1. RBE: open issues and next challenges Francesco Tommasino Workshop: la radiobiologia in INFN Trento, 12-13 Maggio 2016

2. Basic concepts of radiation biophysics Workshop: la radiobiologia in INFN – Trento, Maggio 2016

3. Basic concepts of radiation biophysics  The DNA Double Strand Break (DSB) is considered the type of lesion most directly related to cell killing  Different radiation qualities produce the same spectrum of DNA lesions  BUT the distribution of lesions inside the target can be very different Workshop: la radiobiologia in INFN – Trento, Maggio 2016 Scholz 2006 Adv Pol Sci

4. Basic concepts of radiation biophysics  The DNA Double Strand Break (DSB) is considered the type of lesion most directly related to cell killing  Different radiation qualities produce the same spectrum of DNA lesions  BUT the distribution of lesions inside the target can be very different 12 C High LET 1 MeV/u, ≈ 690 keV/  m 12 C Low LET 200 MeV/u, ≈ 16 keV/  m Photons x-rays Random DSB distribution Workshop: la radiobiologia in INFN – Trento, Maggio 2016 Scholz 2006 Adv Pol Sci

5. High tumor dose, normal tissue sparing Effective for radioresistant tumors Effective against hypoxic tumor cells Increased lethality in the target because cells in radioresistant (S) phase are sensitized Fractionation spares normal tissue more than tumor Reduced angiogenesis and metastatization Potential advantages Energy LET Dose RBE OER Cell-cycle dependence Fractionation dependence Angiogenesis Cell migration 1.2 1.0 0.8 0.6 0.4 0.2 0. 0 050100150200 Tumor Normal tissue high low low high  1 > 1  3 < 3 high low Increased Decreased Relative dose Depth (mm) Durante & Loeffler, Nature Rev Clin Oncol 2010 Charged particle therapy: improved physics and enhanced biological effectiveness

6. Relative Biological Effectiveness (RBE): RBE depends on: -Physical parameters (dose, LET, fractionation). -Biological parameters (cell cycle, oxygenation, end-point). Workshop: la radiobiologia in INFN – Trento, Maggio 2016

7. RBE: what’s on the market Data from PIDE (Friedrich 2014 J Rad Res) -Most data for high  ratio -Few data for 1 H and 4 He at high E -Very poor description for 16 O

8. RBE for protons Workshop: la radiobiologia in INFN – Trento, Maggio 2016

9. RBE=1.1 for protons in radiation therapy (ICRU recommendations) Paganetti 2002 PMB Workshop: la radiobiologia in INFN – Trento, Maggio 2016

10. RBE≠1.1 Classical Radiobiology New Paradigm for Proton Radiobiology H He Belli 2000 Int J Rad Biol Girdhani 2013 Radiat Res Currently trend toward variable RBE: -Primary beam: Range uncertainty, LET distribution -Secondary particles: Target fragments in entrance channel Workshop: la radiobiologia in INFN – Trento, Maggio 2016

11. …are deviations from 1.1 of clinical relevance? Wedenberg 2014 Med Phys -Potential improvements offered by biological optimization -Possible bias when neglecting variable RBE -Sensitivity to RBE model -Only 3 patients considered! Dose (Gy)Dose (Gy-RBE) LET (keV/  m) Workshop: la radiobiologia in INFN – Trento, Maggio 2016

12. Biological Range uncertainty (additional to physical range uncertainty!) Grün 2013 Med Phys Distal SOBP: -Parallel decrease of dose and increase in LET -RBE is highly uncertain -RBE can be >>1 in OAR!! -Better characterization -> more accurate treatments Range defined as distal D80 Cuaron 2016 IJROBP Workshop: la radiobiologia in INFN – Trento, Maggio 2016 DSB induction and repair

13. About 200,000 new cases per year in U.S Most patients survive (> 2 millions survivors) Majority receives radiation “Horror” stories from side effects of radiation leads many women to choose mastectomy over X-rays Cardio-pulmonary toxicity is an issue Protons for breast cancer Department of Physics - University of Trento Darby et al 2012 New Eng J Med Ares et al 20120 Int J Rad Oncol Biol Phys

14. Physical Dose Clinical Outcome ? NTCP models Workshop: la radiobiologia in INFN – Trento, Maggio 2016 Protons will lead to improved clinical outcomes (less serious toxicity) if: 1.Normal tissue sparing can be obtained (  dose)  dose will result in lower clinically significant complication risks (  NTCP) Radiotherapy and Oncology 2013Int J Rad Oncol Biol Phys 2016

15. Target fragmentation in proton therapy About 10% of biological effect in the entrance channel due to secondary fragments Largest contributions of recoil fragments expected from He, C, Be, O, N Heavy fragments have low residual energies and release low doses -> high RBE!! Workshop: la radiobiologia in INFN – Trento, Maggio 2016 Tommasino & Durante 2015 Cancers

16. Impact of target fragmentation in clinical practice -Currently the contribution of target fragments is implicit (RBE=1.1) -Improved description would be needed for:  Better definition of peak-to-entrance ratio  Side effects in the entrance channel (NTCP) and dose to target (TCP)  Prediction of secondary cancer risks  Implications for space radiation research - Experimental Data strongly needed to benchmark and improve existing MC codes…and for implementation in TPS! Workshop: la radiobiologia in INFN – Trento, Maggio 2016

17. Conclusions -Significant advances can still be achieved in charged particle therapy, provided that the uncertainties in key physical and biological aspects are reduced. -Experimental and modeling studies are needed to fill the current gaps (e.g. target fragmentation, range uncertainty, new ions). -The robust implementation of a variable RBE represents the frontier in proton therapy treatment planning. -Integration of NTCP models into planning optimization might become a key tool for patient selection. -Goal: increasing treatment effectiveness and enlarging the spectrum of patients that could benefit from proton therapy (e.g. breast cancer, pancreatic cancer). Workshop: la radiobiologia in INFN – Trento, Maggio 2016

18. Thank you! Workshop: la radiobiologia in INFN – Trento, Maggio 2016