2. The Use of High-Energy Protons in Cancer Therapy Reinhard W. Schulte Loma Linda University Medical Center

3. 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.

4. History of Proton Beam Therapy 1946R. Wilson suggests use of protons 1954First treatment of pituitary tumors 1958 First use of protons as a neurosurgical tool 1967First large-field proton treatments in Sweden 1974Large-field fractionated proton treatments program begins at HCL, Cambridge, MA 1990First hospital-based proton treatment center opens at Loma Linda University Medical Center

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

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

7. 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 nucleus  n p’ p e nucleus (b) (c) (d) (a) 

8. 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 Depth in Tissue Relative Dose 10 MeV X-rays Modulated Proton Beam Unmodulated Proton Beam

9. 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:

10. 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

11. Treatment Delivery Fabrication of apertures and boluses Beam calibration Alignment of patient using DRRs Computer-controlled dose delivery

12. 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

13. Processing of Imaging Data CT Hounsfield values (H) Isodose distribution Calibration curve H = 1000  tissue /  water Relative proton stopping power (SP) SP = dE/dx tissue /dE/dx water H SP Dose calculation

14. 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

15. CT Calibration Curve Stoichiometric Method * Step 1: Parameterization of H –Choose tissue substitutes –Obtain best-fitting parameters A, B, C H = N e rel { A (Z PE ) 3.6 + B (Z coh ) 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.

16. 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

17. CT Range Uncertainties Two types of uncertainties –inaccurate model parameters –beam hardening artifacts Expected range errors Soft tissueBoneTotal H 2 O rangeabs. error H 2 O rangeabs. Errorabs. 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 1 mm4 mm

18. 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 Energy detector

19. 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) SP calc - Sp meas [%] No of PTR pixels [%]

20. 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

21. 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 2EDSi MS 1Si MS 3SC x p cone beam

22. Proton Beam Design Modulator wheel Aperture Bolus Inhomogeneity

23. Proton Beam Shaping Devices Cerrobend apertureWax bolusModulating wheels

24. 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

25. Effect of Heterogeneities W = 10 mm W = 4 mm W = 2 mm W = 1 mm No heterogeneity Bone Water Protons W Central axis Depth [cm] 15510 Central axis dose

26. 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.

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

28. 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

29. Comparison of Dose Algorithms Protons Bone Water Monte CarloRay-tracingPencil beam Petti P. (1991), “Differential-pencil-beam dose calculations for charged particles,” Med Phys. 19, 137.

30. 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.

31. 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 Patch field 1 Critical structure

32. 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] % Dose BA A - no air gap B - 40 cm air gap 80%-20%

33. 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 20-80% penumbra Air gap [cm] Pencil beam Ray tracing

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

35. Nuclear Data for Proton Therapy Application Quantities needed Loss of primary protonsTotal nonelastic cross sections Dose calculation, radiationDiff. and doublediff. cross sections transportfor neutron, charged particles, and  emission Estimation of RBEaverage energies for light ejectiles product recoil spectra PET beam localizationActivation cross sections

36. Selection of Elements Element Mainly present in ’ H, C, OTissue, bolus N, PTissue, bone CaBone, shielding materials SiDetectors, shielding materials Al, Fe, Cu, W, PbScatterers, apertures, shielding materials

37. 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

38. 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, 3 He, , recoils) 4001015202530355 250 MeV Depth [cm] Energy Deposition (dE/dx) All interactions Electronic interactions Nuclear interactions

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

40. Proton Beam Activation Products Activation Product Application / Significance Short-lived  + emittersin-vivo dosimetry (e.g., 11 C, 13 N, 18 F)beam localization 7 Benone Medium mass productsnone (e.g., 22 Na, 42 K, 48 V, 51 Cr) Long-lived products in radiation protection collimators, shielding

41. Positron Emission Tomography (PET) of Proton Beams Reaction Half-life Threshold Energy (MeV) e 16 O(p,pn) 15 O 2.0 min16.6 16 O(p,2p2n) 13 N10.0 min 5.5 16 O(p,3p3n) 13 C20.3 min14.3 14 N(p,pn) 13 N10.0 min11.3 14 N(p,2p2n) 11 C20.3 min 3.1 12 C(p,pn) 17 N20.3 min20.3

42. 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 2468100 Depth [cm] Activity dE/dx PET experiment calculated activity calculated energy deposition 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.

43. 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

44. 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)

45. Linear Energy Transfer (LET) vs. Depth 100 MeV250 MeV40 MeV Depth

46. RBE vs. LET 10 0 10 2 10 3 10 4 10 1 0.0 2.0 3.0 4.0 5.0 6.0 LET [keV/  m] RBE 1.0 high low Source: S.M. Seltzer, NISTIIR 5221

47. RBE of a Modulated Proton Beam 1.7 46812141618200102 0.8 0.6 0.2 0.4 0.9 0.0 1.1 1.2 1.3 1.4 1.5 1.6 1.0 Modulated beam 160 MeV Depth [cm] RBE low high Relative dose 1.0 Clinical RBE Source: S.M. Seltzer, NISTIIR 5221

48. 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

49. 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