement for mutation frequency Dose required to double the percentage of mutations in a generation Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Studies on Genetic Effects
Animal Fruit flies Hermann Muller Determined radiation does not cause unique mutation but does increase mutation frequency of spontaneous mutations No dose threshold Mega-mouse experiments Russell and Russell Human Pregnant atomic bomb survivors Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Goal of Radiation Therapy
“Treat the tumor, spare the normal tissue” Damage is random and nonspecific Equal probability for normal tissue and tumor Do not typically treat to tumoricidal doses Probability of damage increases as dose increases Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Tumor Cell Characteristics
Group 1 (P cells) Well oxygenated and actively proliferating Responsible for growth fraction (GF) Most radiosensitive Group 2 (Q cells) Well oxygenated but not proliferating In quiescence but may be source of future recurrence Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Tumor Cell Characteristics
Group 3 (Q cells) Hypoxic and not proliferating Most radioresistant Group 4 Anoxic and necrotic, dead Not a source of concern Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Tumor Growth Measured in doubling time Time required to double total number of cells Cell cycle General rule: Tumor cells have a shorter cell cycle than normal cells Doubling time of days vs. 60 days for normal cells Growth fraction GF = # of P cells / (# of P cells + # of Q cells) As GF increases, doubling time decreases Cell loss Result of cell death or metastases Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Role of Oxygen in Tumor Growth
Tumors eventually outgrow vasculature Central areas of necrosis if tumor is larger than microns Related to the diffusion distance of oxygen, also known as oxygen tension Cells closer to the vessel are more radiosensitive Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Tumor Radiosensitivity
Varies when total dose to kill tumor is considered Varies by tumor cell type D0 used as measurement Some postulate that it is the cell’s repair capabilities not its radiosensitivity Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Normal Tissue Tolerance Dose
Dose at which additional radiation would significantly increase probability of severe normal tissue reaction Isoeffect curves Tolerance doses TD50/5 Dose that will cause effect in 50% of population in 5 years TD5/5 Dose that will cause effect in 5% of population in 5 years Based on standard fractionation of 10 Gy/week, 2 Gy/day, and 5 days/week Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Time-Dose Fractionation
The division of the total dose into equal smaller parts First used in 1927 Sterilized ram testes without skin reaction Less effective than single dose of same size Also has significantly fewer side effects Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Factors Affecting Effectiveness of Fractionation
Redistribution Synchronization of surviving cell into resistant mitotic phases Normal cells tend to remain in resistant phases, whereas tumor cells enter all phases Reoxygenation Death of aerobic tumor cells allows hypoxic cells to become more oxygenated Regeneration Occurs between fractions for highly mitotic cells Repair Cellular repair of sublethal damage (SLD) Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

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