Assistant Professor Department of Therapeutic Radiology Yale University School of Medicine

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1 A Mechanism-Based Approach to Predict Relative Biological i Effectiveness and the Effects of Tumor Hypoxia in Charged Particle Radiotherapy David J. Carlson, Ph.D. Assistant Professor Department of Therapeutic Radiology Yale University School of Medicine david.j.carlson@yale.edu Presented at the 011 Joint AAPM/COMP Meeting in Vancouver Therapy Symposium: Predicting and Exploiting the Effects of Radiation Quality in Ion Therapy Date and Time: August, 011 from 4:30-6:00 PM Location: Ballroom A

2 Disclosures Conflict of interest: None

3 Overview Monte Carlo Damage Simulation (MCDS) Simple and fast Monte Carlo scheme used to estimate overall yield of DSB, SSB, and clustered base damage produced in cells by low- and high-let radiation Nucleotide-level maps of spatial configuration of lesions within a DNA segment Repair-Misrepair-Fixation (RMF) Model Kinetic reaction-rate model relates DSB induction and processing to cell death Provides formulas linking LQ radiosensitivity parameters to DSB induction and repair that explicitly account for unrejoinable DSB, misrepaired DSB, and exchanges formed through intra- and inter-track DSB interactions RMF and MCDS models used in combination to: Predict trends in intrinsic radiosensitivity with particle LET Investigate putative mechanisms of cell death for low- and high-let radiation Derive practical estimates t of the RBE and HRF for DSB and cell killing for clinically-relevant charged particle therapy (e.g., protons and carbon ions) Investigate the interplay between RBE and oxygen effects

4 Radiation-induced induced DNA damage Many experiments for all types of clustered DNA damage, including DSB, show that damage formation is proportional to dose up to hundreds of Gy (n = lesions) DSBs are formed through one-track mechanisms DSB induction in human fibroblasts DSB induction in human fibroblasts (MRC-5) irradiated by 90 kvp x-rays (Rothkamm and Lobrich 003)

5 One- and two-track track radiation damage Lethal lesions are created by the actions of one or two radiation tracks 1 track damage ( D) Lethal DSB misrepair, unrepairable damage Pairwise interaction of two DSBs track damage ( D ) Pairwise interaction of two DSBs

6 DSB Processing Pathways One-track action: Correct repair Incorrect repair 1) Non-lethal damage ) Lethal damage 1 DSB Incorrect repair Intrinsically unrejoinable 3) Non-lethal damage 4) Lethal damage Damage fixation (unrejoined DSB) 5) Lethal damage Lethal binary misrepair 6) Lethal damage DSB Stable binary misrepair i 7) Non-lethal damage Two-track action: Lethal binary misrepair 8) Lethal damage DSB Stable binary misrepair 9) Non-lethal damage

7 RMF interpretation of LQ parameters Surviving fraction is related to yield of fatal lesions SD ( ) exp F( ) exp D GD 1. Unrejoinable and lethal damage 3. Intra-tracktrack DSB interactions (1 f ) f [ / ][ ] f R R R. Lethal misrepair and fixation [ /( )][ ]( ) 4. Inter-track DSB interactions f R f R fraction of potentially rejoinable DSB rate of DSB repair (~ h -1 ) rate of binary misrepair (~ h -1 ) z F f R # of DSB per track per cell expected # of DSB (Gy -1 cell -1 ) prob. DSB lethally misrepaired/fixed prob. exchange-type aberration lethal Carlson DJ, Stewart RD, Semenenko VA, Sandison GA. Combined use of Monte Carlo DNA damage simulations and deterministic repair models to examine putative mechanisms of cell killing. Radiat. Res. 008; 169:

8 Predicting trends in radiosensitivity Cell-specific model constants calculated based on x zf x 1 low-let reference parameters for 00 kvp X-rays: x / x x (Gy -1 ) z F LET (kev/m) (Gy - ) / LET (kev/m) Radiosensitivity yparameters for V79 cells irradiated in vitro. Symbols: estimates of α and β reported by Furusawa et al. (000) for He-3 (blue circles), C-1 (green triangles) and Ne-0 (red squares). Lines: RMF-predicted parameters. Frese MC, Yu VK, Stewart RD, Carlson DJ. A mechanism-based approach to predict the relative biological effectiveness (RBE) of protons and carbon ions in radiation therapy. Accepted. Int. J. Radiat. Oncol. Biol. Phys. (011)

9 Method to determine RBE for cell killing RMF-derived predictions of and are used to estimate the RBE for cell killing in clinically-relevant ion therapies 1. Estimate cell-specific model constants: x x 1 x x. Calculated radiosensitivity parameters for ion of given energy E i : i z / i i F i 3. Calculate dose-averaged mean values of and as a function of penetration depth for a mixed field of ions of different energy 1 N D D i i D i 1 i 1 N D D i i D i 1 i zf / 4. Calculate RBE for cell killing relative to a reference treatment (simply an isoeffect calculation using D x =RBE D): x RBE,,,, D x x 4 ( D D ) x x D D x D x

10 Clinically-relevant pristine Bragg peaks Physical and biological properties of proton and carbon ion pristine Bragg peaks. Dose and LET calculated using analytical approximations (Bortfeld 1997 and Wilkens and Oelfke 003). DSB yields simulated using MCDS. and calculated lated assuming chordoma reference parameters. All calculations lations include Gaussian particle spectrum.

11 Clinically-relevant spread-out Bragg peaks Physical and biological properties of a proton and carbon ion SOBP. Fluence of the contributing Bragg peaks optimized to deposit total absorbed dose of 1 Gy. SOBP consists of 17 pristine Bragg peaks with 3 mm spacing.

12 RBE for cell killing in Proton SOBP Conditions: 1. Normoxic o chordoma cells: = x Gy,(/) x =.0 Gy. Proximal edge of SOBP: 10 cm 3. Distal edge of SOBP: 15 cm 4. Distance between Bragg peaks: 0.3 cm 5. # of Bragg peaks: 17 Results: 1. Entrance RBE ~1.0. RBE ranges from 1.03 to 1.34 from proximal to distal edge of the SOBP 3. Mean RBE across SOBP is ~1.11 Potential for biological hot and cold spots within proton SOBP ] RBE-weighted dose [Gy (RBE)] Phys sical dose [Gy] / Dose, energy, and LET calculated using analytical approximation proposed by Bortfeld (1997) and Wilkens and Oelfke (003) Physical dose RBE-weighted dose LET Depth [cm] LE ET d [kev/m]

13 RBE for cell killing in Carbon ion SOBP Conditions: 1. Normoxic o chordoma cells: = x Gy,(/) x =.0 Gy. Proximal edge of SOBP: 10 cm 3. Distal edge of SOBP: 15 cm 4. Distance between Bragg peaks: 0.3 cm 5. # of Bragg peaks: 17 Results: 1. Entrance RBE ~1.3. RBE ranges from 1.8 to 5.4 from proximal to distal edge of the SOBP 3. Mean RBE across SOBP is ~.8 ] RBE-weighted dose [Gy (RBE)] Phys sical dose [Gy] / Dose, energy, and LET calculated using analytical approximation proposed by Bortfeld (1997) and Wilkens and Oelfke (003) Physical dose RBE-weighted dose LET Depth [cm] LE ET d [kev/m]

14 Dependence on tissue radiosensitivity Physical (solid line) and RBE-weighted (RWD) dose for a representative clinical spread-out Bragg peaks in proton and carbon ion radiotherapy. Dashed, dash-dotted, dotted and dotted lines represent RWD for chordoma, prostate, and head and neck cancer, respectively.

15 RBE dependence on dose and / RBE values of cell killing for protons and carbon ions for a range of tissue radiosensitivities and physical doses. Estimates are shown for the proximal edge (d =10 cm), distal edge (d =15 cm ), and target average for a clinical SOBP of 5 cm. Dose (Gy) RBE ( / = Gy) Protons RBE ( / =10 Gy) Promixmal Distal Avg. Promixmal Distal Avg Carbon ions Dose RBE ( / = Gy) RBE ( / =10 Gy) (Gy) Promixmal Distal Avg. Promixmal Distal Avg

16 Physical dose optimization Clinical objective in radiotherapy is to deliver a uniform biological effect (RWD) RBE=1.1 1 Spread out Bragg peaks consisting of pristine Bragg peaks whose fluences were optimized to yield a constant RBE-weighted absorbed dose of 3 Gy (RBE) using the method presented by Wilkens and Oelfke (006)

17 Modification of MCDS to Simulate Chemical Repair and Oxygen Fixation HRF ratio of dose at a specific level of hypoxia to the dose under fully aerobic conditions to achieve equal biological effect, quantifies reduction in radiosensitivity as po decreases The HRF can be expressed as a ratio of doses or damage yields, i.e., HRF O D O D N N O D N dose required to produce N individual or clustered DNA lesions (Gy -1 Gbp -1 )i in cells under normoxic conditions D(O ) dose required to produce (O ) individual or clustered DNA lesions in cells under O

18 HRF in proton and carbon ion SOBP Effects of oxygen concentration on the HRF for DSB induction found at the proximal (solid) and the distal (dotted) edge of 5 cm proton and carbon ion SOBP

19 RBE-weighted dose for hypoxic targets (RBE)) Protons (RBE)) 6 5 Carbon ions Dose (Gy) an nd RWD (Gy Depth (cm) Dose (Gy) an nd RWD (Gy Depth (cm) Physical and RBE-weighted (RWD) dose for a representative clinical spread-out Bragg peaks in y g ( ) p p gg p proton and carbon ion radiotherapy. RWD has been calculated for under various O conditions for chordoma cells ( x = 0.1 Gy -1, (/) x =.0 Gy).

20 Optimization of physical dose (Gy (RBE)) Protons (Gy (RBE)) Carbon ions Dose (G Gy) and RWD Depth (cm) Dose (G Gy) and RWD Depth (cm) Physical dose required under various O conditions required to achieve a constant RBE-weighted dose of 1 Gy (RBE) across a 5 cm SOBP for chordoma cells ( x = 0.1 Gy -1, (/) x =.0 Gy). Theoretically, given a 3D distribution of particle energy spectrum and tumor oxygenation, we can optimize a 3D dose distribution for isoeffect across a tumor

21 Conclusions Proposed approach using the biologically-motivated RMF and MCDS models results in: 1. Quantitative evaluation of the effect of particle LET on DSB induction and cell death in proton and carbon ion radiotherapy. Enhanced understanding of the biophysical mechanisms underlying cell killing in x-ray and particle therapy 3. Determination of RBE values for cell killing that can be practically used in proton and carbon ion therapy Protons: entrance RBE ~1.0, RBE ranges from 1.0 to 1.4 from proximal to distal edge of SOBP Carbon : entrance RBE ~1.3, RBErangesfrom15to109fromproximaltodistaledgeofSOBP edge of RBE values increase as particle energy, dose fraction size, and tissue / decrease 4. A method for quantifying the effects of tumor hypoxia in charged particle radiotherapy For extreme hypoxia, proton and carbon ion doses may need to be increased by factors as high as.9 and 1.6, respectively, to compensate for reduced biological effectiveness

22 Acknowledgements Malte C. Frese, M.S. German Cancer Research Center (DKFZ) Yale University Robert D. Stewart, Ph.D. University it of fwashington Victor K. Yu, M.S. Purdue University it Yale University Work supported by: American Cancer Society Institutional Research Grant (IRG )

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