Accelerators and Principles for Hadron Therapy Eal Lee 2012 KAERI REVIEW Major Application Areas of Ion Beam •Nuclear physics •Radiotherapy •Medical radioisotopes production •Radionuclide (medical imaging) •Biomedical research •Other applications (~50%) The main objective of this presentation is to describe the particle accelerators for medical applications, namely for proton therapy. EHL 2012 LECTURE SERIES 2 Contents •Accelerators and Facilities •Physics of Hadron Therapy The goal of any cancer therapy is to destroy the malignant cells in the body while doing minimal damage to the healthy tissue. Modern cancer therapies, no matter if they are chemotherapy, targeted medications, surgery, X-ray therapy, or particle beam therapy, are all about collateral damage: destroy the cancer but not the patient. EHL 2012 LECTURE SERIES 3 Why Use Protons? •Same tumor killing properties as X-rays •Decreased dose to normal tissues by 50-70% •Decreased side-effects and complications •Ability to treat tumors close to critical organs like the spinal cord •With X-rays, 20% of cancers come back because treatment dose was too low to be effective •Possibility to increase the safe dose delivered to tumors •Possibility of increased cure rates •The ability to re-treat tumors after recurrences •The added ability to treat benign conditions Source: Penn Medicine, Perelman Center for Advanced Medicine EHL 2012 LECTURE SERIES 4 Benefits and Experience Benefits • Proton therapy is widely recognized as the most effective external beam method in the selective destruction of cancer cells. • Non-invasive • Minimal side affects • Most precise treatment, targeting only the tumor • Healthy tissue around the tumor is spared Treatment Experience • Treatments are completely painless. • The actual radiation time is a matter of seconds. • Patients receive outpatient treatment, with each appointment time being 15-30 minutes per day for five to eight weeks EHL 2012 LECTURE SERIES 5 Typical Accelerators Used for Hadron Therapy Linac: push particles (timed alternating voltage) Cyclotron: repetitive use of linac (constant B field and constant rf frequency of E-field) Synchrocyclotron: Overcome relativistic effects by synchronized rf E-field (only one dee is used, E-field frequency is decreased as particles get heavier) Synchrotron: Overcome relativistic effects by pulsed magnet and synchronized rf (both B and E field are varied) FFAG: fixed magnet with strong focusing (combine the cyclotron’s advantage of continuous operation with the synchrotron’s relatively inexpensive small magnet ring, of narrow bore) FFAG: Fixed-Field Alternating Gradient EHL 2012 LECTURE SERIES 6 Linear Particle Accelerator (linac) Particles pass through a line of hollow metal tubes enclosed in an evacuated cylinder. An alternating voltage is timed so that a particle is pushed forward each time it goes through a gap between two of the metal tubes. The length of tubes determined by the frequency and power of the driving power source and the nature of the particle to be accelerated, with shorter segments near the source and longer segments near the target. Note that the increased electron energy is exhibited by relativistic changes in mass. Picture source: wikipedia, see also p. 69 Patterson in Ch 3, Rad. Chem. LECTURE SERIES EHL 2012 7 Cyclotron Principle RF Oscillator D1 D2 N So C D1 So D2 S Target Deflector The elements of a cyclotron, showing the particle source ‘So’ and the dees. A uniform magnetic field is directed perpendicular to the dees. Circulating protons spiral outward within the hollow dees, gaining energy every time they cross the gap between the dees, which bias is changing alternately by the RF oscillator. EHL 2012 LECTURE SERIES 8 Inside of Cyclotron The interior of a 235MeV proton cyclotron used for proton therapy The interior of a cyclotron with three spiralled pole sectors with improved vertical focusing properties and more room for the extraction system. -IBA EHL 2012 LECTURE SERIES 9 250 MeV Synchrotron CIS: Circumference = 1/5 C_cooler = 17.364 m Dipole length = 2 m, 90 degree bend, edge angle = 12 deg. Inj KE= 7 MeV, extraction: 250 MeV A synchrotron is a particular type of cyclic particle accelerator in which the magnetic field (to turn the particles so they circulate) and the electric field (to accelerate the particles) are carefully synchronized with the travelling particle beam. However, since the particle momentum increases during acceleration, it is necessary to turn up the magnetic field B in proportion to maintain constant curvature of the orbit. In consequence synchrotrons cannot accelerate particles continuously, as cyclotrons can, but must operate cyclically (cyclic pulse mode), supplying particles in bunches, which are delivered to a target or an external beam in beam "spills" typically every few seconds. - Wikipedia EHL 2012 LECTURE SERIES 10 Lattice Structure of Compact Synchrotron K. Endo, Z. Fang and S. Ninomiya High Energy Accelerator Research Organization (KEK) 1-1 Oho, Tsukuba-shi, Ibaraki-ken 305-0801, Japan EHL 2012 LECTURE SERIES 11 FFAG Accelerator 8 triplet cells A Fixed-Field Alternating Gradient accelerator (FFAG) is a type of circular particle accelerator that has features of cyclotrons and synchrotrons. FFAG accelerators combine the cyclotron's advantage of continuous, unpulsed operation, with the synchrotron's relatively inexpensive small magnet ring, of narrow bore. This is achieved by using magnets with strong focusing alternating-gradient quadrupole fields to confine the beam, accompanied by a dipole bending magnetic field which bends the beam to close the orbital ring. By the use of a strong radial magnetic field gradient in the dipole component, yet with a time-constant "fixed field" as the particles are accelerated, particles with larger energies move successively to slightly larger orbits, where the bending field is larger. The beam thus remains confined to a narrow ring, as in a synchrotron, yet without the synchrotron's requirement that the machine be operated in pulsed acceleration cycles. EHL 2012 LECTURE SERIES 12 Proton Therapy Facilities Typical facility components: (i) accelerator (ii) beam-transport system (iii) treatment-delivery system gantry beam nozzle snout volume-tracking beam-gating device patient-positioning immobilization system (iv) shielded enclosure from radiation EHL 2012 LECTURE SERIES 13 Schematic Representation of Proton Gantry • A rotating beam port, a rotating beam line • For treating the patient in supine position • With maximal flexibility to apply the beam from any desired direction E. Pedroni Center for Proton Radiation Therapy - Paul Scherrer Institute - WE Chiba 01-05-2010 EHL 2012 LECTURE SERIES 14 Energy Selection System (ESS) At 180,000 km/sec, protons penetrate the body to a depth of approximately 38 cm. If a radiation target, i.e., the tumor, is closer to the surface, the protons have to be degraded (slowed down). This occurs immediately after the protons leave the cyclotron in the Energy Selection System (ESS), which places graphite wedges in the path of the beam to achieve the precise speed required. Rinecker Proton Therapy Center, http://www.rptc.de/en/ EHL 2012 LECTURE SERIES 15 Schematic Representation of Nozzle Schematic, not to scale, of the IBA universal nozzle in double-scattering mode. Components are a binary fixed scatterer system (FS: fine-tune the flatness of the lateral dose profile), a range modulator track (RM: flatness of the SOBP in the depth direction), magnets (not used for double scattering), a contoured second scatterer (SS), collimator jaws, monitor unit chamber (IC), and snout, which is the part of the nozzle closest to the patient. The snout supports the aperture/collimator and compensator. -Med Phys. 2009 June; 36(6): 2172–2180. The nozzle also contains beam detectors which control the radiation intensity, the beam energy and thus the penetration depth, and the deflection of the X and Y dimensions. The detectors also match up the desired data for the patient with beam targeting independently of other control functions. The beam then passes through a Kapton plastic window that acts as a vacuum seal and emitted into the open. – Rinecker Proton Therapy Center, http://www.rptc.de/en/ The functions of the nozzles include the 3-D beam shaping to irradiate the target volume at a constant dose, the beam monitoring and dosimetry, to help for patient positioning and field alignment verification, and the support of patient specific devices. The spreading techniques provided by the IBA nozzle are the double scattering for small to moderate fields, and the wobbling technique for the largest and deepest fields. The nozzle is compatible with a future upgrade to pencil beam scanning. – Jongen et al., IBA EHL 2012 LECTURE SERIES 16 Shaping the Beam to the Shape of the Tumor Passive scattering is one possibility to confirm the beam shape to the tumor. By widening the beam and sending it through special collimators the cross section of the beam is shaped to conform exactly to the shape of the tumor in radial direction. Using range modulators (materials with varying thicknesses) together with a compensator bolus (a block of material which is a negative imprint of the far edge of the tumor) the Bragg peak can be adjusted to optimum overlap with the axial dimension of the tumor. Source: EHL 2012 ACT Foundation, llc. LECTURE SERIES 17 Modulator, Collimator, Compensator A modulator (or range shifter wheel) and scatter foil are used to take the thin beam line and widen it to fit the tumor. A collimator and compensator can be used to further shape the beam. A collimator is used to shape the beam coming out of the nozzle and is usually made of brass. A compensator, made of wax or acrylic, shapes the far edge or end of the beam, making some areas more or less deep to contour to the tumor. These pieces are made specifically for each patient's tumor treatment plan. Some cons to passive scatter include the creation of custom pieces for each patient, the disposal of these pieces (as they become radioactive after use and the shifting of dose towards the front end of the beam, towards the skin, which can result in unwanted dose to the patient EHL 2012 LECTURE SERIES 18 Nozzle Operational Modes Single Scattering: Delivers a uniform proton dose in small fields with only one scatterer. Double Scattering: Accepts any energy at nozzle entrance within the 70-235 MeV range. Reduces the distal falloff. Reduces the lateral penumbra and the radiation level. Uniform Scanning: The beam spot is moved by magnetic scanning and allows several mini-irradiations. Full modulation, field uniformity, very safe treatment. Pencil Beam Scanning: Slice-by-slice irradiation of the target with millimeter precision. Primary advantages include: multiple fast repainting, no use of aperture, no compensator devices, dose uniformity, intensity modulation (IMPT), and gating. EHL 2012 LECTURE SERIES 19 Proton Pencil Beam As protons are elementary particles which carry a positive charge they can be deflected and focused in magnetic fields, and the beam can be shaped as desired. The most modern facilities today use a proton beam as thin as a pencil. By varying the energy the depth where the dose is delivered can be varied. By deflecting the beam sideways using magnetic fields one can ‘paint’ a complex picture at a given depth in the body – similar to generating a TV image with a single electron beam scanning across the screen line by line. Combining these two methods (rapidly varying the energy of the beam and painting the tumor cross section slice by slice) any complex shape of a tumor can be covered. Source: EHL 2012 ACT Foundation, llc. LECTURE SERIES 20 Irradiation of Moving Target (e.g., lung tumors) RF-Knock-out (KO) extraction [Moritz et al. 2005]: Allows pausing and resuming within a pulse, Experimental at GSI, standard at HIT Parameters: 2 mm grid spacing; ~18 mm spot size; 1-9 mm gating window Long term: tracking adaptation of beam position to follow target motion Short term: gating restrict irradiation to phases with little motion EHL 2012 LECTURE SERIES 21 Real Time Tumor Tracking Proton Beam Therapy By combining the real-time tumor-tracking radiation therapy and a small system of spot-scanning proton beam technology, it is possible to treat large tumors in moving organs including intractable ones such as lung, liver, and pancreatic cancers, and maximize the effect of proton beam treatment, while greatly reducing the radiation delivered to the surrounding normal tissues. Source: Under development at Hokkaido University Graduate School of Medicine (2011) EHL 2012 LECTURE SERIES 22 Immobilization for Proton Therapy Various patient immobilization devices are used for: • High accuracy and high reproducibility • Patient comfort • Minimization of inter-fraction setup errors • Minimization of residual intra-fraction patient and/or organ motion EHL 2012 LECTURE SERIES 23 Overview of State of The Art Principles of different machine types are used for varying scanning techniques at treatment facilities round the world: NPTC = North East Proton Therapy Centre (USA), PSI = Paul Scherrer Institute (CH), LLUMC = Loma Linda University Medical Centre (USA), HIMAC = Heavy Ion Medical Accelerator (J), GSI = Gesellschaft für Schwerionenforschung (D). M Sholz in M. Regler, M. Benedikt, K. Poljanc, CERN Accelerator School, Hephy-PUB-757/02 LECTURE SERIES EHL 2012 24 Current Locations of Proton Therapy Centers Ilsan, Korea (2007) Fewer than 30 proton therapy centers exist worldwide (red), but a growing number are either planned or already under construction (yellow). (Image courtesy of Jay Flanz, Massachusetts General Hospital.) American Institute of Physics EHL 2012 LECTURE SERIES 25 Ion Beam Therapy in Europe At present, seven facilities in Europe treat deep-seated tumors with particle beams, six with proton beams and one with carbon ions. Three of these facilities are in Moscow, St. Petersburg and Dubna, Russia. Other facilities include the TSL Uppsala, Sweden, CPO Orsay, France, and PSI Villigen, Switzerland, all for proton therapy, and GSI, Darmstadt, Germany, which utilizes carbon ions only. But only two of these facilities irradiate with scanned ion beams: the Paul Scherer Institute (PSI), Villigen (protons) and the Gesellschaft für Schwerionenforschung (GSI), Darmstadt. These two facilities are experimental units within physics laboratories and have developed the technique of intensity-modulated beam scanning in order to produce irradiation conforming to a 3-D target. There are three proton centers presently under construction in Munich, Essen and Orsay, and the proton facility at PSI has added a superconducting accelerator connected to an isocentric gantry in order to become independent of the accelerator shared with the physics research program. The excellent clinical results using carbon ions at National Institute of Radiological Science (NIRS) in Chiba and GSI have triggered the construction of four new heavy-ion therapy projects (carbon ions and protons), located in Heidelberg, Pavia, Marburg and Kiel. The projects in Heidelberg and Pavia will begin patient treatment in 2009, and the Marburg and Kiel projects will begin in 2010 and 2011, respectively. These centers use different accelerator designs but have the same kind of treatment planning system and use the same approach for the calculation of the biological effectiveness of the carbon ions as developed at GSI [1]. There are many other planned projects in the works. Do not replace the word “abstract,” but do replace the rest of this text. If you must insert a hard line break, please use Shift+Enter rather than just tapping your “Enter” key. You may want to print this page and refer to it as a style sample before you begin working on your paper. ©2009 American Institute of Physics EHL 2012 LECTURE SERIES 26 Schematics of Accelerator and Treatment Facilities The proton beam treatment facility at National Cancer Center (NCC), Ilsan Korea, is operational since 2007, which is an IBA 235 MeV cyclotron with energy selection system (ESS), two gantry rooms, one fixed-beam room, expandable by one gantry room. EHL 2012 LECTURE SERIES 27 Construction of Gantry and Treatment Facilities EHL 2012 LECTURE SERIES 28 Cross-Section of Gantry / Treatment Room Curtsey of IBA EHL 2012 LECTURE SERIES 29 Cyclotron A cyclotron accelerates protons to an extremely high speed, then generates a controlled beam that is directed by magnetic fields through a nozzle to the targeted tumor, releasing a dose of protons inside the tumor that kills cancer cells with minimal impact on surrounding healthy tissues. The proton beam can be contoured to the shape of the tumor, further decreasing radiation exposure to healthy cells and limiting side effects. Courtesy of IBA, Belgium EHL 2012 LECTURE SERIES 30 Beam Transport System The beam transport system distributes a beam of proton energy to each of the treatment rooms quickly and efficiently. The beam transport line can be as long as a football field and links the cyclotron to each treatment room. Some treatment rooms are built without a gantry. Courtesy of IBA, Belgium (Installed at Particle Therapy and UFPTI Jacksonville) EHL 2012 LECTURE SERIES 31 Gantry The gantry is a large, sphere shaped structure that houses the equipment used to actually give the protons to the patient. The gantry is three stories tall and built into a large concrete casing. The patient enters the treatment area on the second floor. The gantry allows the beam to spin 360 degrees around the patient. - IBA EHL 2012 LECTURE SERIES 32 Gantry Treatment Room Gantry is a device for rotating the radiation delivery apparatus around the patient during radiation therapy. The gantry rotates around the patient to deliver treatment from different angles, allowing the physician to precisely target the tumor site. Courtesy of IBA, Belgium EHL 2012 LECTURE SERIES 33 Patient Positioning System Courtesy of IBA, Belgium EHL 2012 LECTURE SERIES 34 Nozzle Nozzle is a device through which protons are delivered to the patient. The IBA Universal Nozzle allows the flexibility to select the preferred beam delivery mode automatically within a single treatment room, without manual intervention. One can switch between all four modes (Single Scattering, Double Scattering, Uniform Scanning, Pencil Beam Scanning) from outside the room. Courtesy of IBA EHL 2012 LECTURE SERIES 35 Trend of Technology Currently, only five U.S. health care facilities have large-scale proton beam radiation therapy systems weighing more than 440,000 pounds that require almost 100,000 square feet of space, with a price tag upward of $150 million for the equipment and building. A group of physicists and other scientists from MIT and other academic proton research facilities have spent years developing a smaller, more economical cyclotron that can produce and deliver protons for radiation therapy. This new technology still comes with a hefty price tag. To date, less than ten centers have committed to purchasing this new technology - among them are MD Anderson - Orlando, Barnes-Jewish Hospital, Oklahoma University's Cancer Institute, Tufts New England Medical Center, and Oncologics. EHL 2012 LECTURE SERIES 36 Table-size Superconducting Cyclotron Table-sized superconducting cyclotrons are being developed by Still River Systems for single-room protonradiation treatment. (Image courtesy of Still River Systems.) Accelerators shrink to meet growing demand for proton therapy. http://ptonline.aip.org/journals/doc/PHTOAD-ft/vol_62/iss_3/22_1.shtml, Matthews 2009 LECTURE SERIES EHL 2012 37 Clinical Considerations on Facility Design • The most important elements defining the system performance are the Nozzle, the Patient Positioning System and the Beam Delivery System! • The Accelerator and the Beam Transport System have much less impact on the system performance! • ELISA (Energy, LET, Intensity, Safety, Availability) • The simplest accelerator meeting the clinical specifications in a cost-effective way should be selected! The Accelerator should be transparent at treatment level. EHL 2012 LECTURE SERIES 38 Hadron Therapy u quark matter d u up quark d down quark u proton u d d neutron Hadron: Any of a class of subatomic particles that are composed of quarks and take part in the strong interaction. Particle therapy works by aiming energetic ionizing particles at the target tumor. These particles damage the DNA of tissue cells, ultimately causing their death. Because of their reduced ability to repair damaged DNA, cancerous cells are particularly vulnerable to attack. Source: Wikipedia EHL 2012 LECTURE SERIES 39 Medical Specifications for P- and C-Therapy •Field Size (typical): 20x20 cm2, up to 40x40 cm2 for fixed beam •Range in tissue: up to 30 cm •Energy: Proton: Carbon Ions: 70 – 250 MeV 120 – 400 MeV/n •Spread-out Bragg-peak over whole tumor depth •Treatment duration: ∼2 min •Typical dose: ∼2 Gy, Vol ∼2l These figures are somewhat arbitrary, rather traditional. Have to be redefined if Hypo-fractionation becomes standard in Ion Therapy Up to now, only Cyclotrons, Synchrotrons have been used for Hadron therapy. After its discovery, the FFAG becomes fashionable. EHL 2012 LECTURE SERIES 40 SI ‘Dose’ Unit 1 Becquerei (Bq) = 1 nuclear transformation per sec (s-1) = 2.7x10-11 curie (Ci) 1 Curie (Ci) =3.7× ×1010 decays/s ~ the activity of 1g of 226Ra. (1 g Co-60 (ττ ~5.27y) contains about 50 Ci) 1 Roentgen (R) = 2 58× ×10−4 Coulomb/kg of dry air 1 Rad (radiation absorbed dose) = 1 erg/g = 0.01 J/kg A typical therapy dose for the destruction 1 Gray (Gy) (absorbed dose) of a tumor amounts to approximately 60 = 1 J/kg = 6.24x1018 eV/kg = 104 erg/g to 70 Gy. It is transferred in individual = 100 rad (radiation absorbed dose) fractions in several successive days 1 DE (dose effective) = absorbed dose x RBE (QF) (approx. 30 fractions in total). 1 rem (rad equivalent in man) = absorbed dose in rad x RBE (QF) Sievert (Sv) (effective dose, radiation effect in human ) = 1 Joule per kilogram (J/kg) =100 rem (roentgen equivalent man) =Gy*RBE =100 rad*rbe 1 Roentgen (R)= 2.58x10-4 coulombs per kilogram 1 Roentgen=1 rad In radiology one arbitrarily defines the relative biological Relative biological effectiveness (RBE) (Q factor) effectiveness (RBE) of a radiation type as the ratio of energy (dose) RBE=1 for x-, β-, γ- rays needed for an X-ray treatment using a Cobalt-60 source to inflict the D same damage as when using this new type of radiation under study. γ RBE=3 for thermal n RBE = RBE is a complex concept and the exact number depends on many Dion details of the study, including cell type, definition of damage to be RBE=10 for fast n, α, p studied, and many other things, and one must be careful when RBE=20 for recoil nuclei making quantitative statements on this issue. Low dose: Medium low dose: Medium high dosage exposure: High dosage exposure: EHL 2012 less than 1Sv (100 rem) 1-2 Sv (100 – 200 rem) 2-5 Sv (200 – 500 rem) more than 5 Sv (500 rem and more) LECTURE SERIES 41 Cross-section, Stopping Power, LET Cross-section: affected area (nm2) Stopping Power: energy deposit x cross-section (eV-nm2) LET: atomic density x stopping power (eV/nm) LET: Linear Energy Transfer or energy absorbed in a target per unit length (-dE/dx) EHL 2012 LECTURE SERIES 42 Two Important Factors in Radiotherapy • Ballistic effect - i.e. the improved physical selectivity for charged particles, which means the delivery of a homogeneous dose to the tumor volume while minimizing the dose to surrounding healthy tissues. (Here, the ballistic effect means the straightness of particle trajectory, not nuclear displacement) • Radiobiological effect - i.e. the improved biological effectiveness (RBE) of hadrons due to dense ionizing tracks produced by these particles. EHL 2012 LECTURE SERIES 43 100 keV vs. 200 MeV Energy 100 keV 200 MeV Longitudinal Range Longitudinal Straggle Lateral Projection Lateral Straggle 1.19 µm 876 A 857 A 1136 A 237 mm 3.31 mm 3.16 mm 4.54 mm Dominant effect is the ionization (≥99%) EHL 2012 LECTURE SERIES 44 235 MeV Proton on Human Cell When the velocity of a particle is high, the particle-medium interaction time is short and thus the energy deposition is small, thereby highest energy deposition occurs near the end of ion track. EHL 2012 LECTURE SERIES 45 Coulomb Force between Two Charged Ions Coulomb Force assuming no screening effect: Fc = εo = 8.85x10-12 C2/Nm2 q = 1.6x10-19 C 1 eV = 1.6x10-19 Joule (Nm) q 1q 2 9 q1q 2 = ( 9 x 10 ) 2 N or Joule/m 4πε o r 2 r 1 Energy gained by displaced ions : r2 Ec = ∫ r1 Bond type 1 1 q 1q 2 9 dr = ( x ) q q 9 10 − 1 2 4πε o r 2 r1 r2 1 Bond length nm Nm or Joule F c for q 2 at Bond length Bond energy used for calc bond distance nm eV eV/nm E c for 50% displ of bond length eV E c for r 2 =oo (Fc x bond length) eV C - H 0.1050 0.115 0.1 4.302 144 4.8 14.4 C - C 0.154 0.1203 0.15 3.606 64 2.74 9.6 Coulomb Force between Two Charged Ions Exerts Sufficient Energy to Cause Scission. Coulomb explosion, a dominant mechanism in insulator. EHL 2012 LECTURE SERIES 46 Spurs, Blobs, Short-Tracks (energy deposition entities) Theory: continuous slowing-down approximation (c.s.d.a) In reality: energy deposition occurs discretely as an entity of ‘spur’ (6-100 eV) Spurs begin to make a choppy overlap with increasing LET, such entities are called ‘blob’ (100-500eV) Spurs overlap for high LET creating ‘short track’ (500-5000 eV) Theoretical Example: 20-keV electron consumes its energy: 38% for spurs, 12% for blobs, and 50% for short tracks. 1-MeV electron consumes its energy: 65% for spurs, 15% for blobs, and 20% for short tracks. 10-MeV electron consumes its energy: 76% for spurs, 8% for blobs, and 16% for short tracks. Certain threshold energy is required to free the bound electrons from atoms for ionization or displace atoms. Thus ion tracks can be taken as made up of isolated ionization, for example. The average energy loss per event lies between 30 - 40 eV. The energy loss entities are called ‘spurs’ Spur energy is associated with chemical bond energy or the energy levels of the valance electrons (ionization energy) which are significantly altered in molecules or in polymers. The track of any low-LET radiation is a collection of isolated spurs. Zeiss, G. D.; W. J. et al., J. Radiat. Res. 1975, 63, 64; see p. 23 Chapter by Chartterjee, LECTURE SERIES EHL 2012 47 X-Ray vs. High LET Particles Heavy ion therapy makes use of the high LET, 12C6+ ions for example. The relative radiation damage (relative biological effect or RBE) of fast neutrons is 4 times that of X-rays because of the high LET, meaning 1 rad of fast neutrons is equal to 4 rads of X-rays. The RBE of neutrons is also energy dependent, so neutron beams produced with different energy spectra at different facilities will have different RBE values. Comparison of Low LET electron and High LET neutron effect Source: Wikipedia EHL 2012 LECTURE SERIES 48 Fractionation Effect 1. A typical therapy dose for the destruction of a tumor amounts to approximately 60 to 70 Gy. It is transferred in individual fractions in several successive days (approx. 30 fractions in total). 2. Repair of sublethal DNA damage by normal cells. Radiation damage to cancer cells is the result of DNA strand breaks. Normal cells have better DNA repair machinery. Fractionated treatment preferentially allows normal cells to repair sublethal DNA damage. 3. Repopulation of normal healthy cells. The time interval between radiation fractions allows normal cells to grow, divide, and therefore continue normal function at the level of tissues and organs. 4. Reassortment of tumor cells into more radiosensitive phases of the cell cycle. Cancer cells have varying sensitivity to radiation depending on their current phase of the cell cycle. In between treatments, some proportion of cells will cycle into a more sensitive phase, rendering them more susceptible to radiation damage. 5. Reoxygenation of tumor cells. The majority of radiation damage to the DNA of cancer cells occurs through a free radical mechanism that is enhanced by oxygen. The time interval between fractions allows additional perfusion of oxygen into areas of the tumor that tend to have low levels of oxygen (that is, hypoxic regions), leading to an enhanced effect of radiation in the tumor. EHL 2012 LECTURE SERIES 49 Fractionating Dose Extends Survival Surviving crypt cells per circumference 102 101 1 2 3 5 20 (fractions) 100 10-1 200 300 Dose in Rad EHL 2012 LECTURE SERIES 50 Chronology of Radiation Effects • Initial Physical Interaction Excitation, Ionization 10-24 - 10-14 s EHL 2012 • Physiochemical Free Radical Formation 10-12 - 10-8 s • Chemical Damage: Radical Attack 10-7s - hours • Biomolecular Damage: DNA, Proteins, etc. ms - hours • Early Biological Effects: Toxicity, Mutation hours - weeks • Late Biological Effects: Cancer, Genetic years - centuries LECTURE SERIES 51 Radiation Effects Somatic effects - those which occur in the person exposed Genetic effects - those which occur in the offspring of exposed persons (genetic, DNA) Stochastic effects - likelihood of effect is random, but increases with increasing dose Non-stochastic effects - likelihood of effect is based solely on dose exceeding some threshold Somatic effects and genetic effects show no immediate symptoms. EHL 2012 LECTURE SERIES 52 Physical Dose Distribution for Various Radiation The dose from protons to tissue is maximum just over the last few millimeters of the particle’s range, quite different from that of electrons or x rays. The figure shows how beams of electrons, X-rays or protons of different energies (expressed in MeV) penetrate human tissue. Electrons have a short range and are therefore only of interest close to the skin (e.g., electron therapy). Bremsstrahlung X-rays penetrate more deeply, but the dose absorbed by the tissue then shows the typical exponential decay with increasing thickness. For protons and heavier ions, on the other hand, the dose increases while the particle penetrates the tissue and loses energy continuously. Hence the dose increases with increasing thickness up to the Bragg peak that occurs near the end of the particle's range. Beyond the Bragg peak, the dose drops to zero (for protons) or almost zero (for heavier ions). Source: Wikipedia EHL 2012 LECTURE SERIES 53 X-Ray vs. Particle Therapy Comparison of dose distribution for X-rays and particle beam therapies. The pink box depicts the tumor located some distance in the body, the red curve shows the dose distribution using heavy charged particles, and the black curve shows the effect of X-rays. The yellow area shows the unnecessary irradiation of healthy tissue in front and behind the tumor. Source: ACT Foundation, llc. EHL 2012 LECTURE SERIES 54 Bragg Peak and Spread Out Bragg Peak • Doctors can safely escalate the dose within a confined target area. • The probability of side effects are drastically reduced. • Healthy tissue is left unharmed This graph shows the relative contribution of the (a.) Spread Out Bragg peak (SOBP) for protons and (b.) a photon x-ray. The SOBP, which is the therapeutic radiation distribution, shows that photon treatments give a higher amount of radiation to the skin when compared with proton treatments. This effect is called "skin sparing". Source: Wikipedia EHL 2012 LECTURE SERIES 55 Heavy Ion Therapy EHL 2012 LECTURE SERIES 56 Why Heavy Ion Therapy? Heavier Ions show: • Distinct Bragg peak like protons • Less radial spreading by collision due to heavier mass on the way to the tumor • Thus better confined beam in radial direction • Sharper Bragg peak than for protons • Higher precision in treating tumors in sensitive areas of the body EHL 2012 LECTURE SERIES 57 Choice of Particle Species LET for proton, carbon and neon ions along their path. While for carbon ions the maximum RBE is in the tumor region, neon ions produce an “overkill-effect” inside the target volume where the Bragg maximum is situated. The density of the red color indicates the increased RBE for carbon (schematic). Although the LET of carbon is higher than that of proton, carbon requires much higher energy accelerators than proton! M Sholz in M. Regler, M. Benedikt, K. Poljanc, CERN Accelerator School, Hephy-PUB-757/02 LECTURE SERIES EHL 2012 58 Carbon Ions – The Magic Bullet Mother Nature really has meant Carbon ions to be the magic bullet. Why is that? The RBE increases with penetration into the body and also the dose deposition increases with depth, but only in the case of carbon ions these two increases go hand in hand. If we look at heavier ions the RBE is already high before we reach the Bragg peak, causing an undue amount of biological damage in the healthy tissue; if we use lighter ions (like helium) the RBE is still around 1 when we reach the Bragg peak and only increases significantly at the distal edge of the peak, where the dose has already dropped sharply. However, compared to protons, carbon ions have some disadvantage that beyond the Bragg peak, the dose does not decrease to zero, since nuclear reactions between the carbon ions and the atoms of the tissue lead to production of lighter ions which have a higher range. Therefore, some damage occurs also beyond the Bragg peak. Source: ACT Foundation, llc. EHL 2012 LECTURE SERIES 59 Epilog • Clinical experiences show that the Hadron therapy has advantage over the photon therapy on cancer control. The number of hadron facilities is expanding rapidly worldwide. • Two most common accelerator designs are synchrotron and cyclotron. - Both systems work! Technical experts are eager to work! - Physicists & engineers can interact and work with medical doctors! - Medical physicists are well paid and in high demand. - Dose verifiability, Beam Stability, Reliability and Reproducibility are utmost important in a radiation therapy facility. • Applications of accelerator: Nuclear and High Energy Physics (HEP) - Better resolution and faster detectors - Fast and compact electronics - Better and reliable beam control systems - Online controls, monitoring and fast Data Acquisition - New “in situ” imaging and dose verification technologies (in beam PET..) - Simulation & modeling for treatment planning • Accelerator Design: beamline design, better uniformity of extracted beams, Control system reliability and flexibility, etc. EHL 2012 LECTURE SERIES 60 Extras EHL 2012 LECTURE SERIES 61 Mathematics of Cyclotron and Synchrotron Non-relativistic The centripetal force is provided by the transverse magnetic field B, and the force on a particle travelling in a magnetic field (which causes it to be angularly displaced, i.e. spiral) is equal to Bqv. So, m: mass of the particle q: charge B: magnetic field strength v: velocity Since ω=2π πf Since ω=v/r r: radius of the path ω: (=2π πf) angular frequency Bq Bq Bq fc = = f = fc: classical frequency 2πm m 2πm E: energy p: momentum This shows that for a particle of constant mass, the frequency does not depend upon the radius of the particle's orbit. As the beam spirals out, its frequency does not decrease, and it must continue to accelerate, as it is travelling more distance in the same time. As particles approach the speed of light, they acquire additional mass, requiring modifications to the frequency, or the magnetic field during the acceleration. This is accomplished in the synchrocyclotron. mv 2 = Bqv r v Bq = r m 2Vq v= m ω Relativistic The radius of curvature for a particle moving relativistically in a static magnetic field is r= EHL 2012 γmv qB γ= 1 v 1− c 2 E =v p f = fc LECTURE SERIES v 1− c 2 62 Projected Range, Longitudinal and Lateral Straggle Surface R Incident ion Rp Projected Range, Rp R( E ) = ∫ E 0 ∆Rr ±∆Rp dE ( dE / dx ) total Actual range (R) of an implanted ion and the projected range (Rp) normal to the surface Most of the ions are within a standard deviation (±∆Rp) or lateral straggle of the projected range, which is the range at 0.606 Cp (the peak concentration). ∆Rr : vertical straggle Can be calculated by PRAL (Projected Range Algorithm) in TRIM “The Stopping and Range of Ions in Solids”, Vol. 1, Ziegler, Biersack, and Littmark, Pergamon Press, New York, 1985 EHL 2012 LECTURE SERIES 63 Concentration Distribution and Fluence Symmetric Gaussian Distribution Formula ( x − Rp ) 2 C ( x ) = C p exp − 2 2∆R p Cp: peak concentration Rp: projected range ∆Rp: straggle Fluence (total number of ions implanted) ∞ Q = ∫ C ( x)dx = 2π ∆R p C p Fluence [#/cm2] and peak concentration [cm-3] relationship −∞ Fluence by dosimetry (I, t) Q= I ⋅t q⋅ A I : ion beam current t : duration of implantation A : substrate area q : ion charge Fluence ‘Q’ is in unit of [#/cm2], the number of charges per unit area. Q per unit length [#/cm3] is concentration. Fluence is the number of ions implanted through a surface in unit of [#/cm2], generally accepted definition. But Plummer calls Q as ‘Dose’. EHL 2012 LECTURE SERIES 64 SRIM Simulation for 100 keV H Side View Longitudinal distribution ( x − Rp ) 2 C ( x ) = C p exp − 2 2∆R p Beam Direction (x) View Lateral straggle y2 C ( x, y ) = Cvert ( x) exp − 2 2 ∆ R ⊥ ∆R ┴: vertical straggle Low energy ion species give large straggle, relatively. EHL 2012 LECTURE SERIES 65 Linear Energy Transfer (LET) vs. Ion Energy The stopping power (eV/Å) of water has been plotted for six different particles as a function of specific energy (MeV per nucleon). In region I the LET is low enough that the spurs develop independently; in region II the spurs in the trajectory core are merged right from the beginning, but the overlap is not excessive; ie. The diffusion of radicals competes with the process of radical recombination; in region III the spur overlap is excessive, and recombination of radicals dominate over diffusion. p. 19, Chapter by Chartterjee, EHL 2012 LECTURE SERIES 66 A Dose Calculation Example 1. A 5-MeV α particle is absorbed by 1 gram of water, estimate the dosage in rad and rem. 5MeV 1.6 × 10 −13 J 107 erg 1rad = 8.0 ×10 −8 rad 1g 1MeV 1J 100erg / g The RBE (Q factor) is 10 for α particle, and thus the dose is 8x10-7 rem or 8x10-9 Sv. If the a particle is absorbed by a of 10-9 g cell, then the dose is 109 times higher (0.8 Gy, 8Sv), exceed lethal dose for most living beings. 2. Proton at 250 MeV are used for radiation therapy with a treatment volume of 1 kg. Assuming 70% efficiency in reaching the planted treatment volume (PTV). What is the number of protons per second needed for the dosage of 2 Grays in 2 minutes? 250MeV 1.6 ×10 −13 J N × 120s × 70% = 2 J / kg 1kg 1MeV N = 6 × 108 particles / s EHL 2012 LECTURE SERIES 67 Simulation of Photons vs. “Spot Ionization” of C-ions Left: local dose of photons at 2 Gy is homogeneous on a micrometer scale; Right: carbon ions generate clusters of lesions, with a substantial decrease of repair capacity. The dose distribution on a cell scale (nucleus of the cell app. 100 µm2) is still sufficiently homogeneous (-> “Poisson statistics”). M Sholz in M. Regler, M. Benedikt, K. Poljanc, CERN Accelerator School, Hephy-PUB-757/02 EHL 2012 LECTURE SERIES 68 Immunofluorescence-Stained Visualization of Radiation Damage Left: photons deposit their energy randomly distributed and thus nearly homogeneously over the irradiated medium; Right: C6+ ions (1 MeV/u) transfer their energy to the liberated electrons, which form a track around the particle trajectory. In a high LET track the damage is produced in high density and thus with a high possibility to form "clustered lesions" which are to a large amount irreparable. B. Jakob et al., Radiation Response after Damage Produced by Heavy-Ion Tracks, Radiat.Res. 154, 398-405 (2000). EHL 2012 LECTURE SERIES 69 Positron Emitting Radioisotopes •Carbon-11 •Nitrogen-13 •Oxygen-15 •Fluorine-18 Functional imaging by means of positron emission tomography (PET) or single photon emission computerized tomography (SPECT) can facilitate the evaluation of tumor physiology, metabolism and proliferation. These are parameters determining outcome to radiotherapy treatment. PET can be used to get also quantitative information about the in-vivo distribution of positron-emitting radioisotopes such as 11C, 13N, 15O, 18F. EHL 2012 LECTURE SERIES 70 Typical Isotopes Used in Medical Applications EHL 2012 LECTURE SERIES 71 Positron Annihilation e+ + e- = γ + γ 1. Positron annihilation produces two 511 keV photons leaving in opposite directions. We are detecting “back-to-back” 511 keV (co-incident) photon pairs resulting from positron annihilation. Figure: Timothy G. Turkington, J. Nucl. Med. Technol., V29 (1) 2001, 4-11. EHL 2012 LECTURE SERIES 72 Detection Jonathan “Eoin” Carney, Ph.D., University of Pittsburgh EHL 2012 LECTURE SERIES 73 Basic Principle of PET In clinical applications, a very small amount of labeled compound (called radiopharmaceutical or radiotracer) is introduced into the patient usually by intravenous injection and after an appropriate uptake period, the concentration of tracer in tissue is measured by the scanner. During its decay process, the radionuclide emits a positron which, after travelling a short distance (3-5 mm), encounters an electron from the surrounding environment. The two particles combine and "annihilate" each other resulting in the emission in opposite directions of two γ-rays of 511 keV each. We are detecting “back-to-back” 511 keV (coincident) photon pairs resulting from positron annihilation within 12 nanoseconds between two detectors on opposite sides of the scanner. For accepted coincidences, lines of response connecting the coincidence detectors are drawn through the object and used in the image reconstruction. EHL 2012 LECTURE SERIES 74 Proton Therapy Centers EHL 2012 LECTURE SERIES 75 Need of Proton Therapy Accelerators • Estimates indicate that proton therapy could help a quarter of a million patients. • As of mid-2008, nearly 20,000 patients treated in U.S. First hospital-based proton center opened in 1990 at Loma Linda University Medical Center. Operating proton centers can treat 150-200 patients daily. • However, doctors face agonizing decisions about whom to treat — and some patients are lucky if they're in a waiting room rather than on a waiting list. Proton therapy is a radiotherapy treatment modality that allows high conformality of the dose distribution to the target volume. More than 40,000 patients have been treated worldwide with proton therapy and the number of new institutes is growing rapidly. The vast majority of proton radiotherapy patients have been treated with passively scattered proton beams and this will likely remain the dominant treatment modality for the next few years. EHL 2012 LECTURE SERIES 76 Useful Web-sites http://worldwidescience.org/topicpages/p/proton+therapy+nozzle.html EHL 2012 LECTURE SERIES 77
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