Altered Fractionation

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    Altered fractionation

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    Introduction

    Multi-fraction radiotherapy regimens are largely the result of earlyradiobiological studies performed in the 1920-1930s

    Regaud and Ferroux - 1927

    Sterilization of Rams with single dose of RT extensive scrotal skin da

    multiple fractions over an extended period of time no skin damage

    Postulated that testes were tumor-like tissue, while the scrotal skin dose-limiting normal tissue

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    STRANDQUIST PLOT

    33.0TD

    Isoeffect curves total dose plotted as a function of overalltreatment time

    Dose given as 3-5 # per week

    St. lines with a slope of 0.33

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    A

    B

    C

    D

    E

    1 3 7 10 202

    Do

    se

    in

    R

    Time in days

    A - Skin necrosis

    B cure for skin carcinoma

    C moist desquamation

    D dry desquamation

    E skin erythema

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    ELLIS NSD MODELEllis NSD formula

    Time factor was a composite of N (no. of #s) & T (overall treatmtime)

    Fractionation - twice as important as time

    Hence dose is related to time & no. of #s as

    D = (NSD) T0.11

    N0.24

    Where NSD (Nominal Stand. Dose) is proportionality constant fospecific level of skin damage

    Based on skin rxns and does not anyway predict late effects

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    Time factorCompensation of time factor for acute responding tissue by ex

    dose

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    Clinical model of acute vs. late respondintissue

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    Prolonging overall time within the normaradiotherapy range has little sparing effect

    late reactions but a large sparing effect oearly reactions

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    LQ MODEL

    LQ model is derived from cell survival curves.LQ model is based on fundamental mechanism of interaction of radn biological systems.

    Basis of LQ theory is that cell is damaged when both strands odamaged.

    This can be produced either by single ionizing particleOr it can be accomplished by independent interaction by two separparticles

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    S.F. = e-aD

    Single lethal hits

    S.F. = e-(aD+bD2)

    Single lethal hits plusaccumulated damage

    Linear Quadratic ModelCell kill is the result oaccumulated damagsublethal events

    a/b is dose at wsingle lethal lesioaccumulation of s

    i.e. aD = bD2 and D = a/b

    S.F.

    1.0

    0.1

    0.01

    0.001

    DOSE Gy

    a/b in Gy

    aD

    bD2

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    Biologically effective dose is the quantity by which diff. fracti

    regimens are intercompared

    BED = total dose x relative effectiveness

    baad

    ndE 1

    Wheren - no. of #sd - dose/#

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    RADIATION RESPONSE

    Survival curves of early & late responding cells have

    different shapes.For early effects, / is large; dominates at lowdoses- irreparable damage dominates at low doses

    For late effects, / is small, the term has aninfluence at low doses, (repairable damage)

    If fractionation regimen is changed from many smalldoses to few large dose fractions leads to severelate tissue toxicity.

    Late reacting tissues are more sensitive to changesin fractionation pattern than early respondingtissues

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    Fraction size is the dominant factor in determiningeffects; overall treatment time has little influenc

    By contrast, fraction size and overall treatment time

    determine the response of acutely responding tiss

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    RADIOBIOLOGICAL RATIONALFOR FRACTIONATION

    Delivery of tumoricidal dose in small dose fractions in conmultifraction regimen is based on 4Rs of radiobiology name

    Repair of SLD

    Repopulation

    Redistribution

    Reoxygenation

    Radiosensitivity is considered by some authors to be radiobiology.

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    RADIATION DAMAGE CLASSIFICATION

    Radiation damage to mammalian cells are divided incategories:

    Lethal damage :irreversible, irreparable & leads to cell death

    Sub lethal damage : can be repaired in hours unless additionaldamage is added to it

    Potentially lethal damage : can be manipulated by repair whe

    allowed to remain in non-dividing state.

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    REPAIRMost important rationale for fractionation

    Mammalian cells can repair radn damage in b/w dose fractions.

    dose fractionation enable normal tissue to recover b/w #s reducing normal tissue

    Ability of normal tissue to repair radn damage better than tumor for

    fractionation.small dose /# spares late reactions preferentially & a reasonablduration allows regeneration of early reacting tissues.

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    SLD & ITS REPAIRInitial shoulder in cell survival curvereflects ability of cells to accumulateSLD

    Ability of cells to recover from SLDdemonstrated by Elkind & Sutton bysplit dose experiments.

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    RedistributionIncrease in survival during 1st 2hrs in split doseexperiment results from repair of SLD

    If interval b/w doses is 6hrs then resistant cellsmove to sensitive phases

    If interval is more than 6hrs then cells willrepopulate & results in increase of surviving

    fraction.

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    RedistributionRedistribution of proliferating cell populations throughout the increases cell kill in fractionated treatment relative to a single session

    Cells are most sensitive during M & G2 phase & are resistant duringcell cycle .

    Redistribution can be a benefit in fractionated course of RT if cells arsensitive phase after each fraction .

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    RepopulationIn b/w dose fractions normal cells as well as tumor cells repopulate.

    longer a radiotherapy course lasts, more difficult it becomes to contrmay be detrimental

    acutely responding normal tissue need to repopulate during radiotherapy .

    Thus fractionation must be controlled so as not to allow too mucexcessive repopulation of tumor cells at the same time not treating acute tolerance is exceeded

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    ACCELERATED REPOPULATIONTreatment with any cytotoxic agent , including radn , triggers sur(clonogens) in a tumor to divide faster than before

    Dose escalation is needed to overcome this proliferation.

    e.g. it starts in head & neck cancer 4wks after initiation of fractionate

    Implication Treatment should be completed as soon after it is started .

    It is better to delay a treatment than to introduce delay during treatment .

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    ReoxygenationCells at the center of tumor arehypoxic & are resistant to low LETradiation.

    Hypoxic cells get reoxygenated duringa fractionated course of treatment,making them more radiosensitive tosubsequent doses of radiation.

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    ADV. OF FRACTIONATIONAcute effects of single dose of radiation can be decreased

    Pt.s tolerance improves with fractionated RT

    Exploits diff. in recovery rate b/w normal tissues & tumors.

    Radn induced redistribution & sensitization of rapidly proliferating cells.

    Reduction in hypoxic cells leads to

    Reoxygenation

    Opening of compressed blood vessels

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    VARIOUS FRACTIONATION SCHEDULFractionated radiation exploits difference in 4Rs between tumors and normal tissu

    improving therapeutic index

    Types

    Conventional

    Altered

    Hyper fractionation

    Accelerated fractionation Split course

    Hypofractionation

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    Conventional fractionationFraction sizes of 1.8 - 2.2Gy

    1 fraction per day

    5 fractions per week

    Evolved as conventional regimen because it is

    Convenient (no weekend treatment)

    Efficient (treatment every weekday)

    Effective (high doses can be delivered without exceeding either acute or chronic normal ttolerance)

    Allows upkeep of machines.

    Most tried & trusted method

    Both tumoricidal & tolerance doses are well documented

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    NRationale To take maximal adv. of diff. in repair capacity of late reacting normal tissue co

    tumors.

    Radio sensitization through redistribution.

    Pure hyper fractionation

    total dose & over all t/t same as conventional regimen

    in twice as many #s i.e. treating twice daily.

    Impure hyper fractionation

    total dose is increased.

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    HYPERFRACTIONATIONEORTC 22791

    A hyper fractionated schedule of 80.5Gy/70#(1.15Gy twice/day)/7wks compared w70Gy/35#/7wks in head & neck cancer.

    RESULTS

    Increased local tumor control at 5yr from 40 to59%

    Reflected in improved survival

    No increase in side effects

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    EORTC 22791

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    EORTC 22791

    80.5 Gy / 70 # / 1.15Gy / # /twice daily/ 7

    weeks

    5 yr LC - 59%

    No increased lateeffects

    70Gy / 35# / 2 Gy / #

    5 yr LC - 40%

    UNEQUIVOCAL ADVANTAGE OF HYPERFRACTIONATION IN

    OROPHARYNGEAL CANCERS

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    ACCELERATED TREATMENT

    Rationale To reduce repopulation in rapidly proliferating tumors by reducing ovetime.

    Pure accelerated treatment

    same total dose

    half the overall time

    2 or more #s/day

    acute effects become limiting factor.

    Impure accelerated treatment dose is reduced or rest period is interposed in ttreatment.

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    Types of accelerated treatmentType A: drastic reduction of the overall time with substantial decrease

    total dose

    Type B: duration of treatment is more modestly reduced with total dothe same range and there is a break in treatment

    Type C: duration of treatment is more modestly reduced with total dothe same range with a concomitant boost phase

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    CHART Type AMount Vernon Hospital, London

    treatments 6hrs apart

    Total dose of 54Gy can be delivered in 36# over 12 consecutive days

    Including weekends.

    This schedule was chosen to complete treatment before acute rea

    appearing i.e. 2wks

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    Characteristics- Better local tumor control

    Acute reactions are brisk but peak after treatment is com

    Dose/# small hence late effects acceptable

    Several myelopathies occuring at 50 Gy because time

    fractions ( 6 hrs) was too short

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    Split Co rse Accelerated

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    Split-Course AcceleratedFractionation Regimen (Type B)

    Total dose is delivered in two halves with a gap in b/w.

    Purpose of gap is to allow elderly pts. to recover from acute reactions of treatment

    to exclude pts. from further morbidity who have poorly tolerated 1st half or diseaprogressed despite treatment.

    Applied to elderly pts. in radical treatment of Ca bladder, prostate & lu

    Disadv : impaired tumor control due to prolong T/T time that results icell repopulation

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    Concomitant boost ( Type C) Developed at M.D. Anderson cancer centre

    Boost dose to a reduced volume given concomitantly , with t/t of involume

    54Gy in 30 # over 6 wks & boost dose of 1.5 Gy per # in last 12 # with Inter # interval of

    Last 12 # twice daily 1.8 Gy AM and 1.5 Gy PM

    LC 54% vs. 46% in conventional

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    Concomitant boostImproved rate of local control

    Improved overall survival

    Increased rate of early toxicity

    No increased rates of late toxicity

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    Simultaneous Integrated BoostNasopharynx

    Followed in MSKCC

    2.12 Gy x 33 fractions -GTV

    1.8 Gy x 33# - intermediate risk areas

    1.64 Gy x 33# - low risk areas

    Dose painting technique possible with IMRT

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    2.12 Gy

    1.8 Gy

    1.64 Gy

    GTV

    IR-CTV

    LR- CTV

    SIB

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    ARCONAccelerated to overcome repopulation

    Hyperfractionated to spare normal tissues

    Carbogen breathing to overcome chronic hypoxia

    Nicotinamide to overcome acute hypoxia

    Spectacular results in advanced laryngeal cancers

    Results yet to be published

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    HYPOFRACTIONATIONThe delivery of total dose in fewer numbers of fractions than conventional fractiona

    Rationale

    Treatment completed in a shorter period of time.( palliative)

    Machine time well utilized for busy centers.

    Higher dose /# gives better control for larger tumors.

    Higher dose /# also useful for hypoxic fraction of large tumor.

    Disadv.

    Higher potential for late normal tissue complications.

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    Extreme hypofractionationSmall targets treated with high dose conformal radiotherapy

    SBRT - 1 to 5 total radiation treatments using highly conformal dose distributions

    Radiosurgery lower number of highly conformal treatment (usually a single fractio

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    SBRTTakes more resources

    More technique/ equipment dependent

    Takes longer to plan

    High MU per treatment

    Radiobiologic principles may not apply

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    Thank you

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