Current and Future Trends Current and Future Trends in Proton Treatment of in Proton Treatment of

Prostate CancerProstate CancerReinhard W. SchulteReinhard W. SchulteAssistant ProfessorAssistant Professor

Department of Radiation MedicineDepartment of Radiation MedicineLoma Linda University Medical CenterLoma Linda University Medical Center

Loma Linda, CA, USALoma Linda, CA, USA

OutlineOutline

Physical, biological, & technical aspects of proton beamsPhysical, biological, & technical aspects of proton beams

Results of proton treatment Results of proton treatment –– can we improve?can we improve?

Anatomy of prostate cancerAnatomy of prostate cancer

Need for new imaging strategies for targetingNeed for new imaging strategies for targeting

Controlling the motion of the prostateControlling the motion of the prostate

ImageImage--guided proton therapyguided proton therapy

The Physics of ProtonsThe Physics of ProtonsHighest energy deposition Highest energy deposition per unit length at end of per unit length at end of range (Bragg peak)range (Bragg peak)No exit doseNo exit doseDose advantage over any Dose advantage over any photon beamphoton beamDepth of peak (proton Depth of peak (proton range) adjustable with range) adjustable with energy or bolus materialenergy or bolus materialModulation generates Modulation generates spreadspread--out Bragg peakout Bragg peakNext step in the evolution Next step in the evolution of radiotherapyof radiotherapy

““What has radiobiology done for What has radiobiology done for radiotherapy besides making it more radiotherapy besides making it more expensive?expensive?

““It gave us neutrons, which did not work, It gave us neutrons, which did not work, and protons, that did.and protons, that did.””

Eric Hall, Ph.D., ASTRO Gold Medal Eric Hall, Ph.D., ASTRO Gold Medal Address, 1994Address, 1994

Radiobiologic effects of protons and xRadiobiologic effects of protons and x--rays are rays are nearly identicalnearly identical

1 CGE protons = 1.1 Gy of Cobalt1 CGE protons = 1.1 Gy of Cobalt--60 or MV photons60 or MV photons

Therefore, Therefore, An identical dose of protons and photons will produce an An identical dose of protons and photons will produce an identical tumor responseidentical tumor responseThis is not the case with neutrons or heavy charged This is not the case with neutrons or heavy charged particlesparticles

Superior physical properties of protonsSuperior physical properties of protons

== reduced integral dosereduced integral dose

Proton Beam DeliveryProton Beam Delivery

IsocentricIsocentric beam beam delivery with proton delivery with proton gantrygantryPatient immobilizedPatient immobilizedRobotic 6Robotic 6--degrees of degrees of freedom positioner freedom positioner (future)(future)Digital XDigital X--ray ray verificationverification11--2 minutes per Gy2 minutes per Gy11--2 fields per day2 fields per day

Physical, biological, & technical aspects of proton beamsPhysical, biological, & technical aspects of proton beams

Results of proton treatment Results of proton treatment –– can we improve?can we improve?

Anatomy of prostate cancerAnatomy of prostate cancer

Need for new imaging strategies for targetingNeed for new imaging strategies for targeting

Controlling the motion of the prostateControlling the motion of the prostate

ImageImage--guided proton therapyguided proton therapy

Prostate CancerProstate Cancer--LLUMC ResultsLLUMC ResultsStageStage

PatientsPatientsStageStage

35351A/1B1A/1B

3143141C1C

2912912A2A

2482482B2B

2832832C2C

505033

Prostate CancerProstate Cancer--LLUMC ResultsLLUMC ResultsInitial PSAInitial PSA

PatientsPatientsInitial PSAInitial PSA

133133

339339

606606

106106<< 44

4.1 4.1 –– 10.010.0

10.1 10.1 –– 20.020.0

> 20.0> 20.0

Prostate CancerProstate Cancer--LLUMCLLUMCEffect of Initial PSA on DiseaseEffect of Initial PSA on Disease--free Survivalfree Survival

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10

Years post Proton Radiation

Dis

ease

-fre

e Su

rviv

al

< 4.1 4.1 - 10.0 10.1 - 20.0 20.1 - 50.0

90%81%

62%

p =.0001

43%

PROGPROG9595--0909

T1b-2b prostate cancerPSA <15ng/ml

Proton boost19.8 GyE

Proton boost28.8 GyE

3-D conformal photons 50.4 Gy

3-D conformal photons 50.4 Gy

Total prostate dose 70.2 GyE

Total prostate dose 79.2 GyE

r a n d o m i z a t i o nACR/RTOG

Pretreatment characteristicsPretreatment characteristicsAssigned doseAssigned dose

70.2GyE70.2GyE79.2GyE79.2GyE

(n=197)(n=197) (n=195(n=195))TT--stagestage

1b1b 1%1% 0%0%1c1c 61%61% 62%62%2a2a 22%22% 26%26%2b2b 17%17% 13%13%

PROG 9509PROG 9509

PROG 9509PROG 9509

Pretreatment characteristicsPretreatment characteristics

Assigned doseAssigned dose

70.2GyE70.2GyE 79.2GyE79.2GyE(n=195) (n=195) (n=197)(n=197)

PSAPSA<4<4 12%12% 11%11%44--<10<10 74%74% 74%74%1010--1515 14%14% 15%15%

Freedom from Freedom from Biochemical Failure Biochemical Failure (ASTRO)(ASTRO)

Low risk* Intermediate to high risk

Years since randomization Years since randomization

0 1 2 3 4 5 6 7 80.00.10.20.30.40.50.60.70.80.91.0

0 1 2 3 4 5 6 7 8

70.2GyE 70.2GyE

79.2GyE79.2GyE

n = 230

p = 0.008

n = 162

p = 0.02

55%

79%

61%

78%

Zietman et. al JAMA 294, 10 1233-1239; 2005

PROG 9509

* PSA < 10, Stage T1b-T2a, Gleason score <7

Zietman et. al JAMA 294, 10 1233-1239; 2005

PROG 9509

MorbidityMorbidity

Acute GU or GI (rectal) morbidity Acute GU or GI (rectal) morbidity >>RTOG grade 3 RTOG grade 3 vsvs grade 2:grade 2:

Low dose: 1% Low dose: 1% vsvs 42%42%High dose: 2% High dose: 2% vsvs 49% (49% (n.sn.s.).)

Late GU or GI morbidity of RTOG grade 3 Late GU or GI morbidity of RTOG grade 3 vs. grade 2vs. grade 2

Low dose: 1% Low dose: 1% vsvs 17%17%High dose: 2% High dose: 2% vsvs 8% (p < 0.05)8% (p < 0.05)

How can we improve these results?How can we improve these results?

ImageImage--guided proton guided proton beam therapybeam therapy

Separate macroscopic Separate macroscopic tumor volume (GTV) tumor volume (GTV) from from volume of volume of subclinical disease (CTV)subclinical disease (CTV)Generate Generate inhomogeneous inhomogeneous dose distributiondose distribution by by targeting these GTV targeting these GTV separately to much separately to much higher dose (80higher dose (80--90 CGE) 90 CGE) than CTV (70than CTV (70--75 CGE)75 CGE)

Physical, biological, & technical aspects of proton beamsPhysical, biological, & technical aspects of proton beams

Results of proton treatment Results of proton treatment –– can we improve?can we improve?

Anatomy of prostate cancerAnatomy of prostate cancer

Need for new imaging strategies for targetingNeed for new imaging strategies for targeting

Controlling the motion of the prostateControlling the motion of the prostate

ImageImage--guided proton therapyguided proton therapy

Prostate Cancer: A Multifocal Prostate Cancer: A Multifocal DiseaseDisease

Number of tumor foci Number of tumor foci in wholein whole--mount radical mount radical prostatectomy prostatectomy specimensspecimens

~75% contain 1~75% contain 1--4 4 macroscopic foci macroscopic foci (distance > 4 mm)(distance > 4 mm)Most foci are in the Most foci are in the peripheral zone (~75%)peripheral zone (~75%)

05

1015202530

1 2 3 4 5 >5

Chen, M.E., Johnston, D.A., Tang, K., et al. Detailed Mapping of prostate carcinoma foci. Biopsy strategy implications. Cancer, 89, 1800-1809 (2000).

Arora, R., Koch, M. O., Eble, J.N., et al. Heterogeneity of Gleason grade in multifocal adenocarcinoma of the prostate. Cancer, 100, 2362-2366 (2000).

Prostate Cancer: A Locally Invasive DiseaseProstate Cancer: A Locally Invasive Disease

Frequency and radial distance Frequency and radial distance of microscopic extensions in of microscopic extensions in radical prostatectomy radical prostatectomy specimens (N = 712)specimens (N = 712)

Microscopic extension in Microscopic extension in 42% of specimens42% of specimensExtension beyond capsule in Extension beyond capsule in 26%26%Median radial extension 2 Median radial extension 2 mm (0mm (0--12 mm)12 mm)97% had less than 5 mm 97% had less than 5 mm extensionextension

Teh, B.S., Bastasch, M.D., Wheeler, T.M., et al. IMRT for prostate cancer: Defining target volume based on correlated pathologic volume of disease. Int. J. Radiat. Onco.l Biol. Phys. 56:184-191 (2003).

Prostate cancer with macroscopic extracapsular extension seen in MRI

Physical, biological, & technical aspects of proton beamsPhysical, biological, & technical aspects of proton beams

Results of proton treatment Results of proton treatment –– can we improve?can we improve?

Anatomy of prostate cancerAnatomy of prostate cancer

Need for new imaging strategies for targetingNeed for new imaging strategies for targeting

Controlling the motion of the prostateControlling the motion of the prostate

ImageImage--guided proton therapyguided proton therapy

Targeting with New Imaging Targeting with New Imaging ModalitiesModalities

Available and upcoming Available and upcoming imaging modalitiesimaging modalities

MRI (MRI (++ endorectalendorectal coil)coil)1.5 1.5 --> 3.0 T> 3.0 TMRS (improved resolution)MRS (improved resolution)DWI, DTIDWI, DTIDCEDCE

PET/SPECT (+ CT or MRI)PET/SPECT (+ CT or MRI)New metabolic tracers (New metabolic tracers (1111C C choline, choline, 1111C acetate, C acetate, 1818FF--choline, choline, 1818FF--fluoroacetate)fluoroacetate)Cancer specific tracers Cancer specific tracers (molecular imaging), e.g., (molecular imaging), e.g., antibodies against PSMA or antibodies against PSMA or peptide receptors, Napeptide receptors, Na--I I symporter (NIS), etc.symporter (NIS), etc.

Physical, biological, & technical aspects of proton beamsPhysical, biological, & technical aspects of proton beams

Results of proton treatment Results of proton treatment –– can we improve?can we improve?

Anatomy of prostate cancerAnatomy of prostate cancer

Need for new imaging strategies for targetingNeed for new imaging strategies for targeting

Controlling the motion of the prostateControlling the motion of the prostate

ImageImage--guided proton therapyguided proton therapy

Prostate MotionProstate Motionrespiration

bladder filling

Rectal filling

Prostate MotionProstate Motion

Motion ParametersMotion Parametersintraintra--treatment motiontreatment motion(motion during treatment)(motion during treatment)

respiratoryrespiratorybowelbowel--movementmovementbladder fillingbladder filling

interinter--treatment motiontreatment motion(motion between (motion between treatments)treatments)

Rectal fillingRectal fillingBladder fillingBladder fillingSetup errorSetup error

??

??

IntraIntra--Treatment MotionTreatment Motion(20 patients with implanted gold seeds, (20 patients with implanted gold seeds,

83 treatment sessions)83 treatment sessions)

InterInter--Treatment MotionTreatment Motion

Controlling Prostate MotionControlling Prostate Motion

General measuresGeneral measuresWaterWater--filled rectal balloonfilled rectal balloonFull bladderFull bladderPatient instruction (shallow breathing)Patient instruction (shallow breathing)

PatientPatient--dependent measuresdependent measuresDeepDeep--inspiration breathinspiration breath--hold (DIBH)hold (DIBH)Beam interlock control by patientBeam interlock control by patient

Respiratory gating with surface markersRespiratory gating with surface markers

Respiratory GatingRespiratory Gating

Already in clinical Already in clinical useuseVisual tracking of Visual tracking of markers on the markers on the abdomenabdomen4D4D--imaging (CT, imaging (CT, MRI, PET)MRI, PET)4D4D--treatmenttreatment Respiratory wave

form

Gate signal

CT scanner on/off

ImageImage--Guided Proton Therapy of Guided Proton Therapy of Prostate CancerProstate Cancer

PrinciplesPrinciplesImplant seeds into prostate for image guidanceImplant seeds into prostate for image guidanceImage patient with respirationImage patient with respiration--gated CT or gated CT or proton CTproton CTDevelop treatment plan for prostate + margins Develop treatment plan for prostate + margins (CTV) and tumor (CTV) and tumor subvolumessubvolumes (GTV) (GTV) Verify correct position in treatment room with Verify correct position in treatment room with XX--ray or proton radiography or CTray or proton radiography or CTTreat Treat GTV(sGTV(s) with respiratory) with respiratory--gated proton gated proton beambeam

From XFrom X--ray to Proton CTray to Proton CT

Conventional X-ray CT Scanner

Planned Proton CT Radiography/Scanner in the LLUMC Gantry

Advantages of a Proton CTAdvantages of a Proton CT

Uses same radiation for Uses same radiation for treatment and imagingtreatment and imagingNo separate XNo separate X--ray source ray source for imaging in treatment for imaging in treatment roomroom3D image set acquired with 3D image set acquired with one Gantry revolutionone Gantry revolutionBetter density resolution Better density resolution than with Xthan with X--ray CT or Xray CT or X--ray imaging at low doseray imaging at low doseMore accurate dose More accurate dose treatment planningtreatment planning

The Future: GoldThe Future: Gold--NanoparticleNanoparticleEnhanced Proton CT ImagingEnhanced Proton CT Imaging

PrinciplesPrinciplesAttach solid gold Attach solid gold nanoparticles (1nanoparticles (1--100 nm) to 100 nm) to monoclonal antibodiesmonoclonal antibodiesAntibodies & nanoparticles Antibodies & nanoparticles attach specifically to cancer attach specifically to cancer cellscellsGoldGold--loaded tumors have loaded tumors have higher density than higher density than surrounding normal tissuesurrounding normal tissue

ConclusionsConclusions

The future of conformal proton beam The future of conformal proton beam therapy for prostate cancer has just beguntherapy for prostate cancer has just begunImaging with protons is around the corner Imaging with protons is around the corner (collaboration between INFN, LLUMC, UC (collaboration between INFN, LLUMC, UC Santa Cruz)Santa Cruz)Contributions from multiple subspecialties Contributions from multiple subspecialties required (physics, nuclear medicine, MRI) required (physics, nuclear medicine, MRI)

Thank you!Thank you!