The Use of High-Energy Protons in Cancer Therapy Reinhard W.

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 Medical Center

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

LLUMC Proton Treatment Center Hospital-based facility 40-250 MeV 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 p – Elastic nuclear collision (c), (c) p’ large – Nonelastic nuclear interaction (d) p (d) p’ p’ nucleus e 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 MeV 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 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 X-ray tube Detector array

Processing of Imaging Data H 1000 tissue / water SP dE/dxtissue /dE/dxwater CT CT Hounsfield Hounsfield values values(H) (H) Dose calculation SP Calibration curve Relative Relative proton proton stopping stopping power power(SP) (SP) H Isodose Isodose distribution 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

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 KleinNishina cross section Hounsfield value (observed CT Calibration Curve Stoichiometric Method* 2000 1800 1600 1400 1200 1000 800 800 1000 1200 1400 1600 1800 2000 Hounsfield value (expected) *Schneider U. (1996), “The calibraion of CT Hounsfield units for radiotherapy treatment planning,” Phys. Med. Biol. 47, 487.

CT Calibration Curve Stoichiometric Method 1.8 Step 2: Define Calibration Curve 1.4 Fat 1.2 SP – 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 1.6 1 0.8 0.6 0.4 0.2 0 0 500 1000 1500 H value 2000 2500

CT Range Uncertainties Two types of uncertainties – inaccurate model parameters – beam hardening artifacts Expected range errors Soft tissue H2O range abs. error (cm) (mm) Brain 10.3 1.1 Pelvis 15.5 1.7 1 mm Bone H2O 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 1mm 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 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 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 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 Critical structure 2 ld Pa tc fie hf iel d 1 t ch 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 60 B 40 20 0 Air gap Patient scatter A 0 80%-20% 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 Loss of primary protons Quantities needed Total nonelastic cross sections Dose calculation, radiation Diff. and doublediff. cross sections transportfor neutron, charged particles, and 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 materials Scatterers, apertures, shielding ’

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

Nonelastic Nuclear Reactions Total Nonelastic Cross Sections 0.60 p 16O s [barn] 0.50 p 14N 0.40 p 12C 0.30 0.20 0.10 0.00 0 50 100 150 Energy [MeV] Source: ICRU Report 63, 1999 200 250 300

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

Positron Emission Tomography (PET) of Proton Beams Reaction Half-life Threshold Energy (MeV) e 16 O(p,pn)15O 2.0 min 16 O(p,2p2n)13N 10.0 min 5.5 16 O(p,3p3n)13C 20.3 min 14.3 14 N(p,pn)13N 10.0 min 11.3 14 N(p,2p2n)11C 20.3 min 3.1 12 C(p,pn)17N 20.3 min 20.3 16.6

PET Dosimetry and Localization 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. dE/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 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 40 MeV 100 MeV Depth 250 MeV

RBE vs. LET 6.0 high RBE 5.0 4.0 3.0 2.0 low 1.0 0.0 100 101 Source: S.M. Seltzer, NISTIIR 5221 102 LET [keV/ m] 103 104

Source: S.M. Seltzer, NISTIIR 5221 Relative dose RBE 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 MeV 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