AIOS special: State of the art Radiotherapie en Proton Therapie

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1 AIOS special: State of the art Radiotherapie en Proton Therapie Prof. Dirk De Ruysscher, MD, PhD Radiation Oncologist Maastro clinic, Maastricht University Medical Center, GROW Maastricht The Netherlands

2 Disclosures Advisory board van:. Merck. Pfizer. Roche. Genentech. Bristol-Myers-Squibb

3 Cartoon physics

4 Superior dose distributions with protons De Ruysscher D, Chang J. Sem Radiat Oncol 2013

5 Evidente indicaties voor proton therapie

6 Twee mogelijkheden 1. Vermindering van de dosis op de OAR met dezelfde dosis op de tumor Radioprotectie, ALARA 2. Verhoging van de dosis op de tumor met dezelfde dosis op de OAR Dosis escalatie

7 Vermijden van secundaire maligniteiten Lifetime attributable risk (LAR) tot de leeftijd van 75 jaar van een 4-jarig meisje behandeld voor een opticus glioma aan 1.8 Gy per fractie Paganetti H et al. Phys Med Biol 2012

8 Organs at risk and integral dose in NSCLC Always less dose to organs at risk and less integral dose (related to second cancers) with protons Roelofs E et al. J Thor Oncol 2012

9 I am still sober Leroy et al. Int J Radiat Oncol Biol Phys 2016

10 Systematic introduction of new technology Phase 0: In silico quantitative modelling: Is a measurable clinical benefit probable? Phase I: Can the technology be applied safely? Phase II: Prospective clinical study Phase III: Randomised trial if possible/ needed (evident gain is necessary) Phase IV: Outcome of wide-scale implementation Fiona Hegi, Dirk De Ruysscher, Paul Keall: et al. Submitted 2017

11 Potentials and limitations of proton therapy IMPT with robust plans? Passive Scattering PT? Uncertainties Anatomical changes Range uncertainties Set-up/Movement RBE

12 Anatomical uncertainties Spinal cord 47 Gy=100% 95% 90% 80% 70% 60% 50% 40% 30% 20% 10% Spinal cord 47 Gy=100% 95% 90% 80% 70% 60% 50% 40% 30% 20% 10% (a) Planned dose: field 1 (b) Recalculated dose: field 1 Kraan AC et al. Int J Radiat Oncol Biol Phys 2013

13 RBE uncertainties Tommasino et al. Cancers 2015

14 Wat is de evidence? Chang et al. Int J Radiat Oncol Biol Phys 2016

15 Proton based SABR Vergelijking tussen proton en foton SABR bij een centraal gelegen stadium I NSCLC Protonen sparen meer van de bronchial boom, de long, de grote bloedvaten en het ruggenmerg Chang et al. Int J Radiat Oncol Biol Phys 2016

16 Stadium III NSCLC IMPT spaart het beste alle OAR. PSPT spaart meer hart en contralaterale long, maar niet de slokdarm of de ipsilaterale long t.o.v. VMAT Chang et al. Int J Radiat Oncol Biol Phys 2016

17 Conclusies Proton therapie kan overwogen worden bij patiënten Met een hoog risico op belangrijke bijwerkingen met foton therapie Bij wie de standaard dosis op het PTV niet gehaald wordt Niet voor dosis escalatie

18 Model-based indicaties

19 Model-based indications Langendijk JA, et al. Radiother Oncol. 2013

20 ΔNTCP Graad 1: worden niet meegenomen in de model-based selectie. Graad 2: minimaal 10% Graad 3: minimaal 5% Graad 4: minimaal 2% [meestal late effecten, zoals cardiale complicaties en de ontwikkeling van secundaire tumoren] Indien meerdere complicaties meewegen Graad 2: Σ ΔNTCP minimaal 15% Graad 3: Σ ΔNTCP minimaal 7.5% Graad 4: Σ ΔNTCP minimaal 3% Dit zijn minimale voorwaarden waaraan voldaan moet zijn

21 Keuze NTCP model Collins et al Annals of Internal Medicine 2015

22 Radiation in immune therapy Demaria et al. JAMA Oncology 2015

23 Upregulation of MHC class I by radiation Reits et al. J Exp Med 2006

24 Prognostic value of ICD-genes: Biological meaning Garg A. et al. OncoImmunology 2016

25 Maximum clonal frequency in post-treatment blood of the most frequent TCR clonotypes found in TILs. Twyman-Saint Victor et al. Nature 2015

26 Resistance for anti-pd1 can be overcome by radiation Wang et al. Cancer Res 2016

27 Radiotherapy primary tumour 5x4 Gy, followed by selectikine 2/13 (15 %) patients no progression after 4 years!

28 Abscopal effect of L19-IL2 and radiation Rekers N et al. Nature Comm 2015

29 Subgroup analysis of KEYNOTE-001 phase I trial Shaverdian et al. Lancet Oncol 2017

30 Phase II trial stage III non-small cell lung cancer "ETOP- NICOLAS" Screening, eligibility and enrolment chemo cycle 1 chemo cycle 2 chemo cycle 3 Radiotherapy Stage IIIA / B NSCLC Investigator s choice Nivolumab: 360 mg every 3 weeks, 4 doses Nivolumab: 480mg every 4 weeks up to 1 year chemo cycle 1 chemo cycle 2 chemo cycle 3 Radiotherapy Nivolumab: 240mg every 2 weeks, 8 doses Whole body FDG-PET CT scans year 1: every 9 weeks, year 2: every 12 weeks, beyond 2 years: every 6 months until progression Primary endpoint: Grade 3 pneumonitis (CTCAE V4.0) up to 6 months postradiotherapy Secondary ETOP endpoints: 6-14 NICOLAS Time to first grade 3 pneumonitis; PFS, OS; objective response (RECIST 1.1); time to treatment failure; Adverse events by CTCAE 4.0

31 Phase I trial SBRT + L19-IL2 NCT Synchronous or metachronous oligometastatic solid tumor (NSCLC, RCC, HNSCC, CRC, melanoma) Or poly-metastatic NSCLC SBRT to all (up to 5) oligometastatic sites L19-IL2 (6 cycles: day 1,3,5; Q 21 days) ETOP 6-14 NICOLAS Randomised phase II trial in stage IV NSCLC: HORIZON 2020

32 Why combining protons with immune therapy? 1. Immune therapy needs expansion of the T-cell repertoire avoid depletion of naive T-cells 2. Naive T-cells are killed by the low-dose radiation bath, which typically occurs with IMRT or VMAT photon therapy 3. Immunogenic cell death (ICD) may increase with increasing RBE

33 Conclusions Highly rational to combine radiotherapy with immune therapy Besides immune checkpoint inhibition, also with immunocytokines, vaccination, DC therapy Resistance still emerges: mechanisms? Need for biomarkers for efficacy and toxicity (e.g. pneumonitis) Proton therapy may optimize radiation and immune therapy