Applications of Silicon Detectors in Proton Radiobiology and Radiation Therapy Reinhard W. Schulte Loma Linda University Medical Center Outline • Introduction to proton beam therapy • Applications of silicon detectors – Proton radiography and computed tomography – Particle tracking silicon microscope – Nanodosimetry 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. Short History of Proton Beam Therapy • • • • • • 1946 1954 1956 1958 1967 1974 • 1990 R. Wilson suggests use of protons First treatment of pituitary glands in Berkeley, USA Treatment of pituitary tumors in Berkeley, USA First use of protons as a neurosurgical tool in Sweden 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 Treatment Centers 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 q p – Elastic nuclear collision (c), (c) p’ large q – Nonelastic nuclear interaction (d) p (d) p’ q p’ nucleus e g, n nucleus 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 unity Why Silicon Detectors • Combined measurement of position, angle and energy or LET of single particles • High spatial resolution (microns) • Wide dynamic energy range • radiation hardness • compatibility with physiological conditions of cells Applications of Silicon Detectors • Proton Treatment planning – Proton radiography – Proton computed tomography (CT) • Proton Radiobiology – Particle microscope – Nanodosimetry Proton 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 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 mtissue /mwater SP = dE/dxtissue /dE/dxwater CT Hounsfield values (H) Calibration curve Relative proton stopping power (SP) SP Dose calculation H Isodose distribution CT Calibration Curve Stoichiometric Method* – 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 • Step 1: Parameterization of H 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 Problems with the Current Method • Proton interaction Photon interaction • Multi-segmental calibration curve required • No unique SP values for soft tissue Hounsfield range • Tissue substitutes real tissues • Uncertainty requires larger range to cover tumor • Risk for sensitive structures 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 Proton Range Uncertainties 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 Proton Beam Computed Tomography • Proton CT for diagnosis – first studied for diagnostic use during the 1970s – dose advantage over x rays for similar resolution – not further developed after development of x-ray CT • Proton CT for treatment planning and delivery – renewed interest during the 1990s (2 Ph.D. theses) – fast data acquisition and proton gantries available – further R&D needed Proton Beam Computed Tomography • Applications – Precise calculation of dose distributions – 3D verification of dose patient treatment position – tumor delineation without need of contrast media Proton Beam Computed Tomography • Conceptual design – – – – – – – single particle resolution 3D track reconstruction Si microstrip detectors p cone beam geometry multiple beam directions energy loss measurement analysis of scattering and nuclear interactions SSD 3 SSD 1 p cone beam Trigger logic DAQ SSD 2 SSD 4 ED Development of Proton Beam Computed Tomography • Experimental Study – two detector planes – water phantom on turntable Si module 1 Si module 2 Scattering foil • Theoretical Study – GEANT MC simulation – influence of MCS and range straggling – importance of angular measurements Proton beam Turntable Water phantom Applications of Silicon Detectors • Proton Treatment Planning – Proton radiography – Proton computed tomography (CT) • Proton Radiobiology – Particle microscope – Nanodosimetry Proton Radiobiology in Perspective D = 1 Gy n = 416 dE/dx per mm 1.3 keV 50 MeV protons 36 ionizations n = 112 4.7 keV 10 MeV protons 134 ionizations n = 54 10 keV 4 MeV protons 10 mm 276 ionizations RBE* 1.1 1.4 2.0 * rel to 60 Co g rays Study of Cellular Radiation Responses in vitro (in glass ware): • single cell suspension seeded in culture flasks or Petri dishes • immortalized cell lines • exponential or stationary phase in vivo (in a living organism): • tumor growth in animals • normal tissue response in animals (e.g., crypt cells) • response of microscopic animals (e.g., nematodes) Study of Cell Survival in vitro Study of cell survival in vitro • seeded cells are incubated for 3 - 14 days • ‘surviving cells’ form large colonies (> 50 cells) • surviving fraction is defined as Surviving Fraction ( S ) # colonies counted # cells seeded (PE(%)/100 ) • plating efficiency (PE) is defined as the fraction (%) of cells in an unirradiated culture that form colonies 1- S 0.1 - 0.01 - Dose Applications of Silicon Detectors • Proton Treatment Planning – Proton radiography – Proton computed tomography (CT) • Proton Radiobiology – Particle microscope – Nanodosimetry Particle Tracking Silicon Microscope • Conventional radiobiological experiment – random traversal of cells by a broad particle beam – only average number of hits per cell is known • Particle-tracking radiobiological experiment – number of particles per cell is exactly known – broad beam or microbeam setup l = 1.5 P(n) = ln/n! e-l SSD n=2 1 3 0 collimator SSD n=0 0 3 0 Particle Tracking Silicon Microscope • Conceptual design – biological targets located on detector surface – single-particle tracking – energy or LET measurement – ASIC and controller design adapted to application – dedicated data acquisition system MCM DSSD ASIC RO Control Cables DAQ Low-Dose Cell Survival • Low-dose studies with a proton microbeam – precise low-dose/fluence cell survival curves – hypersensitive region at low doses – more pronounced at higher proton energies (3.2 MeV vs. 1 MeV) Dose (Gy) 3.2 MeV protons Schettino et al. Radiation Res. 156, 526-534, 2001 Adaptive Response & Bystander Effect • Low-dose studies with an alpha particle microbeam – only 10% of cells exposed – more cells inactivated than traversed (bystander effect) – previous exposure to low level of DNA damage increases resistance (adaptive response) --- expected -o- 6 hrs after priming g dose -•- 6 hrs after priming g dose Sawant et al. Radiation Res. 156, 177-180, 2001 Goals of the LLU/SCIPP Particle Tracking Microscope Project • Develop a versatile and inexpensive broad-beam and microbeam particle tracking system for – – – – – protons and alpha particles wide range of energies (1 MeV - 70 MeV protons) in vitro and in vivo radiobiological studies research studies for radiation therapy and protection support of DOE and NASA low-dose research programs Applications of Silicon Detectors • Proton Treatment Planning – Proton radiography – Proton computed tomography (CT) • Proton Radiobiology – Particle microscope – Nanodosimetry Nanodosimetry Collaboration Loma Linda University Medical Center (1997) Weizmann Institute of Science (1997) UCSD (1998) UCSC (2000) SCIPP Nanodosimetry Concepts • DNA is the principle target in radiobiology • Radiation interaction with DNA is a stochastic event • Single damages (break or base oxidation) are easily repaired • Clustered damages are difficult or impossible to repair Single damage reparable charged particle d electron 50 base pair DNA segment Clustered damage irreparable ~2nm Conceptual Approaches Track Structure Imaging Single-Volume Sampling Mean Free Path versus Gas Pressure • Mean free path: 1 Torr Propane (C3H8) l = 1 / (n s) – n, targets per unit volume – s, interaction cross section target projectile l • Assumptions: – same atomic composition – s is independent of density • Density Scaling: lgas = (rref / rgas) lref 1 mm in 1 Torr propane 2.4 nm in unit density material Ion Counting Nanodosimetry E1 ions SV particle gas E2 aperture vacuu m trigger Ion counter DAQ 0.1 Signal [V] • Ionization volume filled with low-pressure gas • single particle detection • ion drift through aperture • wall-less sensitive volume • evacuated ion detection volume SSD SSD 0.0 -0.1 -0.2 -0.3 28 29 30 31 Ion drift time [msec] 32 33 The Ion Counting Nanodosimeter • Pulsed drift field • differential pumping system • electron multiplier • internal alpha source 50mm Anode E1 1 Torr e- particle ion Cathode E2 Intermediate vacuum High vacuum to pump 1 EM to pump 2 Single Charge Counting E1 ions SV Particle detector gas E2 aperture vacuum Ion counter 0.0 -0.1 -0.2 -0.3 trigger DAQ 0.1 Signal [V] • Ionization volume filled with low-pressure gas • single particle detection • ion drift through aperture • wall-less sensitive volume • evacuated ion detection volume 28 29 30 31 Ion drift time [msec] 32 33 The Ion Counting Nanodosimeter • Pulsed drift field • differential pumping system • electron multiplier • four SS detector planes for particle tracking and energy reconstruction Anode 50mm SSD1 SSD2 E1 1 Torr e- particle ion Cathode E2 Intermediate vacuum High vacuum to pump 1 EM to pump 2 Nanodosimetric Spectra • average cluster size increases with increasing LET 1.E+02 Abs. Frequency (%) • ND spectra change with particle type and energy protons alpha 1.E+01 carbon 1.E+00 1.E-01 1.E-02 0 20 40 Cluster size 60 80 Applications • New Standard of Radiation Quality in Mixed Fields • Radiation Treatment Planning: biological weighting factor • Radiation Protection: risk-related weighting factors • Manned Space Flight: Risk prediction (cancer & inherited diseases) Acknowledgements • LLUMC Vladimir Bashkirov George Coutrakon Pete Koss • WIS Amos Breskin Rachel Chechik Sergei Shchemelinin Guy Garty Itzik Orion Bernd Grosswendt - PTB • UCSD - Radiobiology – John Ward – Jamie Milligan – Joe Aguilera • UCSC - SCIPP – – – – – Abe Seiden Hartmut Sadrozinsky Brian Keeney Wilko Kroeger Patrick Spradlin The nanodosimetry project has been funded by the National Medical Technology Testbed (NMTB) and the US Army under the U.S. Department of the Army Medical Research Acquisition Activity, Cooperative Agreement # DAMD17-97-2-7016. The views and conclusions contained in this presentation are those of the presenter and do not necessarily reflect the position or the policy of the U.S. Army or NMTB.