The Use of High-Energy Protons in Cancer Therapy

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 1954 1958 1967 1974 • 1990 R. Wilson suggests use of protons First treatment of pituitary tumors First use of protons as a neurosurgical tool First large-field proton treatments in Sweden Large-field fractionated proton treatments program begins at HCL, Cambridge, MA First hospital-based proton treatment center opens at Loma Linda University Medical Center

World Wide Proton Treatments* Dubna (1967) 172 Moscow (1969) 3414 St. Petersburg (1969) 1029 LLUMC (1990) 6174 HCL (1961) 6174 Uppsala (1957): 309 PSI (1984): 3935 Clatterbridge(1989): 1033 Nice (1991): 1590 Orsay (1991): 1894 Berlin (1998): 166 NAC (1993) 398 *from: Particles, Newsletter (Ed J. Sisterson), No. 28. July 2001 Chiba (1979) Tsukuba (1983) Kashiwa (1998) 133 700 75

LLUMC Proton Treatment Center Hospital-based facility 40 -250 Me. V Synchrotron Gantry beam line Fixed beam line

Main Interactions of Protons p p • Electronic (a) – ionization – excitation • Nuclear (b-d) e (a) p (b) – Multiple Coulomb scattering (b), small q p – Elastic nuclear collision (c), (c) p’ large q – Nonelastic nuclear interaction (d) p’ q p’ nucleus e g, n nucleus

Why Protons are advantageous • Relatively low entrance dose (plateau) • Rapid distal dose fall-off • Energy modulation (Spread-out Bragg peak) • RBE close to unity Relative Dose • Maximum dose at depth (Bragg peak) 10 Me. V X-rays Modulated Proton Beam Unmodulated Proton Beam Depth in Tissue

Uncertainties in Proton Therapy ° Patient related: • • • Patient setup Patient movements Organ motion Body contour Target definition ° Biology related: • Relative biological effectiveness (RBE) ° Physics related: • CT number conversion • Dose calculation ° Machine related: • Device tolerances • Beam energy

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) • Faithful reconstruction of patient’s anatomy • Stacked 2 D maps of linear X-ray attenuation • Electron density relative to water can be derived • Calibration curve relates CT numbers to relative proton stopping power X-ray tube Detector array

Processing of Imaging Data H = 1000 mtissue /mwater SP = d. E/dxtissue /d. E/dxwater CT Hounsfield values (H) Dose calculation SP Calibration curve Relative proton stopping power (SP) H Isodose distribution

CT Calibration Curve • 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 Stoichiometric Method* • Step 1: Parameterization of H – Choose tissue substitutes – Obtain best-fitting parameters A, B, C H = Nerel {A (ZPE)3. 6 + B (Zcoh)1. 9 + C} Rel. electron density Photo electric effect Coherent scattering Klein. Nishina cross section *Schneider U. (1996), “The calibraion of CT Hounsfield units for radiotherapy treatment planning, ” Phys. Med. Biol. 47, 487.

CT Calibration Curve Stoichiometric Method • 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 H 2 O range abs. error (cm) (mm) Brain 10. 3 1. 1 Pelvis 15. 5 1. 7 1 mm Bone H 2 O range abs. Error (cm) (mm) 1. 8 0. 3 9 1. 6 4 mm Total abs. error (mm) 1. 4 3. 3

Proton Transmission Radiography - PTR MWPC 2 p Energy detector • First suggested by Wilson (1946) • Images contain residual energy/range information of individual protons • Resolution limited by multiple Coulomb scattering • Spatial resolution of 1 mm possible MWPC 1 SC

• 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) No of PTR pixels [%] Comparison of CT Calibration Methods SPcalc - Spmeas [%]

Proton Beam Computed Tomography • Proton CT for diagnosis – first studied during the 1970 s – 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 1990 s (2 Ph. D. theses) – preliminary results are promising – further R&D needed

Proton Beam Computed Tomography • Conceptual design – – – single particle resolution 3 D track reconstruction Si microstrip technology cone beam geometry rejection of scattered protons & neutrons Si MS 1 Si MS 2 Si MS 3 SC x p cone beam Trigger logic DAQ ED

Proton Beam Design Aperture Modulator wheel Bolus Inhomogeneity

Proton Beam Shaping Devices Wax bolus Cerrobend aperture 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 Protons Water Bone W Central axis dose No heterogeneity W = 1 mm W = 2 mm W = 4 mm Central axis W = 10 mm 5 10 Depth [cm] 15

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. Alderson Head Phantom

Pencil Beam Dose Algorithm • Cylindrical coordinates • Measured or calculated S pencil kernel • Water-equivalent depth • Accounts for multiple Coloumb scattering • more time consuming WED P

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 Ray-tracing Pencil beam Monte Carlo 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 Lateral field Pa Critical structure d 2 iel tch fie hf ld 1 tc Pa • 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 Penumbra • Penumbra factors: • Upstream devices scattering foils range shifter modulator wheel bolus A - no air gap B - 40 cm air gap 80 % Dose – – 100 A 60 40 20 0 • Air gap • Patient scatter B 80%-20% 0 5 80%-20% 10 15 20 Distance [mm] Air gap 25

Lateral Penumbra • Thickness of bolus , width of air gap lateral penumbra • Dose algorithms can be inaccurate in predicting penumbra 20 -80% penumbra 10 8 Pencil beam 5 cm bolus Ray tracing Measurement 6 4 no bolus 2 0 0 4 8 12 Air gap [cm] 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. 16

Nuclear Data for Treatment Planning (TP) Experiment Theory Evaluation Integral tests, benchmarks † Validation e. g. , ICRU Report 63 ‡ e. g. , Peregrine Quality Assurance Recommended Data† Radiation Transport Codes for TP‡

Nuclear Data for Proton Therapy Application Quantities needed Loss of primary protons Total nonelastic cross sections Dose calculation, radiation Diff. and doublediff. cross sections transport for neutron, charged particles, and g emission Estimation of RBE average energies for light ejectiles product 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 T 2 Nuclear Information System. OECD Nuclear Energy Agency NUKE - Nuclear Information World Wide Web

• Remove primary protons • Contribute to absorbed dose: – 100 Me. V, ~5% – 150 Me. V, ~10% – 250 Me. V, ~20% • Generate secondary particles – neutral (n, g) – charged (p, d, t, 3 He, a, recoils) Energy Deposition (d. E/dx) Nonelastic Nuclear Reactions All interactions Electronic interactions Nuclear interactions 250 Me. V 0 5 10 15 20 25 Depth [cm] 30 35 40

Nonelastic Nuclear Reactions Total Nonelastic Cross Sections p + 16 O p + 14 N p + 12 C Source: ICRU Report 63, 1999

Proton Beam Activation Products Activation Product Application / Significance Short-lived b+ emitters (e. g. , 11 C, 13 N, 18 F) in-vivo dosimetry beam localization 7 Be none Medium mass products (e. g. , 22 Na, 42 K, 48 V, 51 Cr) none Long-lived products in collimators, shielding radiation protection

Positron Emission Tomography (PET) of Proton Beams Reaction 16 O(p, pn)15 O Half-life Threshold Energy (Me. V) e 2. 0 min 16. 6 16 O(p, 2 p 2 n)13 N 10. 0 min 5. 5 16 O(p, 3 p 3 n)13 C 20. 3 min 14. 3 14 N(p, pn)13 N 10. 0 min 11. 3 14 N(p, 2 p 2 n)11 C 20. 3 min 3. 1 12 C(p, pn)17 N 20. 3 min 20. 3

PET Dosimetry and Localization 110 Me. V 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. d. E/dx – activity plateau (experiment) – maximum activity (simulation) – cross sections may be inaccurate – activity fall-off 4 -5 mm before Bragg peak Activity • Experiment vs. simulation PET experiment calculated activity calculated energy deposition 0 2 4 6 Depth [cm] 8 10

PET Localization for Functional Proton Radiosurgery • Treatment of Parkinson’s disease • Multiple narrow p beams of high energy (250 Me. V) • 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 g 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 40 Me. V 100 Me. V Depth 250 Me. V

RBE vs. LET 6. 0 high RBE 5. 0 4. 0 3. 0 2. 0 low 1. 0 0. 0 101 Source: S. M. Seltzer, NISTIIR 5221 102 LET [ke. V/mm] 103 104

Source: S. M. Seltzer, NISTIIR 5221 Relative dose RBE of a Modulated Proton Beam 1. 7 1. 6 1. 5 1. 4 1. 3 1. 2 1. 1 1. 0 0. 9 1. 0 0. 8 0. 6 0. 4 0. 2 0. 0 high 160 Me. V Clinical RBE low Modulated beam 0 2 4 6 8 10 12 Depth [cm] 14 16 18 20

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