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Principles and Practice of Principles and Practice of Radiation TherapyRadiation Therapy
The study of the sequence of events following The study of the sequence of events following the absorption of energy from ionizing the absorption of energy from ionizing radiation, the efforts of the organism to radiation, the efforts of the organism to compensate, and the damage to the compensate, and the damage to the organism that may be producedorganism that may be produced
Can rejoin without damageCan rejoin without damage ee-- can bond with HOH can bond with HOH
• HOH + eHOH + e-- HOHHOH--
Both products disassociateBoth products disassociate HOHHOH++ H H++ + OH + OH HOHHOH-- OH OH-- + H + H
– represents a free radicalrepresents a free radical Typically the HTypically the H++ and OH and OH-- rejoin to form HOH with no rejoin to form HOH with no
Linear Energy Transfer (LET)Linear Energy Transfer (LET)
A measure of the energy transferred or A measure of the energy transferred or deposited into a material as an ionizing deposited into a material as an ionizing particle travels through the materialparticle travels through the material Low LETLow LET
A comparison of doses between a standard A comparison of doses between a standard radiation (250 kV, x-rays) and a test radiation radiation (250 kV, x-rays) and a test radiation (R) that yield the same biologic result(R) that yield the same biologic result RBE = DRBE = D250250/D/DRR
As LET increases, RBE increasesAs LET increases, RBE increases
Oxygen Enhancement Ratio Oxygen Enhancement Ratio (OER)(OER)
A numeric representation of the dose A numeric representation of the dose comparison for a given biologic effect in comparison for a given biologic effect in anoxic and aerobic conditionsanoxic and aerobic conditions OER = DOER = Danoxicanoxic/D/Daerobicaerobic
As LET and RBE increase, OER decreasesAs LET and RBE increase, OER decreases
Loss or change of a baseLoss or change of a base Single-strand breakSingle-strand break Double-strand breakDouble-strand break Cross-linkingCross-linking
An abnormal bond between DNA strands or An abnormal bond between DNA strands or proteinsproteins
Radiation Effects on Radiation Effects on ChromosomesChromosomes
Any change is considered an aberration, Any change is considered an aberration, lesion, or anomalylesion, or anomaly Chromosome aberration vs. chromatid aberrationChromosome aberration vs. chromatid aberration
Cellular Response to RadiationCellular Response to Radiation
In vivo means in the organismIn vivo means in the organism Can observe the effects of radiation only on skin Can observe the effects of radiation only on skin
and hematopoietic systemand hematopoietic system In vitro means in glasswareIn vitro means in glassware
Describes the relationship between dose and Describes the relationship between dose and the percentage of surviving cellsthe percentage of surviving cells
Based on experimental dataBased on experimental data Suggests that there are two mechanisms for Suggests that there are two mechanisms for
cell deathcell death Lethal single-hit killingLethal single-hit killing Accumulation of multiple sublethal hits resulting in Accumulation of multiple sublethal hits resulting in
Straight line portionStraight line portion As dose doubles, the percentage surviving As dose doubles, the percentage surviving
decreases by halfdecreases by half Occurs at higher dosesOccurs at higher doses
ShoulderShoulder The initial portion of the survival curve (low dose) The initial portion of the survival curve (low dose)
does not behave like the straight line portiondoes not behave like the straight line portion Initial slope is much more shallowInitial slope is much more shallow
Can be rewritten to account for fractionationCan be rewritten to account for fractionation SF = SF = D[1 + d/(D[1 + d/(//)])]
d is the fraction dosed is the fraction dose [1 + d/([1 + d/(//)] is the relative effectiveness)] is the relative effectiveness //is the dose at which single-hit and multihit is the dose at which single-hit and multihit
killing are equalkilling are equal SF/SF/ is the biologic effective dose is the biologic effective dose
Law of Bergonié and TribondeauLaw of Bergonié and Tribondeau
Cells are most radiosensitive whenCells are most radiosensitive when Actively proliferatingActively proliferating Highly metabolicHighly metabolic UndifferentiatedUndifferentiated Well nourishedWell nourished
Law of Ancel and VitembergerLaw of Ancel and Vitemberger
Describes biologic stress and sensitivity to Describes biologic stress and sensitivity to radiationradiation
Postulates that all cells have the same Postulates that all cells have the same inherent radiosensitivity because all have the inherent radiosensitivity because all have the same targetsame target
““Radiosensitive” cells are those under Radiosensitive” cells are those under biologic stress, such as the need to dividebiologic stress, such as the need to divide
Investigate the cell’s ability to divideInvestigate the cell’s ability to divide In situ assayIn situ assay
Example: Intestinal crypt cellsExample: Intestinal crypt cells Measure the number of cell colonies after various Measure the number of cell colonies after various
Example: Bone marrowExample: Bone marrow Transplant irradiated cells into a new hostTransplant irradiated cells into a new host Measure the number of cell colonies after various Measure the number of cell colonies after various
Used to assess cells that do not rapidly divide Used to assess cells that do not rapidly divide by measuring function after irradiationby measuring function after irradiation Measure late effectsMeasure late effects
Results in dose-response curves rather than Results in dose-response curves rather than cell survival curvescell survival curves
Measure the number of dead organisms after a Measure the number of dead organisms after a specific dose of radiation to a specific organspecific dose of radiation to a specific organ
LDLD5050
Dose required to kill 50% of the populationDose required to kill 50% of the population Also known as median lethal doseAlso known as median lethal dose LDLD50/3050/30
• Dose required to kill 50% of population in 30 daysDose required to kill 50% of population in 30 days
TDTD5/55/5
Dose that will cause 5% of the population to have Dose that will cause 5% of the population to have effect after 5 yearseffect after 5 years
Factors that alter the cellular response to Factors that alter the cellular response to radiationradiation Physical factorsPhysical factors Chemical factorsChemical factors Biologic factorsBiologic factors
LET and RBELET and RBE Higher LET and RBE leads to a decrease in SFHigher LET and RBE leads to a decrease in SF High LET and RBE result in steeper shoulder and High LET and RBE result in steeper shoulder and
slopeslope Dose rateDose rate
Slower dose rates lead to increase in SFSlower dose rates lead to increase in SF Slow dose rates result in a more shallow shoulder and Slow dose rates result in a more shallow shoulder and
slopeslope High LET radiation is not affected by changes in dose High LET radiation is not affected by changes in dose
Chemical Factors Affecting Chemical Factors Affecting Cellular ResponseCellular Response
RadiosensitizersRadiosensitizers Increase the effect of ionizing radiationIncrease the effect of ionizing radiation Presence of oxygenPresence of oxygen
• Not well understoodNot well understood
• Theorized to increase the production of free radicals or Theorized to increase the production of free radicals or prevent the repair of chemical damage following prevent the repair of chemical damage following radiationradiation
RadioresistersRadioresisters Also known as radioprotectorsAlso known as radioprotectors
Cell cycleCell cycle Most radiosensitive in G2 and M phasesMost radiosensitive in G2 and M phases Least radiosensitive in SLeast radiosensitive in S Cell cycle is less important as dose increasesCell cycle is less important as dose increases
Intracellular repairIntracellular repair Basis for fractionationBasis for fractionation Most repair completed within 24 hoursMost repair completed within 24 hours
Derived from isoeffect curvesDerived from isoeffect curves D = NSD × TD = NSD × T0.110.11 × N × N0.240.24
D = total doseD = total dose NSD = nominal standard doseNSD = nominal standard dose
• 1800 rets was considered standard1800 rets was considered standard T = overall treatment time in daysT = overall treatment time in days N = number of fractionsN = number of fractions
LimitationsLimitations Not useful for late-responding normal tissuesNot useful for late-responding normal tissues Does not account for volume irradiatedDoes not account for volume irradiated
Gastrointestinal tractGastrointestinal tract Moderate doses cause mucositis and esophagitisModerate doses cause mucositis and esophagitis Small bowel is the most radiosensitive GI organSmall bowel is the most radiosensitive GI organ Intestinal crypt cells or cells of LieberkühnIntestinal crypt cells or cells of Lieberkühn
• Replaced dailyReplaced daily
• Extremely high doses lead to intestinal denudingExtremely high doses lead to intestinal denuding
Male reproductive systemMale reproductive system Most tissue is radioresistant, except testesMost tissue is radioresistant, except testes Reduction in spermatogoninReduction in spermatogonin
• Also known as maturation depletionAlso known as maturation depletion
• Mature sperm is radioresistantMature sperm is radioresistant
Temporary sterility occurs after 2.5 GyTemporary sterility occurs after 2.5 Gy Permanent sterility occurs with doses greater than Permanent sterility occurs with doses greater than
6 Gy6 Gy Any dose may lead to inheritable chromosome Any dose may lead to inheritable chromosome
Female reproductive systemFemale reproductive system Sterility is age dependentSterility is age dependent
• Temporary sterility may occur after 6.25 GyTemporary sterility may occur after 6.25 Gy
• Radiation-induced permanent sterility will result in early-Radiation-induced permanent sterility will result in early-onset menopause onset menopause
Any dose may lead to inheritable chromosome Any dose may lead to inheritable chromosome aberrationsaberrations
Life span shortening is the major effect of total-Life span shortening is the major effect of total-body exposurebody exposure Measured by LDMeasured by LD50/3050/30
Actual doses will vary by species and Actual doses will vary by species and individuals within the speciesindividuals within the species Small percentage of mammals will die after 2 GySmall percentage of mammals will die after 2 Gy Between 2 and 10 Gy, survival decreases as dose Between 2 and 10 Gy, survival decreases as dose
increasesincreases Between 10 and 100 Gy, there is little effect on Between 10 and 100 Gy, there is little effect on
survivalsurvival Above 100 Gy, survival decreases as dose Above 100 Gy, survival decreases as dose
Hematopoietic SyndromeHematopoietic Syndrome Doses between 1 and 10 GyDoses between 1 and 10 Gy Prodromal stageProdromal stage
Begins hours after exposure and persists for days to Begins hours after exposure and persists for days to weeks (3 weeks)weeks (3 weeks)
Pancytopenia can result in infection or hemorrhagePancytopenia can result in infection or hemorrhage DeathDeath
After 2 Gy in 6-8 weeks in sensitive individualsAfter 2 Gy in 6-8 weeks in sensitive individuals After 4-6 Gy is the range of LD50/30After 4-6 Gy is the range of LD50/30 After 10 Gy, all die within 2 weeks unless given bone After 10 Gy, all die within 2 weeks unless given bone
Central Nervous System Central Nervous System SyndromeSyndrome
May occur at doses as low as 50 GyMay occur at doses as low as 50 Gy Latent period ends 5-6 hours postexposureLatent period ends 5-6 hours postexposure Death occurs in 2-3 daysDeath occurs in 2-3 days
Individual experiences nervousness and confusionIndividual experiences nervousness and confusion Cause of death is not well understoodCause of death is not well understood Autopsies reveal little cellular damageAutopsies reveal little cellular damage
Preimplantation exposurePreimplantation exposure 200 R leads to an embryonic death rate of 80% 200 R leads to an embryonic death rate of 80%
and a 5% abnormality rateand a 5% abnormality rate Major organogenesis exposureMajor organogenesis exposure
200 R leads to an embryonic death rate of 25% 200 R leads to an embryonic death rate of 25% and a 100% abnormality rateand a 100% abnormality rate• Most abnormalities are skeletal or CNSMost abnormalities are skeletal or CNS
Fetal exposureFetal exposure 200 R yields negligible side effects200 R yields negligible side effects
Embryologic Human StudiesEmbryologic Human Studies
Pregnant survivors of the atomic bomb Pregnant survivors of the atomic bomb Doses greater than 2 Gy resulted in 36% of Doses greater than 2 Gy resulted in 36% of
children born with mental retardationchildren born with mental retardation Doses between 0.5 and 1 Gy yielded a mental Doses between 0.5 and 1 Gy yielded a mental
retardation rate of 4.55%retardation rate of 4.55% Incidence of mental retardation in general Incidence of mental retardation in general
population is less than 1%population is less than 1%
Effects of radiation that occur in the irradiated Effects of radiation that occur in the irradiated individual and cannot be passed on to future individual and cannot be passed on to future generationsgenerations May occur months to years postexposureMay occur months to years postexposure
A probability of developing effect exists with A probability of developing effect exists with all dosesall doses Probability increases as exposure increasesProbability increases as exposure increases Example: Smoking and lung cancerExample: Smoking and lung cancer
Risk associated with doses lower than 1 Gy is Risk associated with doses lower than 1 Gy is not knownnot known
Case studiesCase studies Radium dial paintersRadium dial painters Thymus irradiation in infantsThymus irradiation in infants Early medical radiation personnelEarly medical radiation personnel Uranium mine workersUranium mine workers Survivors of the atomic bombsSurvivors of the atomic bombs
Associated with a latent period and a period of Associated with a latent period and a period of increased risk followed by a return to normal risk increased risk followed by a return to normal risk • Example: LeukemiaExample: Leukemia
Relative riskRelative risk Continuous risk throughout lifeContinuous risk throughout life Population must be followed until deathPopulation must be followed until death
Methods of estimating riskMethods of estimating risk Linear: Assume all doses have same potential for effectLinear: Assume all doses have same potential for effect Linear quadratic: Assume that dose and risk are Linear quadratic: Assume that dose and risk are
Normal lens fibers are transparentNormal lens fibers are transparent Radiation damages lens cells, resulting in cataract Radiation damages lens cells, resulting in cataract
formationformation Dose is species dependentDose is species dependent Dose is patient specificDose is patient specific
May be as low as 2 Gy but all after 7 GyMay be as low as 2 Gy but all after 7 Gy Fractionated dose threshold is 12 GyFractionated dose threshold is 12 Gy
Decrease in average life span documented in Decrease in average life span documented in irradiated animal populationsirradiated animal populations
No unique diseasesNo unique diseases Earlier onsetEarlier onset
Retrospective studies of early radiologistsRetrospective studies of early radiologists Life span shortening of 5 years on averageLife span shortening of 5 years on average
Spontaneous mutationsSpontaneous mutations Changes in DNA that are not the result of outside Changes in DNA that are not the result of outside
stimulistimuli Permanent and possibly inheritablePermanent and possibly inheritable Examples: Down syndrome, hydrocephalusExamples: Down syndrome, hydrocephalus
Mutation frequencyMutation frequency Number of spontaneous mutations in a generationNumber of spontaneous mutations in a generation
MutagensMutagens Source of mutationSource of mutation Examples: Viruses, chemicals, radiationExamples: Viruses, chemicals, radiation
Doubling doseDoubling dose Unit of measurement for mutation frequencyUnit of measurement for mutation frequency Dose required to double the percentage of Dose required to double the percentage of
mutations in a generationmutations in a generation
Goal of Radiation TherapyGoal of Radiation Therapy
““Treat the tumor, spare the normal tissue”Treat the tumor, spare the normal tissue” Damage is random and nonspecificDamage is random and nonspecific
Equal probability for normal tissue and tumorEqual probability for normal tissue and tumor Do not typically treat to tumoricidal dosesDo not typically treat to tumoricidal doses
Probability of damage increases as dose Probability of damage increases as dose increasesincreases
Group 1 (P cells)Group 1 (P cells) Well oxygenated and actively proliferatingWell oxygenated and actively proliferating Responsible for growth fraction (GF)Responsible for growth fraction (GF) Most radiosensitiveMost radiosensitive
Group 2 (Q cells)Group 2 (Q cells) Well oxygenated but not proliferatingWell oxygenated but not proliferating In quiescence but may be source of future In quiescence but may be source of future
Tumor GrowthTumor Growth Measured in doubling timeMeasured in doubling time
Time required to double total number of cellsTime required to double total number of cells Cell cycleCell cycle
General rule: Tumor cells have a shorter cell cycle General rule: Tumor cells have a shorter cell cycle than normal cellsthan normal cells
Doubling time of 40-100 days vs. 60 days for Doubling time of 40-100 days vs. 60 days for normal cellsnormal cells
Growth fractionGrowth fraction GF = # of P cells / (# of P cells + # of Q cells)GF = # of P cells / (# of P cells + # of Q cells) As GF increases, doubling time decreasesAs GF increases, doubling time decreases
Cell lossCell loss Result of cell death or metastasesResult of cell death or metastases
Role of Oxygen in Tumor GrowthRole of Oxygen in Tumor Growth
Tumors eventually outgrow vasculatureTumors eventually outgrow vasculature Central areas of necrosis if tumor is larger than Central areas of necrosis if tumor is larger than
100-180 microns100-180 microns Related to the diffusion distance of oxygen, also Related to the diffusion distance of oxygen, also
known as oxygen tensionknown as oxygen tension Cells closer to the vessel are more Cells closer to the vessel are more
Varies when total dose to kill tumor is Varies when total dose to kill tumor is consideredconsidered
Varies by tumor cell typeVaries by tumor cell type DD00 used as measurement used as measurement Some postulate that it is the cell’s repair Some postulate that it is the cell’s repair
capabilities not its radiosensitivitycapabilities not its radiosensitivity
Normal Tissue Tolerance DoseNormal Tissue Tolerance Dose
Dose at which additional radiation would Dose at which additional radiation would significantly increase probability of severe significantly increase probability of severe normal tissue reactionnormal tissue reaction
The division of the total dose into equal The division of the total dose into equal smaller partssmaller parts
First used in 1927First used in 1927 Sterilized ram testes without skin reactionSterilized ram testes without skin reaction
Less effective than single dose of same sizeLess effective than single dose of same size Also has significantly fewer side effectsAlso has significantly fewer side effects