The Use of High-Energy Protons in Cancer Therapy

Reinhard W. Schulte

Loma Linda University Medical Center

A Man - A Vision

• In 1946 Harvard physicist Robert Wilson (1914-2000) suggested*:– Protons can be used clinically

– Accelerators are available

– Maximum radiation dose can be placed into the tumor

– Proton therapy provides sparing of normal tissues

– Modulator wheels can spread narrow Bragg peak

*Wilson, R.R. (1946), “Radiological use of fast protons,” Radiology 47, 487.

History of Proton Beam Therapy

• 1946 R. Wilson suggests use of protons• 1954 First treatment of pituitary tumors• 1958 First use of protons as a neurosurgical tool• 1967 First large-field proton treatments in Sweden• 1974 Large-field fractionated proton treatments

program begins at HCL, Cambridge, MA• 1990 First hospital-based proton treatment center

opens at Loma Linda University MedicalCenter

World Wide Proton Treatments*

LLUMC (1990)6174

LLUMC (1990)6174

HCL (1961)6174

HCL (1961)6174

Uppsala (1957): 309 PSI (1984): 3935Clatterbridge(1989): 1033Nice (1991): 1590Orsay (1991): 1894Berlin (1998): 166

Uppsala (1957): 309 PSI (1984): 3935Clatterbridge(1989): 1033Nice (1991): 1590Orsay (1991): 1894Berlin (1998): 166

Chiba (1979) 133Tsukuba (1983) 700Kashiwa (1998) 75

Chiba (1979) 133Tsukuba (1983) 700Kashiwa (1998) 75

NAC (1993)398

NAC (1993)398

Dubna (1967) 172Moscow (1969) 3414St. Petersburg (1969) 1029

Dubna (1967) 172Moscow (1969) 3414St. Petersburg (1969) 1029

*from: Particles, Newsletter (Ed J. Sisterson), No. 28. July 2001

LLUMC Proton Treatment Center

Hospital-based facility

Fixed beam line

40-250 MeV Synchrotron

Gantry beam line

Main Interactions of Protons

• Electronic (a)– ionization

– excitation

• Nuclear (b-d)– Multiple Coulomb scattering (b),

small – Elastic nuclear collision (c),

large – Nonelastic nuclear interaction (d)

e

pp

p’

p

p

p’

nucleus

n

p’

p

e

nucleus

(b)

(c)

(d)

(a)

Why Protons are advantageous

• Relatively low entrance dose (plateau)

• Maximum dose at depth (Bragg peak)

• Rapid distal dose fall-off

• Energy modulation (Spread-out Bragg peak)

• RBE close to unityDepth in Tissue

Rel

ativ

e D

ose

10 MeV X-raysModulated

Proton Beam

Unmodulated Proton Beam

Uncertainties in Proton Therapy

• Patient setup• Patient movements• Organ motion• Body contour• Target definition

• Relative biological effectiveness (RBE)

• Device tolerances• Beam energy° Biology related:

° Patient related: ° Physics related:

• CT number conversion• Dose calculation

° Machine related:

Treatment Planning

• Acquisition of imaging data (CT, MRI)

• Conversion of CT values into stopping power

• Delineation of regions of interest

• Selection of proton beam directions

• Design of each beam

• Optimization of the plan

Treatment Delivery

• Fabrication of apertures and boluses

• Beam calibration

• Alignment of patient using DRRs

• Computer-controlled dose delivery

Computed Tomography (CT)

X-ray tube

Detector array

• Faithful reconstruction of patient’s anatomy

• Stacked 2D maps of linear X-ray attenuation

• Electron density relative to water can be derived

• Calibration curve relates CT numbers to relative proton stopping power

Processing of Imaging Data

CT Hounsfield values (H)

CT Hounsfield values (H)

Isodose distribution

Isodose distribution

Calibration curve

H = 1000 tissue /water

Relative proton

stopping power (SP)

Relative proton

stopping power (SP)

SP = dE/dxtissue /dE/dxwater

H

SP

Dose calculation

• Proton interaction Photon interaction

• Bi- or tri- or multisegmental curves are in use

• No unique SP values for soft tissue Hounsfield range

• Tissue substitutes real tissues

• Fat anomaly

CT Calibration Curve

CT Calibration Curve Stoichiometric Method*

• Step 1: Parameterization of H– Choose tissue substitutes

– Obtain best-fitting parameters A, B, C

800

1000

1200

1400

1600

1800

2000

800 1000 1200 1400 1600 1800 2000

Hounsfield value (expected)

Hou

nsf

ield

va

lue

(ob

serv

ed

H = Nerel {A (ZPE)3.6 + B (Zcoh)1.9 + C}

Klein-Nishina cross section

Rel. electron density

Photo electric effect

Coherent scattering

*Schneider U. (1996), “The calibraion of CT Hounsfield units for radiotherapy treatment planning,” Phys. Med. Biol. 47, 487.

CT Calibration Curve Stoichiometric Method

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

0 500 1000 1500 2000 2500

H valueS

P

• Step 2: Define Calibration Curve– select different standard tissues

with known composition (e.g., ICRP)

– calculate H using parametric equation for each tissue

– calculate SP using Bethe Bloch equation

– fit linear segments through data points

Fat

CT Range Uncertainties

• Two types of uncertainties– inaccurate model parameters

– beam hardening artifacts

• Expected range errors

Soft tissue Bone TotalH2O range abs. error H2O range abs. Error abs. error

(cm) (mm) (cm) (mm) (mm) Brain 10.3 1.1 1.8 0.3 1.4Pelvis 15.5 1.7 9 1.6 3.3

1 mm 4 mm

Proton Transmission Radiography - PTR

• First suggested by Wilson (1946)

• Images contain residual energy/range information of individual protons

• Resolution limited by multiple Coulomb scattering

• Spatial resolution of 1mm possible

MWPC 2MWPC 1

SC

p

En

ergy

det

ecto

r

Comparison of CT Calibration Methods

• PTR used as a QA tool• Comparison of measured and

CT-predicted integrated stopping power

• Sheep head used as model• Stoichiometric calibration (A)

better than tissue substitute calibrations (B & C) SPcalc - Spmeas [%]

No

of P

TR

pix

els

[%]

Proton Beam Computed Tomography

• Proton CT for diagnosis– first studied during the 1970s– dose advantage over x rays– not further developed after the advent of X-ray CT

• Proton CT for treatment planning and delivery– renewed interest during the 1990s (2 Ph.D. theses)– preliminary results are promising– further R&D needed

Proton Beam Computed Tomography

• Conceptual design– single particle resolution

– 3D track reconstruction

– Si microstrip technology

– cone beam geometry

– rejection of scattered protons & neutrons

DAQ

Trigger logic

Si MS 2 EDSi MS 1 Si MS 3 SC

x

p cone beam

Proton Beam Design

Modulator wheel

Aperture

BolusInhomogeneity

Proton Beam Shaping Devices

Cerrobend apertureWax bolus Modulating wheels

Ray-Tracing Dose Algorithm

• One-dimensional dose calculation

• Water-equivalent depth (WED) along single ray SP

• Look-up table

• Reasonably accurate for simple hetero-geneities

• Simple and fast

||

WED

S P

Effect of Heterogeneities

W = 10 mmW = 4 mm

W = 2 mm

W = 1 mmW = 1 mm

No heterogeneity

BoneWater

Protons

W

Central axis

Depth [cm]155 10

Cen

t ra l

ax i

s d

o se

Alderson Head Phantom

Effect of Heterogeneities

Range Uncertainties(measured with PTR)

> 5 mm

> 10 mm

> 15 mm

Schneider U. (1994), “Proton radiography as a tool for quality control in proton therapy,” Med Phys. 22, 353.

Pencil Beam Dose Algorithm

• Cylindrical coordinates• Measured or calculated

pencil kernel• Water-equivalent depth• Accounts for multiple

Coloumb scattering• more time consuming

WED

SP

Monte Carlo Dose Algorithm

• Considered as “gold standard”

• Accounts for all relevant physical interactions

• Follows secondary particles• Requires accurate cross

section data bases• Includes source geometry• Very time consuming

Comparison of Dose Algorithms

Protons

Bone

Water

Monte CarloRay-tracing Pencil beam

Petti P. (1991), “Differential-pencil-beam dose calculations for charged particles,” Med Phys. 19, 137.

Combination of Proton Beams

• “Patch-field” design• Targets wrapping around

critical structures• Each beam treats part of

the target• Accurate knowledge of

lateral and distal penumbra is critical

Urie M. M. et al (1986), “Proton beam penumbra: effects of separation between patient and beam modifying devices,” Med Phys. 13, 734.

Combination of Proton Beams

• Excellent sparing of critical structures

• No perfect match between fields

• Dose non-uniformity at field junction

• “hot” and “cold” regions are possible

• Clinical judgment required

Lateral field

Patch field 2

Patc

h fie

ld 1

Critical structure

Lateral Penumbra

• Penumbra factors:• Upstream devices

– scattering foils

– range shifter

– modulator wheel

– bolus

• Air gap• Patient scatter

Air gap

100

80

0

60

40

20

25 0 20 15 10 5

Distance [mm]

% D

ose BA

A - no air gapB - 40 cm air gap

80%-20%80%-20%

Lateral Penumbra

• Thickness of bolus , width of air gap lateral penumbra

• Dose algorithms can be inaccurate in predicting penumbra

Russel K. P. et al (2000), “Implementation of pencil kernel and depth penetration algorithms for treatment planning of proton beams,” Phys Med Biol 45, 9.

10

8

0

6

4

2

16 0 12 8 4

no bolus

Measurement

5 cm bolus

20-8

0% p

enu

mb

ra

Air gap [cm]

Pencil beam

Ray tracing

Nuclear Data for Treatment Planning (TP)

Experiment Theory

Evaluation

Radiation TransportCodes for TP‡

Validation

Quality Assurance

Recommended Data†

† e.g., ICRU Report 63‡ e.g., Peregrine

Integral tests,

benchmarks

Nuclear Data for Proton Therapy

Application Quantities needed

Loss of primary protons Total nonelastic cross sections

Dose calculation, radiation Diff. and doublediff. cross sectionstransport for neutron, charged particles, and

emission

Estimation of RBE average energies for light ejectilesproduct recoil spectra

PET beam localization Activation cross sections

Selection of Elements

Element Mainly present in ’

H, C, O Tissue, bolus

N, P Tissue, bone

Ca Bone, shielding materials

Si Detectors, shielding materials

Al, Fe, Cu, W, Pb Scatterers, apertures, shielding materials

Nuclear Data for Proton Therapy

• Internet sites regarding nuclear data:– International Atomic Energy Agency (Vienna)

– Online telnet access of Nuclear Data Information System

– Brookhaven National Laboratory

– Online telnet access of National Nuclear Data Center

– Los Alamos National Laboratory

– T2 Nuclear Information System.

– OECD Nuclear Energy Agency

– NUKE - Nuclear Information World Wide Web

Nonelastic Nuclear Reactions

• Remove primary protons• Contribute to absorbed dose:

– 100 MeV, ~5%– 150 MeV, ~10%– 250 MeV, ~20%

• Generate secondary particles– neutral (n, )– charged (p, d, t, 3He, ,

recoils)

400 10 15 20 25 30 355

250 MeV

Depth [cm]

En

ergy

Dep

osit

ion

(d

E/d

x) All interactions Electronic interactionsNuclear interactions

Nonelastic Nuclear Reactions

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0 50 100 150 200 250 300

Energy [MeV]

s [

bar

n]

p + 16O

p + 14N

p + 12C

Source: ICRU Report 63, 1999

Total Nonelastic Cross Sections

Proton Beam Activation Products

Activation Product Application / Significance

Short-lived + emitters in-vivo dosimetry(e.g., 11C, 13N, 18F) beam localization7Be none

Medium mass products none(e.g., 22Na, 42K, 48V, 51Cr)

Long-lived products in radiation protectioncollimators, shielding

Positron Emission Tomography (PET) of Proton Beams

Reaction Half-life Threshold Energy (MeV) e

16O(p,pn)15O 2.0 min 16.6 16O(p,2p2n)13N 10.0 min 5.516O(p,3p3n)13C 20.3 min 14.314N(p,pn)13N 10.0 min 11.314N(p,2p2n)11C 20.3 min 3.112C(p,pn)17N 20.3 min 20.3

PET Dosimetry and Localization

• Experiment vs. simulation– activity plateau (experiment)

– maximum activity (simulation)

– cross sections may be inaccurate

– activity fall-off 4-5 mm before Bragg peak

2 4 6 8 100

Depth [cm]

Act

ivit

y dE

/dx

PET experiment

calculated activity

calculated energydeposition

110 MeV p on Lucite, 24 min after irradiation

Del Guerra A., et al. (1997) “PET Dosimetry in proton radiotherapy: a Monte Carlo Study,” Appl. Radiat. Isot. 10-12, 1617.

PET Localization for Functional Proton Radiosurgery

• Treatment of Parkinson’s disease• Multiple narrow p beams of high

energy (250 MeV)• Focused shoot-through

technique• Very high local dose (> 100 Gy)• PET verification possible after

test dose

Relative Biological Effectiveness (RBE)

• Clinical RBE: 1 Gy proton dose 1.1 Gy Cobalt dose (RBE = 1.1)

• RBE vs. depth is not constant• RBE also depends on

– dose

– biological system (cell type)

– clinical endpoint (early response, late effect)

Linear Energy Transfer (LET) vs. Depth

100 MeV 250 MeV40 MeV

Depth

RBE vs. LET

100 102 103 1041010.0

2.0

3.0

4.0

5.0

6.0

LET [keV/m]

RB

E

1.0

high

low

Source: S.M. Seltzer, NISTIIR 5221

RBE of a Modulated Proton Beam

1.7

4 6 8 12 14 16 18 200 102

0.8

0.6

0.20.4

0.9

0.0

1.11.21.31.41.51.6

1.0Modulated beam

160 MeV

Depth [cm]

RB

E

low

high

Rel

ativ

e d

ose

1.0

Clinical RBE

Source: S.M. Seltzer, NISTIIR 5221

Open RBE Issues

• Single RBE value of 1.1 may not be sufficient

• Biologically effective dose vs. physical dose

• Effect of proton nuclear interactions on RBE

• Energy deposition at the nanometer level - clustering of DNA damage

Summary

• Areas where (high-energy) physics may contribute to proton radiation therapy:– Development of proton computed tomography– Nuclear data evaluation and benchmarking– Radiation transport codes for treatment planning– In vivo localization and dosimetry of proton beams– Influence of nuclear events on RBE