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VIEWS: 22 PAGES: 48

									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 (1967)          172
                                                                                   Moscow (1969)        3414
                                                                                   St. Petersburg (1969) 1029
                                                   Uppsala (1957):       309
                             HCL (1961)            PSI (1984):         3935
LLUMC (1990)                   6174                Clatterbridge(1989): 1033                       Chiba (1979)     133
   6174                                            Nice (1991):         1590                       Tsukuba (1983)   700
                                                   Orsay (1991):        1894                       Kashiwa (1998)    75
                                                   Berlin (1998):        166




                                                                            NAC (1993)
                                                                              398


               *from: Particles, Newsletter (Ed J. Sisterson), No. 28. July 2001
 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)
                                                     e
   – ionization                        (a)                  p’
   – excitation                                   q
                                          p
• Nuclear (b-d)                        (b)
   – Multiple Coulomb scattering (b),            p’
     small q                               p
   – Elastic nuclear collision (c),     (c) p’    nucleus
     large q                                     e
   – Nonelastic nuclear interaction (d)
                                            p        g, n
                                        (d)       nucleus
          Why Protons are advantageous
• Relatively low entrance dose
  (plateau)                                      10 MeV X-rays
                                                                  Modulated
                                                                 Proton Beam
• Maximum dose at depth




                                 Relative Dose
  (Bragg peak)
• Rapid distal dose fall-off
• Energy modulation
                                                   Unmodulated
  (Spread-out Bragg peak)
                                                   Proton Beam
• RBE close to unity
                                                     Depth in Tissue
        Uncertainties in Proton Therapy
° Patient related:          ° Physics related:
    •   Patient setup         • CT number conversion
    •   Patient movements     • Dose calculation
    •   Organ motion
    •   Body contour        ° Machine related:
    •   Target definition    • Device tolerances
° Biology related:           • Beam energy
    • Relative biological
      effectiveness (RBE)
             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      X-ray tube
  CT numbers to relative                      Detector array
  proton stopping power
     Processing of Imaging Data

H = 1000   mtissue /mwater            SP = dE/dxtissue /dE/dxwater

            CT                                 Relative
         Hounsfield                             proton
         values (H)                            stopping
                             Calibration      power (SP)
                               curve
                                                               Dose
                                                            calculation
    SP




                                               Isodose
                H                            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*
                                                                                  2000
• Step 1: Parameterization of H




                                                     Hounsfield value (observed
                                                                                  1800
   – Choose tissue substitutes
                                                                                  1600
   – Obtain best-fitting parameters A,
     B, C                                                                         1400


                                                                                  1200


H = Nerel {A (ZPE)3.6 + B (Zcoh)1.9 + C}                                          1000


                                                                                   800
  Rel.       Photo                                                                    800   1000 1200 1400 1600 1800 2000
                        Coherent     Klein-
  electron   electric   scattering   Nishina                                             Hounsfield value (expected)
  density    effect
                                     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
                                              1.8
• Step 2: Define Calibration Curve            1.6
   – select different standard tissues        1.4
     with known composition (e.g.,            1.2        Fat
     ICRP)                                     1




                                         SP
   – calculate H using parametric             0.8

     equation for each tissue                 0.6

   – calculate SP using Bethe Bloch           0.4

                                              0.2
     equation
                                               0
   – fit linear segments through data               0   500    1000   1500   2000   2500
     points                                                    H value
                 CT Range Uncertainties

• Two types of uncertainties
   – inaccurate model parameters
   – beam hardening artifacts
• Expected range errors                1 mm                 4 mm



              Soft tissue                Bone              Total
       H2O range      abs. error   H2O range  abs. Error   abs. error
       (cm)           (mm)         (cm)       (mm)         (mm)
 Brain   10.3          1.1         1.8         0.3          1.4
 Pelvis 15.5           1.7         9           1.6          3.3
 Proton Transmission Radiography - PTR
                                   MWPC 1   MWPC 2
• First suggested by Wilson
  (1946)
                                   p
• Images contain residual




                                                     Energy detector
  energy/range information of
  individual protons
• Resolution limited by multiple
  Coulomb scattering
• Spatial resolution of 1mm
  possible

                                               SC
  Comparison of CT Calibration Methods

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




                                   No of PTR pixels [%]
  CT-predicted integrated
  stopping power
• Sheep head used as model
• Stoichiometric calibration (A)
  better than tissue substitute
  calibrations (B & C)                                    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
                                     Si MS 1 Si MS 2   Si MS 3 SC   ED
• Conceptual design
  –   single particle resolution                             x
  –   3D track reconstruction
  –   Si microstrip technology     p cone
  –   cone beam geometry           beam
  –   rejection of scattered
      protons & neutrons
                                      Trigger logic

                                        DAQ
                  Proton Beam Design
                  Aperture
                                Inhomogeneity
Modulator wheel         Bolus
  Proton Beam Shaping Devices




Wax bolus   Cerrobend aperture   Modulating wheels
           Ray-Tracing Dose Algorithm
• One-dimensional dose
  calculation
• Water-equivalent depth          WED
  (WED) along single ray
  SP
• Look-up table
• Reasonably accurate for   S           P
  simple hetero-geneities
• Simple and fast
                   Effect of Heterogeneities
     Protons

                                                       No heterogeneity



             Bone                                  W = 1 mm
Water                         W = 1 mm
W                                                  W = 2 mm


                                                   W = 4 mm
    Central axis                      W = 10 mm


                                  5               10            15
                                        Depth [cm]
                             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


                                WED
• Cylindrical coordinates
• Measured or calculated
  pencil kernel    S
                                      P
• Water-equivalent depth
• Accounts for multiple
  Coloumb scattering
• more time consuming
        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
• Excellent sparing of
  critical structures
• No perfect match           Lateral field
  between fields
• Dose non-uniformity at
  field junction
• “hot” and “cold” regions
  are possible
• Clinical judgment                     Critical structure
  required
                  Lateral Penumbra

• Penumbra factors:                      100
                                                                               A - no air gap
• Upstream devices                           80                                B - 40 cm air gap

   –                                                    A            B




                                    % Dose
       scattering foils                      60
   –   range shifter
                                             40
   –   modulator wheel
                                             20
   –   bolus                                          80%-20%        80%-20%

• Air gap                                    0
                                                  0     5       10       15      20     25
• Patient scatter                                               Distance [mm]
                          Air gap
                                   Lateral Penumbra
                                                                        10
                                                                                Pencil beam
• Thickness of bolus ,




                                                      20-80% penumbra
                                                                        8       Ray tracing             5 cm bolus
  width of air gap                                                             Measurement
   lateral penumbra                                                   6

                                                                        4
• Dose algorithms can be                                                                                  no bolus
  inaccurate in predicting                                              2
  penumbra
                                                                        0
                                                                            0      4            8             12      16
                                                                                       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.
Nuclear Data for Treatment Planning (TP)
         Experiment                   Theory


                       Evaluation
                                                   †   e.g., ICRU Report 63
  Integral tests,
                       Validation                  ‡   e.g., Peregrine
  benchmarks

                    Quality Assurance

                                               Radiation Transport
                Recommended         Data†
                                                 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
   –   T2 Nuclear Information System.
   –   OECD Nuclear Energy Agency
   –   NUKE - Nuclear Information World Wide Web
           Nonelastic Nuclear Reactions
• Remove primary protons
• Contribute to absorbed




                                Energy Deposition (dE/dx)
                                                                                    All interactions
  dose:                                                                             Electronic interactions
                                                                250 MeV             Nuclear interactions
  – 100 MeV, ~5%
  – 150 MeV, ~10%
  – 250 MeV, ~20%
• Generate secondary
  particles
  – neutral (n, g)
  – charged (p, d, t, 3He, a,                               0   5   10    15   20   25       30      35       40
    recoils)                                                              Depth [cm]
                      Nonelastic Nuclear Reactions
                                     Total Nonelastic Cross Sections
           0.60
                                                                            p + 16O
           0.50                                                             p + 14N
           0.40                                                             p + 12C
s [barn]




           0.30
           0.20
           0.10
           0.00
                  0             50               100       150        200      250    300
                                                       Energy [MeV]
                  Source: ICRU Report 63, 1999
  Proton Beam Activation Products

Activation Product             Application / Significance
Short-lived b+ emitters           in-vivo dosimetry
(e.g., 11C, 13N, 18F)             beam localization
7Be                               none
Medium mass products              none
(e.g., 22Na, 42K, 48V, 51Cr)
Long-lived products in            radiation protection
collimators, 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            5.5
16O(p,3p3n)13C    20.3 min          14.3
14N(p,pn)13N      10.0 min          11.3
14N(p,2p2n)11C    20.3 min            3.1
12C(p,pn)17N      20.3 min          20.3
           PET Dosimetry and Localization
                                                                     110 MeV p on Lucite,
• Experiment vs. simulation                                          24 min after irradiation
   – activity plateau (experiment)
   – maximum activity




                                                      Activity
     (simulation)




                                                                                                          dE/dx
                                                                           PET experiment
   – cross sections may be                                                 calculated activity
                                                                           calculated energy
     inaccurate                                                            deposition
   – activity fall-off 4-5 mm
     before Bragg peak
   Del Guerra A., et al. (1997) “PET Dosimetry in
   proton radiotherapy: a Monte Carlo Study,” Appl.
   Radiat. Isot. 10-12, 1617.                                    0   2        4          6       8   10
                                                                           Depth [cm]
     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 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 MeV      100 MeV     250 MeV




                Depth
                             RBE vs. LET

          6.0

          5.0                        high

          4.0
   RBE




          3.0

          2.0

          1.0                               low

          0.0
             100               101        102       103   104
                                     LET [keV/mm]
Source: S.M. Seltzer, NISTIIR 5221
            RBE of a Modulated Proton Beam
                                        1.7
                                        1.6                                                   high
                                                                          160 MeV
                        RBE             1.5
                                        1.4
                                        1.3
                                        1.2           Clinical RBE
                                        1.1                                                   low
                                        1.0
                                        0.9

                                        1.0
                        Relative dose




                                        0.8                              Modulated beam
                                        0.6
                                        0.4
Source: S.M. Seltzer,                   0.2
NISTIIR 5221                            0.0
                                              0   2     4    6       8   10   12   14   16   18 20
                                                                     Depth [cm]
                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

								
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