radiobiology behind dose fractionation

$: Radiobiology behind dose fractionation$
www.rwww.radbioladbiol.ucla.edu.ucla.edu

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The Radiobiology Behind Dose The Radiobiology Behind Dose Fractionation Fractionation

Bill McBrideBill McBrideDept. Radiation OncologyDept. Radiation Oncology

David Geffen School MedicineDavid Geffen School MedicineUCLA, Los Angeles, Ca.UCLA, Los Angeles, Ca.

[email protected]@mednet.ucla.edu


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ObjectivesObjectives• To understand the mathematical bases behind survival curvesTo understand the mathematical bases behind survival curves• Know the linear quadratic model formulationKnow the linear quadratic model formulation• Understand how the isoeffect curves for fractionated radiation Understand how the isoeffect curves for fractionated radiation

vary with tissue and how to use the LQ model to change dose vary with tissue and how to use the LQ model to change dose with dose per fractionwith dose per fraction

• Understand the 4Rs of radiobiology as they relate to clinical Understand the 4Rs of radiobiology as they relate to clinical fractionated regimens and the sources of heterogeneity that fractionated regimens and the sources of heterogeneity that impact the concept of equal effect per fractionimpact the concept of equal effect per fraction

• Know the major clinical trials on altered fractionation and their Know the major clinical trials on altered fractionation and their outcomeoutcome

• Recognize the importance of dose heterogeneity in modern Recognize the importance of dose heterogeneity in modern treatment planningtreatment planning


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Relevance of Radiobiology to Clinical Relevance of Radiobiology to Clinical Fractionation ProtocolsFractionation Protocols

Conventional treatment: Conventional treatment:

Tumors are generally irradiated with 2Gy Tumors are generally irradiated with 2Gy dose per fraction dose per fraction delivered daily delivered daily to a more or less homogeneous field over a 6 week to a more or less homogeneous field over a 6 week time periodtime period to a to a specified specified total dosetotal dose

The purpose of convenntional dose fractionation is to increase dose to the The purpose of convenntional dose fractionation is to increase dose to the tumor while PRESERVING NORMAL TISSUE FUNCTIONtumor while PRESERVING NORMAL TISSUE FUNCTION

• Deviating from conventional fractionation protocol impacts outcomeDeviating from conventional fractionation protocol impacts outcome• How do you know what dose to giveHow do you know what dose to give; for example if you want to change ; for example if you want to change dose per dose per

fraction fraction or or timetime? Radiobiological modeling provide the guidelines. It uses? Radiobiological modeling provide the guidelines. It uses– Radiobiological principles derived from preclinical dataRadiobiological principles derived from preclinical data– Radiobiological parameters derived from clinical altered fractionation protocolsRadiobiological parameters derived from clinical altered fractionation protocols

• hyperfractionation, accelerated fractionation, some hypofractionation scheduleshyperfractionation, accelerated fractionation, some hypofractionation schedules

The number of non-homogeneous treatment plans (IMRT) and extreme hypofractionated The number of non-homogeneous treatment plans (IMRT) and extreme hypofractionated treatments are increasing. Do existing models cope? treatments are increasing. Do existing models cope?


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In theory, knowing relevant radiobiological parameters In theory, knowing relevant radiobiological parameters one day one day may predict the response formay predict the response for• Dose given in a single or a small number of fractions Dose given in a single or a small number of fractions

• SBRT, SRS, SRT, HDR or LDR brachytherapy, protons, SBRT, SRS, SRT, HDR or LDR brachytherapy, protons, cyberknife, gammaknife cyberknife, gammaknife

• Non-uniform dose distributions optimized by IMRT Non-uniform dose distributions optimized by IMRT • e.g. dose e.g. dose ““paintingpainting”” of radioresistant tumor subvolumes of radioresistant tumor subvolumes

• Combination therapies with chemo- or biological agentsCombination therapies with chemo- or biological agents• Different RT options when tailored by molecular and Different RT options when tailored by molecular and

imaging theragnosticsimaging theragnostics• If you know the molecular profile and tumor phenotype, can you If you know the molecular profile and tumor phenotype, can you

predict the best delivery method?predict the best delivery method?

• Biologically optimized treatment planningBiologically optimized treatment planning


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The First Radiation DosimeterThe First Radiation Dosimeter

prompted the use of dose fractionation


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In general, history has shown repeatedly that single high doses of radiation do not allow a therapeutic

differential between tumor and critical normal tissues.

Dose fractionation does.

SBRT/SRS often aims at TISSUE ABLATION


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How to modify a treatment How to modify a treatment scheduleschedule


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Which are fitted by a Poisson DistributionWhich are fitted by a Poisson DistributionP of x = eP of x = e-m-m.m.mxx/x! /x!

where m = mean # hits, x is a hitwhere m = mean # hits, x is a hit

P survival P survival (when x = 0) (when x = 0)

100 targets 100 hits m=1 e100 targets 100 hits m=1 e-1-1=0.368=0.368



Modeling Radiation ResponsesModeling Radiation Responses

N.B. Lethal hits in DNA are not really randomly N.B. Lethal hits in DNA are not really randomly distributed, e.g. condensed chromatin is more distributed, e.g. condensed chromatin is more sensitive, but it is a reasonable approximationsensitive, but it is a reasonable approximation

Assumes that ionizing ‘hits’ are random events in space


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This Gives a Survival Curve Based on a Model This Gives a Survival Curve Based on a Model where one hit will eliminate a single targetwhere one hit will eliminate a single target

• When there is single lethal hit per target When there is single lethal hit per target S.F.= eS.F.= e-1-1 = 0.37 = 0.37

• This is the mean lethal dose DThis is the mean lethal dose D0 0

• DD1010 = 2.3 xD = 2.3 xD00

• In general, S.F. = eIn general, S.F. = e-D/D-D/D00

or LnS.F. = -D/Dor LnS.F. = -D/D00

or S.F. = eor S.F. = e--D D , i.e. D, i.e. D0 0 = 1/= 1/

Where is the slope of the curve and D0 the reciprocal of the slope

DOSE GyDOSE Gy

1.01.0

0.10.1

0.010.01

0.0010.001 DD00

S.F.S.F.

DD1010

0.37

How many logs of cells would be killed How many logs of cells would be killed by 23 Gy if Dby 23 Gy if D0 0 = 1 Gy?= 1 Gy?


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Mean Inactivation Dose (Do)Mean Inactivation Dose (Do)

• Virus D0 approx. = 1500 Gy• E. Coli D0 approx. = 100 Gy• Mammalian bone marrow cells D0 = 1 Gy• Generally, for mammalian cells D0 = 1-1.5 Gy

Why the differences?


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Puck and Marcus, J.E.M.103, 563, 1956First in vitro mammalian survival curve

1.01.0

0.10.1

0.010.01

0.0010.001

Accumulation ofAccumulation ofsub-lethal sub-lethal damagedamage

single single lethal lethal

hitshits

nn

dosedose

Two component modelTwo component model

Eukaryotic Survival Curves are Exponential, but have a ‘Shoulder’


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DOSE Gy

11DD0 0 = = reciprocal reciprocal initial slopeinitial slope

nnDD00 = = reciprocal reciprocal final slopefinal slope

S.F.

Two Component ModelTwo Component Model

• Two Component Model (or single target, single hit + multi-target (n), single hit)

• S.F.=e-D/1D0[1-(1-e-D/nD0)n]

Single hitSingle hit Accumulated Accumulated damagedamage

1.0

0.1

0.01

0.001

Accumulation of sublethal

damage

single lethal hits

n

ExtrapolationExtrapolationNumberNumber


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242420201616121288440000

.01.01

.1.1

11

Dose (Gy)Dose (Gy)

S.F.S.F.

Single doseSingle dose

limiting slope/limiting slope/low dose ratelow dose rate

3 fractions3 fractions

5 fractions5 fractions

Multi-fraction survival curves can be Multi-fraction survival curves can be considered linear if sublethal damage is considered linear if sublethal damage is repaired between fractions repaired between fractions they have an extrapolation number (n) = 1.0they have an extrapolation number (n) = 1.0

•The resultant slope is the effective DThe resultant slope is the effective D00

•eD0 is often 2.5 - 5.0Gy and eD10 5.8 - 11.5Gy

•S.F. = eS.F. = e-D/-D/eeDD00

•If S.F. after 2Gy = 0.5, eD0 = 2.9Gy; eD10 = 6.7Gy and 30 fractions of 2 Gy (60Gy) would reduce survival by (0.5)30 = almost 9 logs (or 60/6.7)•If a 1cm tumor had 109 clonogenic cells, there would be an average of 1 clonogen per tumor and cure rate would be about 37%


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S.F. = eS.F. = e--DD

Single lethal hitsSingle lethal hits

S.F. = eS.F. = e-(-(D+D+DD22))

Single lethal hits plus Single lethal hits plus accumulated damageaccumulated damage

• Cell kill is the result of single lethal hits Cell kill is the result of single lethal hits plus accumulated damage from 2 plus accumulated damage from 2 independent sublethal eventsindependent sublethal events

• The generalized formula is E = D + D2

• For a fractionated regimen E= nd( + d) = D ( + d) Where d = dose per fraction and D = total dose

// is dose at which death due to single lethal is dose at which death due to single lethal lesions = death due to accumulation of sublethal lesions = death due to accumulation of sublethal lesions i.e.lesions i.e.D = D = DD22 and D = and D = // in Gy in Gy

S.F.

1.0

0.1

0.01

0.001

DOSE Gy

in Gyin Gy

DD

DD22

Linear Quadratic ModelLinear Quadratic Model


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• Over 90% of radiation oncologists use the LQ model:Over 90% of radiation oncologists use the LQ model:– it is simple and has a microdosimetric underpinning / is large (> 6 Gy) when survival curve is almost

exponential and small (1-4 Gy) when shoulder is wide– the value quantifies the sensitivity of a

tissue/tumor to fractionated radiation.• But:But:

– Both and vary with the cell cycle. At high doses, S phase and hypoxic cells become more important.

– The / ratio varies depending upon whether a cell is quiescent or proliferative

– The LQ model best describes data in the range of 1 - 6Gy and should not be used outside this range


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Thames et al Int J Radiat Oncol Biol Phys 8: 219, 1982.Thames et al Int J Radiat Oncol Biol Phys 8: 219, 1982.

•The slope of an isoeffect curve changes The slope of an isoeffect curve changes with size of dose per fraction depending on with size of dose per fraction depending on tissue type• Acute responding tissues have Acute responding tissues have flatterflatter curves than do late responding tissuescurves than do late responding tissues• measures the sensitivity of tumor or tissue to fractionation i.e. it predicts how total i.e. it predicts how total dose for a given effect will change when you dose for a given effect will change when you change the size of dose fractionchange the size of dose fraction

Reciprocaltotal dose

for an isoeffect

Dose per fraction

Intercept =

Slope =

Douglas and Fowler Rad Res 66:401, 1976

Showed and easy way to arrive at an ratio


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Response to Fractionation Varies With Response to Fractionation Varies With TissueTissue

16128400

.01

.1

1

Dose (Gy)

S.F.

Late RespondingLate RespondingTissues - Tissues - = 2Gy= 2Gy

AcuAcute Respondingte RespondingTissues Tissues = 10Gy= 10Gy

// is high (>6Gy) when survival is high (>6Gy) when survival curve is almost exponential and low curve is almost exponential and low (1-4Gy) when shoulder is wide(1-4Gy) when shoulder is wide

2016128400.01

.1

1

Dose (Gy)

S.F.

Single DoseSingle DoseLate EffectsLate Effects= 2Gy= 2Gy

Single DoseSingle DoseAcute EffectsAcute Effects= 10Gy= 10Gy

FractionatedFractionatedLate EffectsLate Effects

FractionatedFractionatedAcute EffectsAcute Effects

Fractionation spares late responding tissues


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Sensitivity of Tissue to Dose Sensitivity of Tissue to Dose Fractionation can be estimated by Fractionation can be estimated by

the the ratio ratio


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What are What are ratios for human ratios for human cancers? cancers?

In fact, for some tumors e.g. prostate, breast, melanoma, soft tissue sarcoma, In fact, for some tumors e.g. prostate, breast, melanoma, soft tissue sarcoma, and liposarcoma and liposarcoma ratios may be moderately low ratios may be moderately low

ProstateProstate

– Brenner and Hall IJROBP 43:1095, 1999 Brenner and Hall IJROBP 43:1095, 1999 • comparing implants with EBRTcomparing implants with EBRT ratio is 1.5 Gy [0.8, 2.2]ratio is 1.5 Gy [0.8, 2.2]

– Lukka JCO 23: 6132, 2005 Lukka JCO 23: 6132, 2005 • Phase III NCIC 66Gy 33F in 45days vs 52.5Gy 20F in 28 daysPhase III NCIC 66Gy 33F in 45days vs 52.5Gy 20F in 28 days• Compatible with Compatible with ratio of 1.12Gy (-3.3-5.6) ratio of 1.12Gy (-3.3-5.6)

BreastBreast– Owen, J.R., et al. Lancet Oncol, 7: 467-471, 2006 and Dewar et al JCO, ASCO Owen, J.R., et al. Lancet Oncol, 7: 467-471, 2006 and Dewar et al JCO, ASCO

Proceedings Part I. Vol 25, No. 18S: LBA518, 2007.Proceedings Part I. Vol 25, No. 18S: LBA518, 2007. • UK START Trial UK START Trial

– 50Gy in 25Fx c.w. 39Gy in 13Fx; or 41.6Gy in 13Fx [or 40Gy in 15Fx (3 wks)]50Gy in 25Fx c.w. 39Gy in 13Fx; or 41.6Gy in 13Fx [or 40Gy in 15Fx (3 wks)]

• Breast Cancer Breast Cancer = 4.0Gy (1.0-7.8) = 4.0Gy (1.0-7.8)• Breast appearance Breast appearance = 3.6Gy; induration = 3.6Gy; induration = 3.1Gy = 3.1Gy

If fractionation sensitivity of a cancer is similar to dose-limiting healthy If fractionation sensitivity of a cancer is similar to dose-limiting healthy tissues, it may be possible to give fewer, larger fractions without tissues, it may be possible to give fewer, larger fractions without

compromising effectiveness or safetycompromising effectiveness or safety


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What total dose (D) to give if the What total dose (D) to give if the dose/fx (d) is changeddose/fx (d) is changed

NewNew OldOldDDnewnew (d (dnewnew + + ) = D) = Doldold (d (doldold + +))

So, for late responding tissue, what total dose in 1.5Gy So, for late responding tissue, what total dose in 1.5Gy fractions is equivalent to 66Gy in 2Gy fractions?fractions is equivalent to 66Gy in 2Gy fractions?

DDnewnew (1.5+2) = 66 (2 + 2) (1.5+2) = 66 (2 + 2)

DDnewnew = 75.4Gy = 75.4Gy

NB: Small differences in for late responding tissues can make a big difference in estimated D!


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Biologically Effective Dose (BED)Biologically Effective Dose (BED)

Biologically Biologically Effective DoseEffective Dose Total doseTotal dose

RelativeRelativeEffectivenessEffectiveness

S.F. = eS.F. = e-E -E = e= e-(-(D+D+DD22))

E = nd(E = nd( + + d)d)

E/E/ = nd(1+d/ = nd(1+d/))

35 x 2Gy = B.E.D.of 84Gy35 x 2Gy = B.E.D.of 84Gy1010 and 117Gy and 117Gy33

NOTE: 3 x 15Gy = B.E.D.of 113GyNOTE: 3 x 15Gy = B.E.D.of 113Gy1010 and 270Gy and 270Gy33 Normalized total doseNormalized total dose2Gy2Gy

= BED/RE= BED/RE

= BED/1.2 for = BED/1.2 for of 10Gy of 10Gy

= BED/1.67 for = BED/1.67 for of 3Gyof 3Gy

Equivalent to 162 Gy in 2Gy Fx Equivalent to 162 Gy in 2Gy Fx -unrealistic!-unrealistic!(Fowler et al IJROBP 60: 1241, 2004)(Fowler et al IJROBP 60: 1241, 2004)


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80807070606050504040303020202020

3030

4040

5050

6060

7070

8080

=30Gy; 4Gy/fx=30Gy; 4Gy/fx

=3Gy; 4Gy/fx=3Gy; 4Gy/fx

=3Gy; 1.5Gy/fx=3Gy; 1.5Gy/fx=30Gy; 1.5Gy/fx=30Gy; 1.5Gy/fx

2.0Gy/fx2.0Gy/fx

D oldD old

D newD new

Note how badly late responding tissues respond to increased dose/fraction


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Prescribed Dose:25 fractions of 2Gy = 50GyHot spot: 110%Physical dose: 55GyBiological dose: 60.5Gy

Does this Matter?

““Double Double TroubleTrouble””


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The Linear Quadratic FormulationThe Linear Quadratic Formulation

• Does not work well at high dose/fxDoes not work well at high dose/fx

• Assumes equal effect per fractionAssumes equal effect per fraction


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N.B. Survival curves may N.B. Survival curves may deviate from L.Q. at low and deviate from L.Q. at low and high dose!!!!high dose!!!!

• Certain cell lines, and tissues, are Certain cell lines, and tissues, are hypersensitive at low doses of 0.05-hypersensitive at low doses of 0.05-0.2Gy. 0.2Gy.

• The survival curve then plateaus over The survival curve then plateaus over 0.05-1Gy0.05-1Gy

• Not seen for all cell lines or tissues, but Not seen for all cell lines or tissues, but has been reported in skin, kidney and has been reported in skin, kidney and lunglung

• At high dose, the model probably does not At high dose, the model probably does not fit data well because Dfit data well because D22 dominates the dominates the equationequation

HT29 cells

Lambin et al. Int J Radiat Biol 63:639 1993


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The Linear Quadratic FormulationThe Linear Quadratic Formulation

• Does not work well at low or high dose/fxDoes not work well at low or high dose/fx

• Assumes equal effect per fractionAssumes equal effect per fraction


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RedistributionRedistribution

RepairRepair

RepopulationRepopulation

700R 1500R

4Rs OF DOSE FRACTIONATION4Rs OF DOSE FRACTIONATION

• Assessed by varying the Assessed by varying the time between 2 or more time between 2 or more doses of radiationdoses of radiation


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4Rs OF DOSE FRACTIONATION4Rs OF DOSE FRACTIONATION

These are radiobiological mechanisms that impact the These are radiobiological mechanisms that impact the response to a fractionated course of radiation therapyresponse to a fractionated course of radiation therapy

• Repair of sublethal damageRepair of sublethal damage– spares late responding normal tissue preferentially spares late responding normal tissue preferentially

• Redistribution of cells in the cell cycleRedistribution of cells in the cell cycle– increases acute and tumor damage, no effect on late responding increases acute and tumor damage, no effect on late responding

normal tissue normal tissue

• RepopulationRepopulation– spares acute responding normal tissue, no effect on late effects,spares acute responding normal tissue, no effect on late effects,

– danger of tumor repopulation danger of tumor repopulation

• ReoxygenationReoxygenation– increases tumor damage, no effect in normal tissuesincreases tumor damage, no effect in normal tissues


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RepairRepair

• ““RepairRepair”” between fractions should be complete - N.B. we are between fractions should be complete - N.B. we are dealing with tissue recovery rather than DNA repairdealing with tissue recovery rather than DNA repair– Correction for incomplete repair is possible (Thames)Correction for incomplete repair is possible (Thames)

• In general, time between fractions for most tissues should be >6 In general, time between fractions for most tissues should be >6 hourshours

• Some tissues, such as CNS, recover slowly making b.i.d. Some tissues, such as CNS, recover slowly making b.i.d. treatment inadvisabletreatment inadvisable

• Bentzen - Radiother Oncol 53, 219, 1999 Bentzen - Radiother Oncol 53, 219, 1999 – CHART analysis HNC showed that late morbidity was less than CHART analysis HNC showed that late morbidity was less than

would be expected assuming complete recovery between would be expected assuming complete recovery between fractionsfractions

– Is the T1/2 for recovery for late responding normal tissues 2.5-Is the T1/2 for recovery for late responding normal tissues 2.5-4.5hrs? 4.5hrs?


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Regeneration in Normal TissuesRegeneration in Normal Tissues

• The lag time to regeneration varies with the tissue The lag time to regeneration varies with the tissue • In acute responding tissues,In acute responding tissues,

– Regeneration has a considerable sparing effectRegeneration has a considerable sparing effect

• In human mucosa, regeneration starts 10-12 days into a 2Gy Fx In human mucosa, regeneration starts 10-12 days into a 2Gy Fx protocol and increases tissue tolerance by at least 1Gy/dyprotocol and increases tissue tolerance by at least 1Gy/dy

– Prolonging treatment time has a sparing effect Prolonging treatment time has a sparing effect

– As treatment time is reduced, acute responding tissues become As treatment time is reduced, acute responding tissues become dose-limitingdose-limiting

• In late responding tissues,In late responding tissues, – Prolonging overall treatment time beyond 6wks has little effect, butProlonging overall treatment time beyond 6wks has little effect, but

prolonging time to retreatment may increase tissue toleranceprolonging time to retreatment may increase tissue tolerance


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Human SCC head and neckHuman SCC head and neck

4 weeks to start of accelerated repopulation. 4 weeks to start of accelerated repopulation. Thereafter T1/2 of 4 days = loss of 0.6Gy per dayThereafter T1/2 of 4 days = loss of 0.6Gy per day

Withers, H.R., Taylor, J.M.G., and Maciejewski, B.

Acta Oncologica 27:131, 1988

TotalTotalDoseDose

(2 Gy equiv.)(2 Gy equiv.)

Treatment DurationTreatment Duration

local controllocal control

no local controlno local control

7070

5555

4040

T2 T3T2 T3

Repopulation in Tumor TissueRepopulation in Tumor Tissue

Hermens and Barendsen, EJC 5:173, 1969

Treatment breaks are often “bad”

Rat rhabdosarcomaRat rhabdosarcoma


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Other Sources of HeterogeneityOther Sources of Heterogeneity

• Biological DoseBiological Dose– Cell cycleCell cycle– Hypoxia/reoxygenation Hypoxia/reoxygenation

– Clonogenic Clonogenic ““stem cellsstem cells”” (G.F.) (G.F.) • NumberNumber• Intrinsic radiosensitivityIntrinsic radiosensitivity• Proliferative potentialProliferative potential• Differentiation statusDifferentiation status

• Physical DosePhysical Dose– Need to know more about the importance of dose-volume constraintsNeed to know more about the importance of dose-volume constraints

Dose

oxic

hypoxicS.F

Phillips, J Natl Cancer Inst 98:1777, 2006


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• Heterogeneity within and between between tumors in dose-response characteristics, often resulting in large error bars for values

• In spite of this, the outcome of clinical studies of altered fractionation generally fit the models, within the constraints of the clinical doses used


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Altered FractionationAltered Fractionation

oror

How to optimally distribute dose How to optimally distribute dose over timeover time


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PlayersPlayers

• Total dose (D)Total dose (D)• Dose per fraction (d)Dose per fraction (d)• Interval between fractions (t)Interval between fractions (t)• Overall treatment time (T)Overall treatment time (T)• Tumor typeTumor type• Acute reacting normal tissuesAcute reacting normal tissues• Late reacting normal tissuesLate reacting normal tissues


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DefinitionsDefinitions

• Conventional fractionationConventional fractionation– Daily doses (d) of 1.8 to 2 GyDaily doses (d) of 1.8 to 2 Gy– Dose per week of 9 to 10 GyDose per week of 9 to 10 Gy– Total dose (D) of 40 to 70 GyTotal dose (D) of 40 to 70 Gy

• HyperfractionationHyperfractionation– The number of fractions (N) is increasedThe number of fractions (N) is increased– T is kept the sameT is kept the same– Dose per fraction (d) less than 1.8 GyDose per fraction (d) less than 1.8 Gy– Two fractions per day (t)Two fractions per day (t)

Rationale:Rationale: Spares late responding tissuesSpares late responding tissues


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DefinitionsDefinitions• Accelerated fractionationAccelerated fractionation

– Shorter overall treatment timeShorter overall treatment time

– Dose per fraction of 1.8 to 2 GyDose per fraction of 1.8 to 2 Gy

– More than 10 Gy per weekMore than 10 Gy per week

Rationale:Rationale: Overcome accelerated tumor repopulationOvercome accelerated tumor repopulation

• HypofractionationHypofractionation– Dose per fraction (d) higher than 2.2 GyDose per fraction (d) higher than 2.2 Gy

– Reduced total number of fractions (N)Reduced total number of fractions (N)

Rationale: Tumor has low Rationale: Tumor has low ratio and there is no therapeutic ratio and there is no therapeutic advantage to be gained with respect to late complicationsadvantage to be gained with respect to late complications


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TCPor NTC

Dose

HyperfractionationAcceleratedFractionation

Tumor controlLate responding tissuecomplications

Complication-free cure

TCPor NTC


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Conventional

70 Gy - 35 fx - 7 wks

Very acceleratedwith reduction of dose

54 Gy - 36 fx - 12 days

Moderately accelerated

72 Gy - 42 fx - 6 wks

Hyperfractionated81.6 Gy - 68 fx - 7 wks


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HyperfractionatedHyperfractionatedBarcelona (586), Brazil (112), RTOG 90-03 (1113), EORTC 22791 (356), Barcelona (586), Brazil (112), RTOG 90-03 (1113), EORTC 22791 (356),

Toronto (331)Toronto (331)

Very acceleratedVery acceleratedCHART (918), Vancouver (82), TROG 91-01 (350),GORTEC 94-02 (268)CHART (918), Vancouver (82), TROG 91-01 (350),GORTEC 94-02 (268)

Moderately acceleratedModerately acceleratedRTOG 90-03 (1113), DAHANCA (1485), EORTC 22851 (512) CAIR (100), RTOG 90-03 (1113), DAHANCA (1485), EORTC 22851 (512) CAIR (100),

Warsaw (395)Warsaw (395)

OtherOther EORTC 22811 (348), RTOG 79-13 (210)EORTC 22811 (348), RTOG 79-13 (210)

7623 patients in 18 randomized phase III trials !! 7623 patients in 18 randomized phase III trials !!

HNSCC only will be discussedHNSCC only will be discussed


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Oropharyngeal Ca T2-3, N0-1Oropharyngeal Ca T2-3, N0-1

YearsYears

LOCAL CONTROL LOCAL CONTROL SURVIVAL SURVIVAL

YearsYears

Horiot 1992Horiot 1992

80.5 Gy - 70 fx - 7 wks80.5 Gy - 70 fx - 7 wks control: 70 Gy - 35-40 fx - 7-8 wks control: 70 Gy - 35-40 fx - 7-8 wks

pp = 0.02 = 0.02 pp = 0.08 = 0.08

EORTC hyperfractionation trial in EORTC hyperfractionation trial in oropharynx cancer (N = 356)oropharynx cancer (N = 356)


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Loco-regional controlLoco-regional control SurvivalSurvival

conventionalconventionalCHARTCHART

conventionalconventionalCHARTCHART

54 Gy - 36 fx - 12 days control: 66 Gy - 33 fx - 6.5 wks54 Gy - 36 fx - 12 days control: 66 Gy - 33 fx - 6.5 wks

Dische 1997Dische 1997

Favourable outcome with CHART:Favourable outcome with CHART: well differentiated tumors well differentiated tumors larynx carcinomaslarynx carcinomas

Very Accelerated: CHART (N = 918)Very Accelerated: CHART (N = 918)


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54 Gy - 36 fx - 12 days control: 66 Gy - 33 fx - 6.5 wks54 Gy - 36 fx - 12 days control: 66 Gy - 33 fx - 6.5 wks

CHART: MorbidityCHART: MorbidityDische 1997

Moderate/severe subcutaneousModerate/severe subcutaneousfibrosis and oedemafibrosis and oedema

PP = 0.04 = 0.04

Moderate/severe dysphagiaModerate/severe dysphagia

PP = 0.04 = 0.04

Mucosal ulceration andMucosal ulceration anddeep necrosisdeep necrosis

PP = 0.003 = 0.003

Laryngeal oedemaLaryngeal oedema

PP = 0.009 = 0.009


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DAHANCA 6: only glottic, (N = 694)DAHANCA 6: only glottic, (N = 694)DAHANCA 7: all other sites, + nimorazole (N = 791)DAHANCA 7: all other sites, + nimorazole (N = 791)

Overgaard 2000Overgaard 2000

66-68 Gy - 33-34 fx - 6 wks control: 66-68 Gy - 33-34 fx - 7 wks66-68 Gy - 33-34 fx - 6 wks control: 66-68 Gy - 33-34 fx - 7 wks

Actuarial 5-year ratesActuarial 5-year ratesLocal controlLocal control

DAHANCA 6DAHANCA 6DAHANCA 7DAHANCA 7

Nodal controlNodal controlDAHANCA 6 + 7DAHANCA 6 + 7 ..

Disease-specific survivalDisease-specific survival DAHANCA 6 + 7 DAHANCA 6 + 7

Overall survivalOverall survivalLate effectsLate effects (edema, fibrosis) (edema, fibrosis)

Moderately AcceleratedModerately Accelerated

5 fx/wk5 fx/wk 6 fx/wk6 fx/wk

73%73% 81% p=0.0481% p=0.0456%56% 68% p=0.00968% p=0.009

87%87% 89% n.s.89% n.s.

65%65% 72% p=0.0472% p=0.04

n.s.n.s.n.s.n.s.


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Skladowski 2000

OVERALL SURVIVAL

CONTROL

CAIR

log-rank p=0.00001

Follow-up (months)

Pro

ba

bil

ity

66-72 Gy - 33-36 fx - 5 wks control: 70-72 Gy - 35-36 fx - 7 wks66-72 Gy - 33-36 fx - 5 wks control: 70-72 Gy - 35-36 fx - 7 wks68.4-72 Gy - 38-40 fx - 5.5 wks control: 66.6-72 Gy - 37-40 fx - 7.5-8 wks68.4-72 Gy - 38-40 fx - 5.5 wks control: 66.6-72 Gy - 37-40 fx - 7.5-8 wks

CAIR: 7-day-continuous accelerated irradiation (N = 100)CAIR: 7-day-continuous accelerated irradiation (N = 100)

Moderately AcceleratedModerately Accelerated


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ConventionalConventional

Accelerated with splitAccelerated with split

70 Gy - 35 fx - 7 wks70 Gy - 35 fx - 7 wks

67.2 Gy - 42 fx - 6 weeks (including 2-week split)67.2 Gy - 42 fx - 6 weeks (including 2-week split)

72 Gy - 42 fx - 6 wks72 Gy - 42 fx - 6 wks

HyperfractionatedHyperfractionated

81.6 Gy - 68 fx - 7 wks81.6 Gy - 68 fx - 7 wks

Accelerated withAccelerated withConcomitant boostConcomitant boost

Fu 2000Fu 2000

RTOG 90-03, Phase III comparison of fractionation RTOG 90-03, Phase III comparison of fractionation schedules in Stage III and IV SCC of oral cavity, schedules in Stage III and IV SCC of oral cavity, oropharynx, larynx, hypopharynx (N = 1113)oropharynx, larynx, hypopharynx (N = 1113)


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RTOG 90-03,RTOG 90-03, loco-regional controlloco-regional controlFu 2000


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RTOG 90-03, RTOG 90-03, survivalsurvivalFu 2000


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RTOG 90-03, adverse effects

Maximum toxicity Conventional Hyperfract Concom Acc +per patient boost split

Grade 1 15% 4% 4% 7%Grade 2 57% 39% 36% 41%Grade 3 35% 54% 58% 49%Grade 4 0% 1% 1% 2%

Fu 2000

Acute

Maximum toxicity Conventional Hyperfract Concom Acc +per patient boost splitGrade 1 11% 8% 7% 16%Grade 2 50% 56% 44% 50%Grade 3 19% 19% 29% 20%Grade 4 8% 9% 8% 7%Grade 5 1% 0% 1% 1%

Late


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Acute effects in accelerated or hyperfractionated RT

Author Regimen Grade 3-4 mucositis

ContCont ExpExpHoriot (n=356)Horiot (n=356) HFHF 49%49% 67%67%Horiot (n=512) Acc fx + splitHoriot (n=512) Acc fx + split 50%50% 67%67%Dische (n=918)Dische (n=918) CHARTCHART 43%43% 73%73%Fu (n=536)Fu (n=536) Acc fx(CB) Acc fx(CB) 25%25% 46%46%Fu (n=542)Fu (n=542) Acc fx + split Acc fx + split 25%25% 41%41%Fu (n=507)Fu (n=507) HFHF 25%25% 42%42%Skladowski (n=99) Skladowski (n=99) Acc fx Acc fx 26%26% 56%56%

Toxicity of RT in HNSCCToxicity of RT in HNSCC


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Altered fractionation in head and Altered fractionation in head and neck cancer: meta-analysisneck cancer: meta-analysis

Bourhis, Lancet 2006Randomized trials 1970-1998 (no postop RT)Randomized trials 1970-1998 (no postop RT)15 trials included (6515 patients)15 trials included (6515 patients)

Survival benefit: 3.4% (36% 39% at 5 years, Survival benefit: 3.4% (36% 39% at 5 years, pp = 0.003) = 0.003)Loco-regional control benefit: 7% (46.5% 53% at 5 years, Loco-regional control benefit: 7% (46.5% 53% at 5 years, pp < 0.0001) < 0.0001)


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Conclusions for HNSCCConclusions for HNSCC

• Hyperfractionation increases TCP and protects late responding tissues• Accelerated treatment increase TCP but also increases acute toxicity• What should be considered standard for patients treated with radiation

only?– Hyperfractionated radiotherapy– Concomitant boost accelerated radiotherapy

• Fractions of 1.8 Gy once daily when given alone, cannot be considered as an acceptable standard of care

• TCP curves for SSC are frustratingly shallow … selection of tumors?


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Conclusions for HNSCCConclusions for HNSCC• The benefit derived from altered fractionation is consistent The benefit derived from altered fractionation is consistent

with can be of benefit but should be used with carewith can be of benefit but should be used with care• In principle, tumors should be treated for an overall In principle, tumors should be treated for an overall

treatment time that is as short as possible consistent with treatment time that is as short as possible consistent with acceptable acute morbidity, but with a dose per fraction acceptable acute morbidity, but with a dose per fraction that does not compromise late responding normal tissues, that does not compromise late responding normal tissues, or total dose.or total dose.

• Avoid treatment breaks and treatment prolongation Avoid treatment breaks and treatment prolongation wherever possible wherever possible –– and consider playing “catch-up” if and consider playing “catch-up” if there are anythere are any

• Start treatment on a Monday and finish on a Friday, and Start treatment on a Monday and finish on a Friday, and consider working Saturdaysconsider working Saturdays

• Never change a winning horse!Never change a winning horse!


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Other Major ConsiderationsOther Major Considerations• Not all tumors will respond to hyper or accelerated Not all tumors will respond to hyper or accelerated

fractionation like HNSCC, especially if they have a low fractionation like HNSCC, especially if they have a low ratio.ratio.

• High single doses or a small number of high dose per High single doses or a small number of high dose per fractions, as are commonly used in SBRT or SRS generally fractions, as are commonly used in SBRT or SRS generally aim at tissue ablation. Extrapolating based on a linear aim at tissue ablation. Extrapolating based on a linear quadratic equation to total dose is fraught with danger.quadratic equation to total dose is fraught with danger.

• Addition of chemotherapy or biological therapies to RT Addition of chemotherapy or biological therapies to RT always requires caution and preferably thoughtful pre-always requires caution and preferably thoughtful pre-consideration!!!consideration!!!

• Don’t be scared to get away from the homogeneous field Don’t be scared to get away from the homogeneous field concept, but plan it if you intend to do so.concept, but plan it if you intend to do so.


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Questions:Questions: The Radiobiology Behind Dose FractionationThe Radiobiology Behind Dose Fractionation


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Modeling of radiation responses are based Modeling of radiation responses are based on on

1.1. Random events occurring in cell nucleiRandom events occurring in cell nuclei

2.2. Random events in space as defined by Random events in space as defined by the Poisson distributionthe Poisson distribution

3.3. A Gaussian distributionA Gaussian distribution

4.4. Logarithmic dose response curvesLogarithmic dose response curves


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D0 isD0 is

1.1. Is a measure of the shoulder of a survival Is a measure of the shoulder of a survival curvecurve

2.2. Is the mean lethal dose of the linear Is the mean lethal dose of the linear portion of the dose-response curveportion of the dose-response curve

3.3. Represents the slope of the log linear Represents the slope of the log linear survival curvesurvival curve

4.4. Is constant at all levels of radiation effect Is constant at all levels of radiation effect


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Dq isDq is1.1. A measure of the inverse of the terminal A measure of the inverse of the terminal

slope of the survival curveslope of the survival curve2.2. A measure of the inverse of the initial A measure of the inverse of the initial

slope of the survival curveslope of the survival curve3.3. A measure of the shoulder of the survival A measure of the shoulder of the survival

curvecurve4.4. A measure of the intercept of the terminal A measure of the intercept of the terminal

portion of the survival curve on the y axisportion of the survival curve on the y axis


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If Dq for a survival curve is 2Gy, what dose If Dq for a survival curve is 2Gy, what dose is equivalent to a single dose of 6Gy given in is equivalent to a single dose of 6Gy given in 2 fractions, assuming complete repair and 2 fractions, assuming complete repair and no repopulation between fractions.no repopulation between fractions.

1.1. 4 Gy4 Gy

2.2. 6 Gy6 Gy

3.3. 8 Gy8 Gy

4.4. 10 Gy 10 Gy


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A whole body dose of 7 Gy of x‑rays would produce severe, potentially lethal hematologic toxicity. Assuming that the Do of the hematopoietic stem cells is 1 Gy and that these cells have a negligible capacity to repair sublethal radiation damage, what is the surviving fraction of these stem cells after this dose of radiation?

1. 0.00012. 0.0013. 0.0254. 0.0675. 0.1167


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If 90% of a tumor is removed by surgery, If 90% of a tumor is removed by surgery, what does this likely represent in term of what does this likely represent in term of radiation dose given in 2 Gy fractions?radiation dose given in 2 Gy fractions?1.1. 1-2 Gy1-2 Gy2.2. 3-4 Gy3-4 Gy3.3. 6-7 Gy6-7 Gy4.4. 9-12 Gy9-12 Gy5.5. 20-30 Gy20-30 Gy


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What is true for the What is true for the ratio ratio1.1. It is unitlessIt is unitless2.2. It is a measure of the shoulder of the It is a measure of the shoulder of the

survival curvesurvival curve3.3. It measures the sensitivity of a tissue to It measures the sensitivity of a tissue to

changes in size of dose fractionschanges in size of dose fractions4.4. It is the ratio where the number of non-It is the ratio where the number of non-

repairable lesions equals that for repairable lesions equals that for repairable lesionsrepairable lesions


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The alpha component in the linear quadratic The alpha component in the linear quadratic formula for as radiation survival curve formula for as radiation survival curve representsrepresents1.1. Unrepairable DNA double strand breaksUnrepairable DNA double strand breaks2.2. Lethal single track eventsLethal single track events3.3. Multiply damaged sites in DNAMultiply damaged sites in DNA4.4. Damage that can not be altered by Damage that can not be altered by

hypoxiahypoxia


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Which parameter is most relevant for Which parameter is most relevant for standard clinical regimens in RTstandard clinical regimens in RT

1.1. The The ratio ratio

2.2. DoDo

3.3. AlphaAlpha

4.4. BetaBeta

5.5. The extrapolation numberThe extrapolation number


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If cells have a Do of 2 Gy, assuming no shoulder, what dose is required to kill 95% of the cells?1. 6 Gy2. 12 Gy3. 18 Gy4. 24 Gy5. 30 Gy


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The extrapolation number N for a multi-The extrapolation number N for a multi-fraction survival curve, allowing complete fraction survival curve, allowing complete repair between fractions and no repopulation repair between fractions and no repopulation isis1.1. 112.2. < 1< 13.3. >1>14.4. Dependent on the size of the dose per Dependent on the size of the dose per

fraction fraction


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The extrapolation number N for a single The extrapolation number N for a single dose neutron survival curve isdose neutron survival curve is

1.1. 11

2.2. < 1< 1

3.3. >1>1

4.4. Dependent on the size of the dose per Dependent on the size of the dose per fraction fraction


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The extrapolation number N for a low dose The extrapolation number N for a low dose rate survival curve israte survival curve is

1.1. 11

2.2. < 1< 1

3.3. >1>1

4.4. Dependent on the size of the dose per Dependent on the size of the dose per fraction fraction


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The inverse of the slope of a multifraction The inverse of the slope of a multifraction survival curve (survival curve (effeffDo) is generally within the Do) is generally within the

rangerange

1.1. 1.0-1.5 Gy1.0-1.5 Gy

2.2. 1.5-2.5 Gy1.5-2.5 Gy

3.3. 2.5-5.0 Gy2.5-5.0 Gy

4.4. 5.0-10.0 Gy5.0-10.0 Gy


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If the If the effeffDo for a multifraction survival curve is Do for a multifraction survival curve is

3.5 Gy, what dose would cure 37% of a 3.5 Gy, what dose would cure 37% of a series of 1cm diameter tumors (10series of 1cm diameter tumors (1099 clonogens).clonogens).

1.1. 56 Gy56 Gy

2.2. 64 Gy64 Gy

3.3. 72 Gy72 Gy

4.4. 80 Gy 80 Gy


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If the If the effeffDo for a multifraction survival curve is Do for a multifraction survival curve is

3.5 Gy, what dose would cure 69% of a 3.5 Gy, what dose would cure 69% of a series of 1cm diameter tumors (10series of 1cm diameter tumors (1099 clonogens).clonogens).

1.1. 56 Gy56 Gy

2.2. 64 Gy64 Gy

3.3. 72 Gy72 Gy

4.4. 80 Gy 80 Gy


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If a tumor has an effective Do of 3.5 Gy,what is the S.F. after 70 Gy?1. 2 x 10-11

2. 2 x 10-9

3. 2 x 10-7

4. 2 x 10-5

5. 2 x 10-3


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If 16 x 2 Gy fractions reduce survival by 10-4, what dose would be needed to reduce survival to 10-10?1. 50 Gy2. 60 Gy3. 64 Gy4. 70 Gy5. 80 Gy


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If 16 x 2 Gy fractions reduce survival by 10-4, what is the effective D0?1. 2.0 Gy2. 2.3 Gy3. 3.0 Gy4. 3.5 Gy5. 3.8 Gy


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The The ratio for mucosal tissues is closest ratio for mucosal tissues is closest toto

1.1. 2 Gy2 Gy

2.2. 4 Gy4 Gy

3.3. 6 Gy6 Gy

4.4. 8 Gy8 Gy

5.5. 10 Gy10 Gy


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Which of the following human tumors Is Which of the following human tumors Is thought to have an thought to have an ratio of 1-2 Gy ratio of 1-2 Gy

1.1. Oropharyngeal CaOropharyngeal Ca

2.2. Prostate CaProstate Ca

3.3. GlioblastomaGlioblastoma

4.4. Colorectal CaColorectal Ca


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The TD5/5 for a certain tissue irradiated at 2 Gy/fraction is 60 Gy whereas at 4 Gy/fraction it is 40 Gy. Assuming that the linear quadratic equation, ‑lnSF= N (D + D2), accurately represents cell survival for this tissue, what is the value of ?

1. 1 Gy2. 2 Gy3. 4 Gy4. 10 Gy5. 20 Gy


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It is decided to treat a patient with hypofractionation at 3 Gy/fraction instead of the conventional schedule of 60 Gy in 2 Gy fractions. What total dose should be delivered in order for the risk of late normal‑tissue damage to remain unchanged according to the linear‑quadratic model with for late damage = 3 Gy?

1. 40 Gy2. 48 Gy3. 50 Gy4. 55.4 Gy5. 75 Gy


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A standard treatment for HNSCC tumors is 70 Gy delivered at 2 Gy/fraction. Hyperfractionation is being attempted with a fraction size of 1.2 Gy. What total treatment dose should be used to maintain the same complication rate for the late responding normal tissues. Assume full repair of sublethal damage between fractions and an of 3 Gy.

1. 42 Gy2. 58 Gy3. 70 Gy4. 83 Gy5. 117 Gy


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A standard treatment for HNSCC tumors is 70 Gy delivered at 2 Gy/fraction. Hyperfractionation is being attempted with a fraction size of 1.2 Gy. What total treatment dose should be used to maintain the same complication rate for the late responding normal tissues. Assuming no proliferation and complete repair between fractions, an of 3 Gy for late responding tissue and 12 Gy for tumor, what would be the therapeutic gain.1.1. 6%6%2.2. 12%12%3.3. 18%18%4.4. 24%24%


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Which of the following sites is the least Which of the following sites is the least suitable for b.i.d. treatmentsuitable for b.i.d. treatment

1.1. Head and neckHead and neck

2.2. BrainBrain

3.3. LungLung

4.4. ProstateProstate


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The rationale behind accelerated The rationale behind accelerated fractionation isfractionation is1.1. To spare late responding normal tissueTo spare late responding normal tissue2.2. To combat encourage tumor To combat encourage tumor

reoxygenationreoxygenation3.3. To exploit redistribution in tumorsTo exploit redistribution in tumors4.4. To combat accelerated repopulation in To combat accelerated repopulation in

tumorstumors


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The CHART regimen for HNSCC of 54Gy in 36 fractions over The CHART regimen for HNSCC of 54Gy in 36 fractions over 12 days compared with 66 Gy in 33 fractions in 6.5 weeks, 12 days compared with 66 Gy in 33 fractions in 6.5 weeks, overall showedoverall showed

1.1. Superior locoregional control, no increase in overall Superior locoregional control, no increase in overall survival, increased late effectssurvival, increased late effects

2.2. Superior locoregional control that translated into an Superior locoregional control that translated into an increase in overall survival, no change in late effectsincrease in overall survival, no change in late effects

3.3. No change in locoregional control and overall survival, No change in locoregional control and overall survival, decreased late effectsdecreased late effects

4.4. Superior locoregional control, no increase in overall Superior locoregional control, no increase in overall survival, increased acute effectssurvival, increased acute effects


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DAHANCA 6 and 7 clinical trials with 66-DAHANCA 6 and 7 clinical trials with 66-68Gy given in 6 compared to 7 weeks68Gy given in 6 compared to 7 weeks

1.1. Was a hyperfractionation trialWas a hyperfractionation trial

2.2. Treated 6 days a weekTreated 6 days a week

3.3. Showed no increase in local controlShowed no increase in local control

4.4. Showed no increase in disease-specific Showed no increase in disease-specific survivalsurvival


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RTOG 90-03, which compared hyperfractionation, RTOG 90-03, which compared hyperfractionation, accelerated fractionation with a split, and accelerated fractionation with a split, and accelerated fractionation with a boost showedaccelerated fractionation with a boost showed1.1. Hyperfractionation to be superior in terms of Hyperfractionation to be superior in terms of

loco-regional control and late effectsloco-regional control and late effects2.2. Accelerated fractionation with a split to be Accelerated fractionation with a split to be

equivalent to hyperfractionation in terms of loco-equivalent to hyperfractionation in terms of loco-regional controlregional control

3.3. There to be no advantage to altered fractionationThere to be no advantage to altered fractionation4.4. Accelerated fractionation to be superior to Accelerated fractionation to be superior to

hyperfractionationhyperfractionation


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AnswersAnswers1. NA2. 23. 24. 45. 16. 57. 28. 49. 210. 411. 412. 313. 214. 115. 316. 217. 118. 219. 320. 321. 122. 323. 124. 225. 526. 127. 328. 129. 330. 3

radiobiology behind dose fractionation

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