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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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