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WMcB2008

The Radiobiology Behind Alternate The Radiobiology Behind Alternate Physical Forms of Radiation Delivery Physical Forms of Radiation Delivery

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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Alternatives Forms of Radiation Alternatives Forms of Radiation DeliveryDelivery

Sometimes called plesiocurie therapy


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PhotonPhoton

PhotonPhoton

ParticleParticle

TomotherapyTomotherapy®®

CyberKnifeCyberKnife®®

X-KnifeX-Knife®®

SRT, 3D-CRT, IMRT, IGRTSRT, 3D-CRT, IMRT, IGRT

Linear Linear AcceleratorAccelerator

SRS - GammaKnifeSRS - GammaKnife®®CobaltCobalt6060 Based Based

Heavy IonHeavy Ion

ProtonProton

Heavy Ion CentersHeavy Ion Centers

Synchrotron Synchrotron

ParticleParticle

ImplementationImplementationCategoryCategory

The Alternatives are Growing!The Alternatives are Growing!

BrachytherapyBrachytherapy Isotope BasedIsotope Based Ultra low dose rate, LDR, HDRUltra low dose rate, LDR, HDR


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BrachytherapyBrachytherapy

Dose falls off with one upon the square of distance Dose falls off with one upon the square of distance

rr22

rr11

SeedSeed

0.10.1

11

1010

100100

Rel

ativ

e do

seR

elat

ive

dose

00 11 22 33 44 55 66

125I

Distance (cm)

NormalNormaltissuetissue

Therapeutically relevant range 3-20mm

Potential radiobiological Potential radiobiological advantage in reduced advantage in reduced exposed normal tissue exposed normal tissue volume and dose volume and dose distribution fall-off. distribution fall-off.


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BrachytherapyBrachytherapy

• Potential radiobiological advantages of brachytherapy Potential radiobiological advantages of brachytherapy include varying treatment times include varying treatment times – Short treatment time could prevent tumor Short treatment time could prevent tumor

repopulation, repopulation, – Longer could redistribute cells into sensitive cell Longer could redistribute cells into sensitive cell

cycle phases, cycle phases, – Longer could allow re-oxygenation with time after Longer could allow re-oxygenation with time after

implantation.implantation.


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• ULDRULDR– 0.01 - 0.3 Gy/hr0.01 - 0.3 Gy/hr– permanent implantspermanent implants– 125125I, I, 103103 Pd Pd

• LDR LDR – 0.4 - 2 Gy/hr0.4 - 2 Gy/hr– treatment times of 24 - 144 hrstreatment times of 24 - 144 hrs– 226226 Ra, Ra, 137137 Cs Cs

• HDRHDR

– 12 - 430 Gy/hr at 1 cm12 - 430 Gy/hr at 1 cm– treatment time in mins to hrstreatment time in mins to hrs

– 6060Co, Co, 192192IrIr


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LDR and HDR BrachytherapyLDR and HDR Brachytherapy

• LDR differentially spares late-responding tissues LDR differentially spares late-responding tissues compared to early-responding normal tissue and compared to early-responding normal tissue and tumorstumors

• HDR is assumed to compromise the radiobiological HDR is assumed to compromise the radiobiological advantage of LDR in favor of patient convenience, advantage of LDR in favor of patient convenience, minimizing risk to staff, and better dosimetryminimizing risk to staff, and better dosimetry


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Dose Rate EffectsDose Rate Effects

• In general decreasing dose rate decreases In general decreasing dose rate decreases killing, however in some cases there is an killing, however in some cases there is an inverse dose rate effect, which is thought to inverse dose rate effect, which is thought to be due to redistribution and cells piling up in be due to redistribution and cells piling up in the radiosensitive G2 cell cycle check point.the radiosensitive G2 cell cycle check point.


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Inverse Dose Rate EffectInverse Dose Rate Effect

Mitchell J.B. et al., Rad. Res. 79:552, 1979

V79 cells log phase

HeLa cells log phase

0.55 Gy/hr

1.43 Gy/hr

Dose (cGy) Dose (cGy)

1.54 Gy/hr

1.43 Gy/hr

1.54 Gy/hr

0.55 Gy/hr


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Inverse Dose Rate EffectInverse Dose Rate Effect = 10= 101/2 1/2 2 2 = 0.02= 0.02T1/2 repair = 0.7 hrT1/2 repair = 0.7 hrT1/2 resens. = 4 hrT1/2 resens. = 4 hr

T1/2 pot = 33 hrT1/2 pot = 33 hr

Dose (Gy)Dose (Gy)

0.0010.001

0.010.01

0.10.1

11

S.F.S.F.

00 1010 2020 3030 4040

0.1Gy/hr0.1Gy/hr

0.15 Gy/hr0.15 Gy/hr1 Gy/hr1 Gy/hr

0.75 Gy/hr0.75 Gy/hr0.25 Gy/hr0.25 Gy/hr

R. Suwinski


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Determinants of Radiation ResponseDeterminants of Radiation Response

• RepairRepair

• RepopulationRepopulation

• RedistributionRedistribution

ResensitizationResensitization• ReoxygenationReoxygenation


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LQR ModelLQR Model

• A LQR model that takes into account repair, repopulation, and A LQR model that takes into account repair, repopulation, and resensitizationresensitization

• Assumes decrease in radiosensitivity immediately after Assumes decrease in radiosensitivity immediately after irradiation followed by a resensitization phaseirradiation followed by a resensitization phase

• Assumes intratumoral heterogeneity that averages out Assumes intratumoral heterogeneity that averages out oscillations in the process of resensitizationoscillations in the process of resensitization

• Assumes resensitization can be described by a single amplitude Assumes resensitization can be described by a single amplitude and a single characteristic timeand a single characteristic time

Brenner et al. Int. J. Rad. Oncol. Biol. Phys. 32:379, 1995Brenner et al. Int. J. Rad. Oncol. Biol. Phys. 32:379, 1995


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A Mathematical ModelA Mathematical Model

S = exp [ - S = exp [ - D D one-track killing one-track killing

- - G(G(rr).D).D22 two-track killingtwo-track killing

+ (1/2+ (1/222).G().G(s).Ds).D22 resensitization resensitization

+ T/+ T/pp]] repopulationrepopulation

where:where: is average of a Gaussian distribution with variance is average of a Gaussian distribution with variance 22,,

G is the generalized Lea-Catcheside function, and represents reduction in damage due to repair or G is the generalized Lea-Catcheside function, and represents reduction in damage due to repair or resensitizationresensitization

rr is repair time in min.- hrs., is repair time in min.- hrs.,

s is resensitization time in hrs.- dys.,s is resensitization time in hrs.- dys.,

pp is the repopulation time, is the repopulation time,

and a total dose D is delivered in time T.and a total dose D is delivered in time T.


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Suggested ParametersSuggested Parameters

Tpot T1/2repair

T1/2sens

1/22

Early 0.3 0.03 10 2 dys 1 hr 4 hr 0.01

Late 0.15 0.075 2 60 dys 4 hr 4 hr 0.01

ProstateCa

0.225 0.053 4.3 30 dys 3 hr 4 hr 0.01

FastGrowing

Tumor0.3 0.03 10 10 dys 2 hr 4 hr 0.02


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00..00

00..55

11..00

11..55

22..00

22..55

33..00

33..55

0.060.060.080.080.100.10

0.200.20

0.400.40

0.600.600.800.801.001.00

2.002.00

4.004.00

6.006.00

8.008.00

10.0010.00

20.0020.00

30.0030.0040.0040.00

TTUUMMOORR ((//==1100,, TTdd==3300 ddaayyss))

vvss..LLAATTEE EEFFFFEECCTT

((//==22,, TTdd>>330000 ddaayyss))

Dose Rate (Gy/dy)Dose Rate (Gy/dy)

A Mathematical ModelA Mathematical Model

The The ““Golden ZoneGolden Zone””

TherapeuticTherapeuticBenefitBenefit

R. Suwinski


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125125I ImplantsI Implants

0.0010.001

0.010.01

0.10.1

11

00 1010 2020 3030 4040 5050

SFSF

Dose (Gy)Dose (Gy)

Fast GrowingFast GrowingTumorTumor

Normal tissueNormal tissueSlow Growing Slow Growing

TumorTumor

Initial dose rate ofInitial dose rate of1.68 Gy/day1.68 Gy/day

R. Suwinski


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• Spatial distribution of dose Spatial distribution of dose

– advantage can be taken of dose fall off and optimizing dose advantage can be taken of dose fall off and optimizing dose distributions. The geometric sparing factor (f)= effective normal tissue distributions. The geometric sparing factor (f)= effective normal tissue dose/effective tumor dose, varies with timedose/effective tumor dose, varies with time

• RBE (RBE (125125I may be 1.4, but hard to estimate)I may be 1.4, but hard to estimate)

• Dose inhomogeneity, including, associated dose rate effects, can Dose inhomogeneity, including, associated dose rate effects, can however, be particularly severe in brachytherapyhowever, be particularly severe in brachytherapy

• Inhomogeneity may be beneficial when implant is sub-optimal and tumor Inhomogeneity may be beneficial when implant is sub-optimal and tumor rapidly growingrapidly growing

• Adequate dosage to the whole tumor is paramountAdequate dosage to the whole tumor is paramount


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Energetic Protons (65-250 MeV)Energetic Protons (65-250 MeV)• AdvantagesAdvantages

– Good dose distribution with finite range in tissue and Good dose distribution with finite range in tissue and rapid fall off (Bragg peak), but not laterally due to rapid fall off (Bragg peak), but not laterally due to scatteringscattering

– But need to spread out the Bragg peak - SOBPBut need to spread out the Bragg peak - SOBP• Active scattering using deflecting magnets and scanning Active scattering using deflecting magnets and scanning

(IMPT)(IMPT)• Passive scattering Passive scattering

• DisadvantagesDisadvantages• Best use of fall off depends on knowing the tumor marginsBest use of fall off depends on knowing the tumor margins• Tissue density issuesTissue density issues• Limited clinical data, no randomized clinical trialsLimited clinical data, no randomized clinical trials• High energy secondary neutrons with passive scattering High energy secondary neutrons with passive scattering

from materials in the beamline may carry increased from materials in the beamline may carry increased cancer risk with high Q factor cancer risk with high Q factor

– Brenner and Hall Radiotherapy Oncol. 86: 165-170, 2000Brenner and Hall Radiotherapy Oncol. 86: 165-170, 2000

Biological properties of Biological properties of protonsprotons (RBE and (RBE and OER) OER) similar to X-rays similar to X-rays RBE=1.1 but may be 2 at RBE=1.1 but may be 2 at distal edge of Bragg peakdistal edge of Bragg peak

From Chen Neurosurg 23: 1-5, 2007


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ProtonsProtons• About 25 facilities operating world-About 25 facilities operating world-

wide, and growing. wide, and growing. – Over 50,000 patients have Over 50,000 patients have

been treatedbeen treated• Due to excellent dose distributions, Due to excellent dose distributions,

have shown clear efficacy for:have shown clear efficacy for:– Choroidal melanomaChoroidal melanoma– Some spinal cord and brain Some spinal cord and brain

tumorstumors– Sphenoid sinus tumorsSphenoid sinus tumors

• Also being used for a wide Also being used for a wide spectrum of tumors (e.g., prostate, spectrum of tumors (e.g., prostate, pediatric, lung, breast, head and pediatric, lung, breast, head and neck, etc.) neck, etc.)


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Heavy Charged ParticlesHeavy Charged Particles

• Helium ions in UCB-LBL since 1954 to treat AVMs but the beams Helium ions in UCB-LBL since 1954 to treat AVMs but the beams were contaminated with photons and alpha particleswere contaminated with photons and alpha particles

• Helium ions have biophysical properties like protonsHelium ions have biophysical properties like protons– Good dose localization (Bragg peak)Good dose localization (Bragg peak)– Must use spread out Bragg peak (SOBP)Must use spread out Bragg peak (SOBP)

• Carbon ions have the biological advantages of high LETCarbon ions have the biological advantages of high LET– Less OER and cell cycle dependency Less OER and cell cycle dependency – RBE increases strongly with LET and therefore depth doses are RBE increases strongly with LET and therefore depth doses are

hard to calculatehard to calculate• An additional advantage may be ability to use PET to image target An additional advantage may be ability to use PET to image target

volumevolume• Currently, only Japan and Germany heavy ion clinical facilitiesCurrently, only Japan and Germany heavy ion clinical facilities

– Over 5,000 patients now treated with heavy carbon ionsOver 5,000 patients now treated with heavy carbon ions– Very good efficacy reported, e.g., chondrosarcoma at the base of skull, spinal Very good efficacy reported, e.g., chondrosarcoma at the base of skull, spinal

tumors, adeno cystic ca, locally advanced HNSCC.tumors, adeno cystic ca, locally advanced HNSCC.


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H2

High energy deuterons captured by beryllium target

n

Be9

NeutronsNeutrons

Stone, at LBL between 1938 and 1943, used Cyclotron neutrons to treat 240 patients using the wrong RBE with severe late sequelae.


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Potential Biological Advantages of High Potential Biological Advantages of High LET RadiationsLET Radiations

• Reduced influence of hypoxiaReduced influence of hypoxia– OER 1.4-1.7OER 1.4-1.7

• Reduced influence of repairReduced influence of repair• Reduced cell cycle differentialReduced cell cycle differential• Higher RBE for slowly cycling tumorsHigher RBE for slowly cycling tumors

– RBE for most normal tissues 3.0-3.5RBE for most normal tissues 3.0-3.5– RBE for CNS 4.0-4.5RBE for CNS 4.0-4.5– RBE for salivary gland tumors = 8RBE for salivary gland tumors = 8

(Larimore, G. Adv Radiat Biol 15:153, 1992)(Larimore, G. Adv Radiat Biol 15:153, 1992)RBE varies with the energyRBE varies with the energy


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Poor Depth Dose Distribution of NeutronsPoor Depth Dose Distribution of Neutrons

(from Hall 2000)


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Isoeffect Curves for NeutronsIsoeffect Curves for Neutrons

Withers et al. Int J Radiat Oncol Biol Phys. 8:2071-6, 1982


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Clinical Trials with NeutronsClinical Trials with Neutrons

• Have been tested at a number of centers world-wideHave been tested at a number of centers world-wide• Disappointing resultsDisappointing results

– high incidence of late complications high incidence of late complications – relatively poor depth dose distribution; fixed relatively poor depth dose distribution; fixed

horizontal beamshorizontal beams– reoxygenation in conventional radiation may reoxygenation in conventional radiation may

reduce importance of hypoxic cellsreduce importance of hypoxic cells– poor patient selectionpoor patient selection– Currently only about 5 centersCurrently only about 5 centers

• Current uses primarily limited to salivary gland and Current uses primarily limited to salivary gland and prostate cancers, and (limited) soft tissue sarcomasprostate cancers, and (limited) soft tissue sarcomas


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Boron Neutron Capture Therapy (BNCT)Boron Neutron Capture Therapy (BNCT)

LET ~ 200-300 keV/mm RBE highOER low


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BNCTBNCT

• LimitationsLimitations– Lack of boron compounds with specificity Lack of boron compounds with specificity

for tumor rather than normal tissuefor tumor rather than normal tissue– Getting enough into tumorGetting enough into tumor– Thermal neutrons are poorly penetratingThermal neutrons are poorly penetrating

• Tumors tested clinicallyTumors tested clinically– Glioblastoma multiformeGlioblastoma multiforme– Cutaneous melanomaCutaneous melanoma

• Currently few sites conducting studiesCurrently few sites conducting studies


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SRS and SRTSRS and SRT

• SRS - one fractionSRS - one fraction– First proposed by Leksell First proposed by Leksell

• Arch Chir Scand 102:316-319, 1951Arch Chir Scand 102:316-319, 1951

– SRS loses the advantage of dose fractionation SRS loses the advantage of dose fractionation and often ends up as SRTand often ends up as SRT

• SRT - fractionatedSRT - fractionated• There may be no advantage to dose fractionation There may be no advantage to dose fractionation

based on differences between tumor and normal based on differences between tumor and normal tissue in terms of tissue in terms of values, but this is based on values, but this is based on values around 2Gy. Other differences may exist values around 2Gy. Other differences may exist between large fraction size and single doses. between large fraction size and single doses.


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IMRT etc.IMRT etc.• Since mid 1990s IMRT and related procedures have Since mid 1990s IMRT and related procedures have

been use to conform high dose areas to target been use to conform high dose areas to target volumes with sharp dose fall-off to organs at risk volumes with sharp dose fall-off to organs at risk (OARs), potentially reducing morbidity(OARs), potentially reducing morbidity

• This raises questionsThis raises questions– How do you best define GTV? CT, PET, MRI…How do you best define GTV? CT, PET, MRI…

• Geometric miss a problem as margins decrease?Geometric miss a problem as margins decrease?

– Higher volume receiving lower doseHigher volume receiving lower dose– Higher Higher ‘‘integralintegral’’ dose dose

• Increased risk of cancer inductionIncreased risk of cancer induction• Should IMRT be used for pediatric patients?Should IMRT be used for pediatric patients?

– Increased time for delivery may decrease efficacyIncreased time for delivery may decrease efficacy


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2. Diagnostic Imaging2. Diagnostic Imaging

~ 10 Gy~ 10 Gy~100 Gy~100 Gy< 5 MeV< 5 MeVPhotons, electrons, alphas (Y-90, Bi-214, Photons, electrons, alphas (Y-90, Bi-214, etc)etc)

c. Radioimmuno-c. Radioimmuno-therapy (RIT)therapy (RIT)

~ 1 Gy~ 1 Gy~60 Gy~60 Gy< 2 MeV< 2 MeVGamma-ray photons, electrons, and Gamma-ray photons, electrons, and neutrons (neutrons (Ra-226, Cs-137, Ir-192, I-Ra-226, Cs-137, Ir-192, I-125, etc)125, etc)

b. Brachytherapy b. Brachytherapy

Low dose region:Low dose region:D< 5 Gy D< 5 Gy Intermediate dose regionIntermediate dose region5 Gy < D < 45 Gy 5 Gy < D < 45 Gy High dose regionHigh dose regionD > 45 GyD > 45 Gy

Up to 100 Gy Up to 100 Gy (or Gy x RBE)(or Gy x RBE)

6-250 MeV6-250 MeVX-ray photons, electrons, protons and X-ray photons, electrons, protons and neutronsneutrons

a. External Beam a. External Beam

1. Radiotherapy1. Radiotherapy

Approx. dose to tissue Approx. dose to tissue outside the treatment outside the treatment

volumevolume

Approx. dose to Approx. dose to primary primary targettarget

EnergyEnergyRadiation TypeRadiation Type

0.02 – 0.1 Sv per scan0.02 – 0.1 Sv per scanKV or MVKV or MVX-ray photonsX-ray photonse. Cone beam CT e. Cone beam CT IGTRIGTR

~ 0.02 Sv ~ 0.02 Sv 0.511 keV0.511 keVPhotons/positronsPhotons/positronsd. Hybrid PET/CTd. Hybrid PET/CT

~ 0.5 Sv~ 0.5 Sv<140 kVp<140 kVpX-rays photonsX-rays photonsc. Interventional c. Interventional FluoroscopyFluoroscopy

~ 0.05 – 0.1 Sv~ 0.05 – 0.1 Sv<140 kVp<140 kVpX-ray photonsX-ray photonsa.a.Multi-slice CT (4D)Multi-slice CT (4D)

~ 0.01 Sv~ 0.01 Sv<150 kVp<150 kVpX-ray photonsX-ray photonsa.a.Radiography Radiography

Xu et al. Phys. Med. Biol. 53 (2008) R193–R241


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Non-Homogeneous Dose Non-Homogeneous Dose DistributionsDistributions

• Historically, in RT homogeneous dose Historically, in RT homogeneous dose distributions have been used. With IMRT, distributions have been used. With IMRT, more opportunities exist to use non-more opportunities exist to use non-homogeneous dose distributionshomogeneous dose distributions– Dose painting eg hypoxic regions, PET Dose painting eg hypoxic regions, PET

positive regions, etc.positive regions, etc.– Simultaneous boost techniqueSimultaneous boost technique


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Simultaneous Integrated Boost (SIB) Technique Simultaneous Integrated Boost (SIB) Technique • Dose > 2 Gy/fraction to the tumor and < 2 Gy/fraction on Dose > 2 Gy/fraction to the tumor and < 2 Gy/fraction on

the normal tissuesthe normal tissues

• Small volume with dose/fraction > 2 GySmall volume with dose/fraction > 2 Gy

• Benefit of a reduced overall treatment timeBenefit of a reduced overall treatment time


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SIB IMRT(49.9 Gy + 19.7 Gy)

Two-phase IMRT(50 Gy + 20 Gy)

Courtesy of Ph. Maingon


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Final ThoughtsFinal Thoughts

• How much are we going to gain by pushing How much are we going to gain by pushing the limits of conformal types of therapy?the limits of conformal types of therapy?

• Will the gains ever be properly evaluated?Will the gains ever be properly evaluated?• What about the economics?What about the economics?• The greatest gain may come from being sure The greatest gain may come from being sure

we hit the tumor…….we hit the tumor…….• The radiobiology of low dose and high dose The radiobiology of low dose and high dose

delivery, and low dose rate and high dose delivery, and low dose rate and high dose rate, are very likely different rate, are very likely different


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Questions:Questions: The Radiobiology of Alternate Physical Forms of Radiation DeliveryThe Radiobiology of Alternate Physical Forms of Radiation Delivery


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139. Low dose rate implants deliver139. Low dose rate implants deliver– <0.01 Gy/hr<0.01 Gy/hr– 0.1-0.4 Gy/hr0.1-0.4 Gy/hr– 0.4-2.0Gy/hr0.4-2.0Gy/hr– 2.0-4.0 Gy/hr 2.0-4.0 Gy/hr

#3 – A generally accepted figure…


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140. What is least likely to give a radiobiological 140. What is least likely to give a radiobiological advantage for low dose rate implantsadvantage for low dose rate implants– Increased reoxygenation during treatmentIncreased reoxygenation during treatment– Sparing of late effect tissuesSparing of late effect tissues– Sparing of acute effects tissuesSparing of acute effects tissues– Cell cycle redistributionCell cycle redistribution– Decreased dose heterogeneityDecreased dose heterogeneity

#5 – Dose heterogeneity is an advantage with implantsDose heterogeneity is an advantage with implants


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141. The RBE of protons compared to standard 141. The RBE of protons compared to standard forms of RT isforms of RT is– 1.01.0– 1.1-1.21.1-1.2– 1.4-1.51.4-1.5– 2.0-2.52.0-2.5– 3.0-3.53.0-3.5

#2 – The advantage, if there is one, is in dose The advantage, if there is one, is in dose distributiondistribution


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142. The RBE of fast neutrons compared to standard 142. The RBE of fast neutrons compared to standard forms of RT isforms of RT is– 1.01.0– 1.1-1.21.1-1.2– 1.4-1.51.4-1.5– 2.0-2.52.0-2.5– 3.0-3.53.0-3.5

#5 – However, for CNS it may be over 4.0 However, for CNS it may be over 4.0


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143. Which is an advantages of fast neutrons143. Which is an advantages of fast neutrons• Increased influence of oxygenIncreased influence of oxygen• They are more potent if given as a fractionated They are more potent if given as a fractionated

coursecourse• They are more effective against rapidly cycling They are more effective against rapidly cycling

tumorstumors• They are particularly effective against salivary tumorsThey are particularly effective against salivary tumors

#4 – The data from Seattle (G. Larimore) suggests an The data from Seattle (G. Larimore) suggests an RBE of 8 for salivary gland tumorsRBE of 8 for salivary gland tumors


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144. The OER of fast neutrons for most normal 144. The OER of fast neutrons for most normal tissues istissues is– 1.01.0– 1.1-1.21.1-1.2– 1.4-1.71.4-1.7– 2.0-2.52.0-2.5– 3.0-3.53.0-3.5

#3 – This may be due in part to beam contaminationThis may be due in part to beam contamination

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