principles and practice of radiation therapy chapter 4 overview of radiobiology copyright © 2010 by...

Principles and Practice of Principles and Practice of Radiation TherapyRadiation Therapy

Chapter 4Chapter 4

Overview of RadiobiologyOverview of Radiobiology

Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.

Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.Copyright © 2010 by Mosby, Inc., an affiliate of Elsevier Inc. 22

Review of Cell BiologyReview of Cell Biology

Cytology is the study of the structure and Cytology is the study of the structure and function of the cellfunction of the cell

The human body contains both somatic and The human body contains both somatic and sex cellssex cells


Review of Cell BiologyReview of Cell Biology

Inorganic Inorganic componentscomponents HOH HOH

• 70%-80%70%-80%

SaltsSalts• Potassium inside cellPotassium inside cell

• Sodium outside cellSodium outside cell

Organic componentsOrganic components ProteinsProteins

• 15%15%

• Monomers vs. Monomers vs. polymerspolymers

• Amino acidsAmino acids

CarbohydratesCarbohydrates• 1%1%

Nucleic AcidNucleic Acid• RNA and DNARNA and DNA

LipidsLipids


Cellular StructureCellular Structure

CytoplasmCytoplasm Cell membraneCell membrane Endoplasmic reticulumEndoplasmic reticulum RibosomeRibosome MitochondriaMitochondria LysosomeLysosome Golgi complexGolgi complex


Cellular StructureCellular Structure

NucleusNucleus DNADNA

• Nitrous basesNitrous bases

• PurinesPurines AdenineAdenine GuanineGuanine

• PyrimidinesPyrimidines ThymineThymine CytosineCytosine


MitosisMitosis

ProphaseProphase MetaphaseMetaphase AnaphaseAnaphase TelophaseTelophase

InterphaseInterphase G0G0 G1G1 SS G2G2


RadiobiologyRadiobiology

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


Interactions of Interactions of Radiation and MatterRadiation and Matter

Direct actionDirect action Radiation interacts with the targetRadiation interacts with the target

Indirect actionIndirect action Radiation interacts with something else that Radiation interacts with something else that

eventually causes an interaction with the targeteventually causes an interaction with the target• Typically HOHTypically HOH

• More common than directMore common than direct


Indirect ActionIndirect Action

Free radicalFree radical An atom or molecule with an unpaired electron An atom or molecule with an unpaired electron

and no chargeand no charge Very reactiveVery reactive


Free Radical ProductionFree Radical Production

HOH + ionizing radiation HOH + ionizing radiation HOHHOH++ + e + e--

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

damagedamage


Free Radical ProductionFree Radical Production

Interactions of free radicalsInteractions of free radicals Possible resultsPossible results

• HH+ OH+ OH HOH HOH

• HH+ H+ HHH22

• OHOH+ OH+ OH H H22OO22

• Join with other normal moleculeJoin with other normal molecule HH+ O+ O22

HOHO22


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

• X and gamma raysX and gamma rays

Moderate LETModerate LET• NeutronsNeutrons

High LETHigh LET• Alpha particlesAlpha particles


Relative Biologic Effectiveness Relative Biologic Effectiveness (RBE)(RBE)

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


Radiation Effects on DNARadiation Effects on DNA

RepairRepair Base damageBase damage

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


Radiation Effects on Radiation Effects on ChromosomesChromosomes

Acentric fragmentAcentric fragment Two broken ends without a centromereTwo broken ends without a centromere

Dicentric chromatidDicentric chromatid Two chromosomes with broken ends join, resulting Two chromosomes with broken ends join, resulting

in one chromosome with two centromeresin one chromosome with two centromeres RingRing TranslocationTranslocation InversionInversion DeletionDeletion


Radiation Effects on Other Cell Radiation Effects on Other Cell ComponentsComponents

Cell membraneCell membrane Changes in the permeabilityChanges in the permeability

MitochondriaMitochondria LysosomeLysosome


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


Fate of Irradiated CellsFate of Irradiated Cells

No damageNo damage Division delay or mitotic delayDivision delay or mitotic delay

Cell is held in G2 before entering mitosisCell is held in G2 before entering mitosis Mitotic overshootMitotic overshoot

Interphase deathInterphase death Dose dependentDose dependent

Reproductive failureReproductive failure Cell fails to enter mitosisCell fails to enter mitosis


Cell Survival CurveCell Survival Curve

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

deathdeath


Semilogarithmic Graphing PaperSemilogarithmic Graphing Paper

Vertical axisVertical axis Logarithmic portionLogarithmic portion Represents percent survivalRepresents percent survival

Horizontal axisHorizontal axis NonlogarithmicNonlogarithmic Represents doseRepresents dose


Cell Survival CurveCell Survival Curve

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


Target TheoryTarget Theory DD11

Sometimes called 1DSometimes called 1D00

Represents the initial slope Represents the initial slope of the curveof the curve

DD00

Represents the terminal Represents the terminal slope or straight line slope or straight line portionportion

D37D37 Dose required to kill all but Dose required to kill all but

37% of the cells37% of the cells

DDqq

Quasithreshold doseQuasithreshold dose Extrapolation of DExtrapolation of D00 to the to the

100% line100% line NN

Extrapolation number or Extrapolation number or target numbertarget number

Extrapolation of DExtrapolation of D00 back to back to

the vertical axisthe vertical axis Thought to represent the Thought to represent the

number of targets in the cellnumber of targets in the cell


Surviving FractionSurviving Fraction

Sometimes labeled ESometimes labeled E SF = NeSF = Ne-(D/D-(D/D00))


Linear Quadratic ModelLinear Quadratic Model

Dual radiation action theoryDual radiation action theory Lethal single-hit killsLethal single-hit kills Accumulation of sublethal dose killsAccumulation of sublethal dose kills D: DoseD: Dose

SF = SF = D +D +DD2 2 D is the linear componentD is the linear component DD22 is the quadratic component is the quadratic component


Linear Quadratic ModelLinear Quadratic Model

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


Cell PopulationsCell Populations

Categories based on radiosensitivityCategories based on radiosensitivity Vegetative intermitotic (VIM) cellsVegetative intermitotic (VIM) cells Differentiating intermitotic (DIM) cellsDifferentiating intermitotic (DIM) cells Multipotential connective tissue (MPCT) cellsMultipotential connective tissue (MPCT) cells Reverting postmitotic (RPM) cellsReverting postmitotic (RPM) cells Fixed postmitotic (FPM) cellsFixed postmitotic (FPM) cells


Clonogenic AssayClonogenic Assay

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

dosesdoses Transplantation assayTransplantation assay

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

dosesdoses


Functional AssaysFunctional Assays

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


Lethality AssaysLethality Assays

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


Cellular ResponseCellular Response

Factors that alter the cellular response to Factors that alter the cellular response to radiationradiation Physical factorsPhysical factors Chemical factorsChemical factors Biologic factorsBiologic factors


Physical Factors Affecting Physical Factors Affecting Cellular ResponseCellular Response

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

raterate


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


Biologic Factors Affecting Biologic Factors Affecting Cellular ResponseCellular Response

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


Nominal Standard DoseNominal Standard Dose

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


Acute vs. Late ChangesAcute vs. Late Changes

Acute effectsAcute effects The result of the depletion of parenchymal cellsThe result of the depletion of parenchymal cells

Chronic (late) effectsChronic (late) effects Primary chronic effectsPrimary chronic effects

• The result of the depletion of nonparenchymal cellsThe result of the depletion of nonparenchymal cells

Secondary chronic effectsSecondary chronic effects• Consequence of irreversible early changesConsequence of irreversible early changes


Tissue HealingTissue Healing

RegenerationRegeneration Replacement of a dead cell with a cell with the Replacement of a dead cell with a cell with the

same functionsame function RepairRepair

Replacement of a dead cell with a different cell Replacement of a dead cell with a different cell typetype• Example: ScarExample: Scar

Both are tissue type and dose specific Both are tissue type and dose specific


Organ-Specific EffectsOrgan-Specific Effects

Bone marrowBone marrow Reduction in number of stem cellsReduction in number of stem cells Principle of TBIPrinciple of TBI

BloodBlood Cell type specificCell type specific

• Circulating RBCs are radioresistantCirculating RBCs are radioresistant

• Lymphocytes are the most sensitiveLymphocytes are the most sensitive



SkinSkin High doses may lead to atrophy, fibrosis, High doses may lead to atrophy, fibrosis,

pigmentation changes, and/or necrosispigmentation changes, and/or necrosis Hair follicles are radiosensitiveHair follicles are radiosensitive Sweat glands are somewhat radioresistantSweat glands are somewhat radioresistant Skin-sparing effects of high-energy radiationSkin-sparing effects of high-energy radiation



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

aberrationsaberrations



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


Normal Tissue Tolerance DosesNormal Tissue Tolerance Doses

Refer to Table 4-9 on page 82 of the textbook Refer to Table 4-9 on page 82 of the textbook

for tolerance doses.for tolerance doses.


Total-Body ResponseTotal-Body Response

Conditions for radiation syndromesConditions for radiation syndromes Acute exposureAcute exposure

• Seconds to minutesSeconds to minutes

Total- or near-total-body exposureTotal- or near-total-body exposure External source of radiationExternal source of radiation


Survival TimeSurvival Time

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

increasesincreases


Radiation SyndromesRadiation Syndromes

Stages of responseStages of response All patients, regardless of syndrome, experience All patients, regardless of syndrome, experience

the same stagesthe same stages• Length of stage variesLength of stage varies

ProdromalProdromal• Nausea, vomiting, diarrheaNausea, vomiting, diarrhea

LatentLatent• Patient appears to be healthyPatient appears to be healthy

Manifest illnessManifest illness• Specific syndrome presentsSpecific syndrome presents


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

marrow transplantmarrow transplant• Rarely successfulRarely successful


Gastrointestinal SyndromeGastrointestinal Syndrome

Doses between 10 and 100 GyDoses between 10 and 100 Gy Death is independent of doseDeath is independent of dose

All die at same timeAll die at same time• 3-10 days without medical intervention3-10 days without medical intervention

• 2 weeks with medical intervention2 weeks with medical intervention

Death is the result of intestinal denudingDeath is the result of intestinal denuding


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


Embryologic EffectsEmbryologic Effects

Most sensitive during first few weeks of Most sensitive during first few weeks of developmentdevelopment

Divisions of pregnancyDivisions of pregnancy PreimplantationPreimplantation

• First 8-10 daysFirst 8-10 days

Major organogenesisMajor organogenesis• Second week to seventh weekSecond week to seventh week

FetusFetus


Embryologic Animal StudiesEmbryologic Animal Studies

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%


Somatic EffectsSomatic Effects

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


CarcinogenesisCarcinogenesis

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


RiskRisk Absolute riskAbsolute risk

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

proportional proportional


CataractogenesisCataractogenesis

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


Life Span ShorteningLife Span Shortening

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


Genetic EffectsGenetic Effects

Damage to the genetic material may be Damage to the genetic material may be passed on to future generationspassed on to future generations

Latent periodLatent period


MutationsMutations

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


Measuring RiskMeasuring Risk

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


Studies on Genetic EffectsStudies on Genetic Effects

AnimalAnimal Fruit fliesFruit flies

• Hermann MullerHermann Muller• Determined radiation does not cause unique mutation but Determined radiation does not cause unique mutation but

does increase mutation frequency of spontaneous mutationsdoes increase mutation frequency of spontaneous mutations• No dose thresholdNo dose threshold

Mega-mouse experimentsMega-mouse experiments• Russell and RussellRussell and Russell

HumanHuman Pregnant atomic bomb survivorsPregnant atomic bomb survivors


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


Therapeutic RatioTherapeutic Ratio

Difference between probability of tumor Difference between probability of tumor control and normal tissue damagecontrol and normal tissue damage

Varies by doseVaries by dose


Tumor Cell CharacteristicsTumor Cell Characteristics

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

recurrencerecurrence


Tumor Cell CharacteristicsTumor Cell Characteristics

Group 3 (Q cells)Group 3 (Q cells) Hypoxic and not proliferatingHypoxic and not proliferating Most radioresistantMost radioresistant

Group 4 Group 4 Anoxic and necrotic, deadAnoxic and necrotic, dead Not a source of concernNot a source of concern


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

radiosensitiveradiosensitive


Tumor RadiosensitivityTumor Radiosensitivity

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

Isoeffect curvesIsoeffect curves Tolerance dosesTolerance doses

TDTD50/550/5

• Dose that will cause effect in 50% of population in 5 years Dose that will cause effect in 50% of population in 5 years

TDTD5/55/5

• Dose that will cause effect in 5% of population in 5 yearsDose that will cause effect in 5% of population in 5 years

Based on standard fractionation of 10 Gy/week, Based on standard fractionation of 10 Gy/week, 2 Gy/day, and 5 days/week2 Gy/day, and 5 days/week


Time-Dose FractionationTime-Dose Fractionation

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


Factors Affecting Effectiveness Factors Affecting Effectiveness of Fractionationof Fractionation

RedistributionRedistribution Synchronization of surviving cell into resistant Synchronization of surviving cell into resistant

mitotic phasesmitotic phases Normal cells tend to remain in resistant phases, Normal cells tend to remain in resistant phases,

whereas tumor cells enter all phaseswhereas tumor cells enter all phases ReoxygenationReoxygenation

Death of aerobic tumor cells allows hypoxic cells Death of aerobic tumor cells allows hypoxic cells to become more oxygenatedto become more oxygenated

RegenerationRegeneration Occurs between fractions for highly mitotic cellsOccurs between fractions for highly mitotic cells

RepairRepair Cellular repair of sublethal damage (SLD)Cellular repair of sublethal damage (SLD)

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