Future outlook Marco Durante PTCOG vice-chair, TIFPA-INFN, Italy 5.23.2018 1 “I keep thinking, we should include something in the Constitution in case the people elect a moron” 2 https://www.ptcog.ch/ Protons C-ions 3 1 4 9 16 2 24 2 2 5 1 1 AAPM poll, August 2012 What is the main obstacle to proton therapy replacing X-rays? 19 Cost/benefit ratio 35 Range uncertainties Protons will never replace X-rays 33 Range uncertainty Source of range uncertainty in the patient Range uncertainty Independent of dose calculation: Measurement uncertainty in water for commissioning ± 0.3 mm Compensator design ± 0.2 mm Beam reproducibility ± 0.2 mm Patient setup ± 0.7 mm Dose calculation: Biology (always positive) + 0.8 % CT imaging and calibration ± 0.5 % CT conversion to tissue (excluding I-values) ± 0.5 % CT grid size ± 0.3 % Mean excitation energies (I-values) in tissue ± 1.5 % Range degradation; complex inhomogeneities - 0.7 % Range degradation; local lateral inhomogeneities * ± 2.5 % Total (excluding *) 2.7% + 1.2 mm Total 4.6% + 1.2 mm Durante & Paganetti, Rep. Prog. Phys. 2016 5 Protons stop... X-rays Protons Courtesy of Marco Schwarz 6 ...but where? Treating moving targets % of target dose . Motion: Geometric miss of target . Range changes: Position of Bragg Peak under motion . Interplay: Interference between scanning and tumor motion 9 Courtesy of Christian Graeff, GSI, Germany Motion compensation and tracking Riboldi et al., Lancet Oncol. 2012 4D TP % of target dose Conservative approach Innovative approach Enlarged target . Motion 4D-Optimization (range ITV) . Range changes synchronized Rescanning . Interplay delivery 11 Graeff et al. Med. Phys. 2012; Graeff TCRT 2014 Future: high-energy particle radiography In situ control with PET dose plan measured Courtesy of Wolfgang Enghardt, HZDR, Dresden Future: imaging with RIB Positron- Half-life (min) emitting Chie Toramatsu et accelerated al Biomed. Phys. ion Eng. 2018 10C 0.32 11C 20.3 15O 2.04 Mohammadi et al., NIM A (2017) 14 3D Modulator: ultrafast delivery Simeonov et al., Phys. Med. Biol. 2017 Example for a spherical target volume, 5cm diameter, 12C, E=400 MeV/u Fluence map in lateral direction (FLUKA simulation) Central axis Dose profile Central axis Dose profile Reducing costs: accelerators • All current facilities use either a cyclotron or a synchrotron and RFQ or low-energy linacs as injectors • High-field superconducting magnets for compact, lightweight synchrocyclotrons (e.g. SRS, IBA, INFN) • Fixed-field alternating gradient Still Rivers single-room protontherapy unit (FFAG) accelerators (e.g. KEK, Japan, and RACCAM, France) • Cyclinac (TERA) IBA-C400 • Dielectric wall accelerators (CPAC) • Laser driven accelerators Courtesy of Dr. Kojii Noda Improving benefit: treating noncancer diseases Dose escalation study: 25-55 Gy single-fraction Convincing the non- believers: phase-III clinical trials Durante et al., Nat. Rev. Clin. Oncol. 2017 The big question: shall we need radiotherapy at all in the future? Courtesy of Dr. Paolo Ascierto, Istituto Pascale, Naples, Italy 5.16.2018 IPI (Pooled analysis)1 NIVO Monotherapy (Phase 1 CA209-003)2 Raising the bar …… PEMBRO Monotherapy (Phase 1 Keynote-001)4 Pretreated and Naïve Patients NIVO Monotherapy (Phase 3 Checkmate 066)3 PEMBRO Monotherapy (Phase 1 Keynote-001)4 Naïve Patients 100 9 0 8 0 7 0 +radiotherapy 6 ~ 60% 0 N=210 + targeted therapy 5 ipi/nivo 50% 0 45% + chemotherapy 4 40% 40%N=655 0 35%N=107 3 N=152 0 20% 2 N=1,861 0 1 0 Overall Overall (%) Survival 0 0 1 2 3 4 5 6 7 8 9 10 Years 1.Schadendorf et al. J Clin Oncol 2015;33:1889-1894; 2.Hosi FS. AACR 2016 3.Poster presentation by Dr. Victoria Atkinson at SMR 2015 International Congress. 4.Robert et al. Oral presentation ASCO 2016 5.Daud et al. Oral presentation ASCO 2015 Radioimmunotherapy Formenti & Demaria, Lancet Oncol. 2009 Radiation and immune response: a patient with metastatic melanoma treated by monoclonal antibody (Ipilimumab) and 28 Gy/3f IMRT Regression of the targeted pleral- based paraspinal mass Abscopal regression in right hilar lymph node (1 Gy) and spleen (2 cGy) Postow et al., N. Eng. J. Med. 2012 Combined radiotherapy and immunotherapy in the clinics: Courtesy of Silvia Formenti lung cancer trial NSCLC progressing after 3 lines of chemo and chest RT: Multiple lung, bone and liver metastasis 48 months after RT+immunotherapy RT to one liver met 6 Gy X 5 ( TD 30 GY) Golden et al Cancer Immunology Research, 2014 Ipilimumab, 3 mg/Kg, after first RT q3 weeks, X 4 cycles 27 Particle therapy + immunotherapy Radiotherapy (and chemotherapy) compromise the immune system Yovino et al Cancer Invest. 2013 A single radiation fraction delivered 0.5 Gy to 5% of circulating cells, after 30 fractions 99% of circulating blood had received ≥0.5 Gy Circulating lymphocytes :D10 = 3 Gy D50 = ~2 Gy D90 = ~.5 Gy Need: - High dose-rate - Hypofractionation - Reduced integral dose 30 Physical advantages of particle therapy for immunology Durante et al., Int. J. Radiat. Oncol. Biol. Phys. 2000 Particle immunotherapy: biological adavantages GFP-NSBS1 Jakob et al., Proc. Natl. Acad. Sci. USA 2009; Nucl. Acids Res. 2011 cGAS/STING pathway Chen et al., Nat. Immunol. 2016 Micronuclei can trigger the cGAS/STING pathway Mackenzie et al., Nature 2017 Harding et al., Nature 2017 Helm et al., Front. Oncol. 2016 Durante & Formenti, Front. Oncol. 2018 Ionizing radiation Durante & Formenti, Front. Oncol. 2018 cGAS CA Cell-cycle Cell-cycle progression arrest Mitosis with Increased NPB and cell MN mobility MN NE NE rupture collapse Control Protons 8 Gy c a c b Human mammary epithelial cells AFM images courtesy of Simonetta Croci Conclusions The future of particle therapy will strongly depend on the solution of technical issues (range uncertainty) and decreasing the cost/benefit ratio Future strategies to reduce range uncertainty include RIB, particle radiography and ultrafast dose delivery Cost reduction is dependent on new, compact accelerator design Benefits can be extended by treating noncancer diseases and successful phase III clinical trials The big question is whether particle therapy can prove to be more effective than conventional treatments in combination with new drugs, especially immunotherapy ! .