Rela%ve Biological Efficiency of An%protons The AD- 4/ACE Experiment

Transcription

1 Rela%ve Biological Efficiency of An%protons The AD- 4/ACE Experiment Michael H. Holzscheiter University of New Mexico, Albuquerque, USA University of Aarhus, Demark Introduc%on and historical background Protons, Pions, and An%protons An%proton Cell Experiment (AD- 4/ACE) Rela%ve Biological Efficiency (RBE) Experimental Methods Data Analysis and Error Discussions 1

2 Ra%onale for Conformal Radiotherapy Dose and tumor control are limited due to organs at risk. Tumor control Probability (%) TherapeuLc gain TherapeuLc window ComplicaLons ComplicaLons Dose to target (arb. Gy) 2

3 The last 100 years in conformal radiotherapy where all about increasing the therapeu%c window (Physics for Medicine) Also: IMRT Cyberknife Gamma Knife Image guided RT.... Michael H. Holzscheiter LEAP 2016, Kazanawa, Japan - March

4 Historical Background Heavy Charged Par%cles proposed for cancer treatment by Robert Wilson in 1946 (R R Wilson; Radiology 47 (1946) pp ) Higher- energy machines are now under construclon, however, and the ions from them will in general be energelc enough to have a range in Lssue comparable to body dimensions. It must have occurred to many people that the parlcles themselves now become of considerable therapeulc interest. The object of this paper is to acquaint medical and biological workers with some of the physical proper:es and possibili:es of such rays. 4

5 Wilson already included all essen%al elements: Straggling in target, Ioniza%on density, Rela%ve biological effec%veness, Benefits and dangers of heavier par%cles. Ini%al work at Berkeley (1955) Founda%on for cancer treatment with heavy ions (He, C, Ar) Only proton treatment survived the funding cuts by NSF and NIH.* Harvard Cyclotron (1963) Clinical treatment of Uveal Melanoma started in 1975 First Hospital based Par%cle Therapy Loma Linda (1992) Northwestern Par%cle Therapy Center (NPTC) MD Anderson *) Luckily young researchers involved in the early work in the US (Gerhard Krag and Hirohiko Tsujii) took the knowledge home allowing the development of carbon ion therapy. 5

6 Historical Background More exo%c par%cles were proposed early on: Pion Therapy was established at Los Alamos, SIN, and TRIUMF. Enhancements in therapeulcal efficiency was expected due to annihilalon of pions (Star formalon). LANL: 227 palents / SIN/PSI: 126 palents TRIUMF: randomized trials of pions versus photons S.B. CurBs and M.R. Raju; Rad. Res. 34 (1968) Pion Therapy eventually faded away due to poor spalal conformity of high dose region. 6

7 Historical Background An%proton Therapy was first proposed in 1984 by L. Gray and T. Kalogeropoulos: The par%cle/energy spectrum generated by annhila%on of anlprotons obtained with Monte Carlo showed a significant enhancement of energy deposi%on at end of range 7

8 Historical Background And also predicted extra enhancement of the biological dose. (Rad. Res. 97 (1984) ). Everything needed to perform an Experiment was available, but 8

9 A very first Experiment A.H. Sullivan, CERN: A measurement of the local energy deposi%on by an%proton coming to rest in %ssue- like material Phys. Med. Biol. 30 (1985) ONLY 30 MeV of 1.9 GeV BUT THAT s A FACTOR OF TWO MORE THAN FROM PROTONS 9

10 The birth of AD- 4/ACE 18 years later Proposal PS- 324 submifed October 2002 and accepted February AD- 4 ran at 46.7 MeV for 17 individual shiis between June 2003 and November No absolute dosimetry of anlproton beam Measured relalve biological effect Peak- to- Plateau compared to protons (BEDR) From: M.H. Holzscheiter et al. / Radiotherapy and Oncology 81 (2006) An%protons are 4x %mes more powerful in killing cancer cells than protons. 10

11 Goals: AD- 4 ACE Phase II Build clinically relevant Spread Out Bragg Peak (SOBP) Penetra%on in Target 10 cm/width of SOBP 1 cm. Include absolute Dosimetry in order to measure Rela%ve Biological Efficiency (RBE) which then can be used for dose planning exercises. Requirements to AD- Team: Increase beam energy to 500 MeV/c (126 MeV kine%c) Resul%ng in fewer but longer shigs due to more difficult switch- over of the AD machine from 5 MeV to 126 MeV 11

12 AD- 4/ACE Experimental Set- Up INGREDIENTS:! V-79 Chinese Hamster cells embedded in gelatin! Antiproton beam from AD (126 MeV) METHOD:! Irradiate cells for prescribed fluencies to give dose values where survival in the peak is between 0 and 90 %! Slice samples, dissolve gel, incubate cells, and look for number of colonies Radiochromic Film Ion Chamber Target Tube Water Bath Antiproton Beam Vacuum Line Degrader Beam Monitor 7 step (0-12mm) Rotating Wheel Mimotera ANALYSIS:! Study survival vs. dose along beam axis in 2 mm slices. Obtain dose for 10% survival and compare to D 10% for γ-rays 12

13 Rela%ve Biological Effect = ra%o of DOSE of reference radia%on to dose of test radia%on producing same BIOLOGICAL ENDPOINT Survivin SF Gy RBE SF Gy Radiation dose (Gy) RBE is a func%on of many variables: Cell line Tissue type Dose Energy of primary beam LET α/β ra%o Biological Endpoint Frac%ona%on. 13

14 Measuring RBE requires Dose and Biological Effect Biological Effect:! Embed cells in gela%n matrix inside 6 mm diameter tube! Irradiate with different fluence of an%protons (various doses)! Extract gela%n from tube and take 2 mm slices at several posi%ons! Dissolve slices and seed number of cells determined by predicted survival in growth medium using a fluorescence cell counter! Incubate for 5 6 days! Stain cells and count number of colonies! extract survival frac%on 14

15 Measuring RBE requires Biological Effect and Dose Biological Effect:! Embed cells in gela%n matrix inside 6 mm diameter tube! Irradiate with different fluences of an%protons (various doses)! Extract gela%n from tube and take 2 mm slices at several posi%ons! Disolve slices and seed number of cells determined by predicted survival in growth medium using a fluorescence cell counter! Incubate for 5 6 days! Stain cells and count number of colonies! extract survival frac%on Monte Carlo Assisted Dosimetry: " Determine number of an%protons entering experimental set- up " Measure beam spot and posi%on at entrance to target tank " Es%mate beam divergence (0 mrad/source distance 200 cm) " Build model of experimental set- up in FLUKA " Transport 5 million primaries through FLUKA " Rerun using +/- sigma for parameters with know errors " Study systema%c errors due to arbitrary assump%ons 15

16 Building the Spread- Out Bragg Peak (SOBP) 9.0# Depth%Dose%Distribu3ons%2012% Dose%[Gy]% 8.0# 7.0# 6.0# 5.0# 4.0# 3.0# 2.0# 1.0# Tube#A# Tube#BB# Tube#BB# Tube#C# Tube#C# Tube#D# Tube#D# Tube#E# Tube#E# Tube#H# Tube#H# Tube#I# Tube#I# Tube#J# Tube#J# Tube#K# Tube#K# Tube#L# Tube#O# Tube#O# Tube#A# 0.0# 0# 2# 4# 6# 8# 10# 12# 14# 16# Depth%[cm]% 16

17 RBE Analysis Correct survival frac%on for Pla%ng Efficiency (obtained from unirradiated tubes and/or from unrestricted fits) Fit data to ln(sf) = - αx- βx 2, obtain α, β, and σ α, σ β 84 mm 2012 Extract Dose for 10% survival (D 10% ) 17

18 RBE Analysis - Errors Use σ α and σ β from fit to establish error band and σ D10% ln(sf) = - αx- βx 2! ln(sf) = - (α±κ*σ α )x (β±κ*σ β )x 2 κ is chosen so that 68 % of data points are in between the two curves 84 mm 2012 RBE depth, year = D 10%,x- rays /D 10%, pbars 18

19 Error Analysis Error bars contain only sta%s%cal varia%ons (coun%ng of survival) Systema%c errors affec%ng the result for each year are: Error in Pla%ng efficiency (11% - 15%) Obtained from un- irradiate tubes with iden%cal history or from fits to unrestricted linear quadra%c model Error in Dose calcula%on (<10%) Repeat dose calcula%ons with all parameters changed by respec%ve sigma s and add variances in quadrature (defini%on of beam spot size, posi%on and beam divergence) 19

20 Combined RBE Analysis To obtain final data set including proper error bars: Combine sta%s%cal errors with systema%c uncertainles from biology (PlaLng Efficiency) and physics (Dose calculalon) Calculated weighted average for each depth slice: RBE ave = Σ (ω i *RBE i ) with ω i = [ / Σ j ( )] Validate combinalon of different data sets by applying χ 2 test: χ 2 = Σ j (Φ x j ) 2 /σ i 2 < ndf Test only fails at distal edge of Bragg peak (steep dose gradient) Inflate error in order to account for undetected uncertain%es (ParLcle Data Group): σ corr. = σ * χ 2 /(ndf-1) 20 1 σ i 2 1 σ j 2

21 Summary and Discussions # RBE of an%protons vs. depth up to the distal edge of the Bragg Peak. # Steep increase of RBE confined to the SOBP region enhances biological dose in the peak. # Comparison to Carbon Ions points to possible applica%ons Next steps (if any)? Include RBE in Dose planning exercises to iden%fy tumor incidents that could benefit 21

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