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

Disclosures

Advisory board van:

. Merck

. Pfizer

. Roche

. Genentech

. Bristol-Myers-Squibb

Cartoon physics

De Ruysscher D, Chang J. Sem Radiat Oncol 2013

Superior dose distributions with protons

“Evidente” indicaties voor proton therapie

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”

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

Roelofs E et al. J Thor Oncol 2012

Always less dose to organs at risk and less integral dose (related to second cancers) with protons

Organs at risk and integral dose in NSCLC

I am still sober …

Leroy et al. Int J Radiat Oncol Biol Phys 2016

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

Potentials and limitations of proton therapy

• IMPT with robust plans? Passive Scattering PT?

• Uncertainties

– Anatomical changes

– Range uncertainties

– Set-up/Movement

– RBE

Anatomical uncertainties

Kraan AC et al. Int J Radiat Oncol Biol Phys 2013

(a)Planneddose:field1 (b)Recalculateddose:field1

20%10%

47Gy=100%95%90%80%

60%

70%

50%40%30%

20%10%

47Gy=100%95%90%80%

60%

70%

50%40%30%

SpinalcordSpinalcord

Tommasino et al. Cancers 2015

RBE uncertainties

Wat is de “evidence”?

Chang et al. Int J Radiat Oncol Biol Phys 2016

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

Proton based SABR

Chang et al. Int J Radiat Oncol Biol Phys 2016

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

Stadium III NSCLC

Chang et al. Int J Radiat Oncol Biol Phys 2016

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

Model-based indicaties

Langendijk JA, et al. Radiother Oncol. 2013

Model-based indications

• 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

ΔNTCP

Keuze NTCP model

www.tripod-statement.org

Collins et al Annals of Internal Medicine 2015

Radiation in immune therapy

Demaria et al. JAMA Oncology 2015

Upregulation of MHC class I by radiation

Reits et al. J Exp Med 2006

Prognostic value of ICD-genes: Biological meaning

Garg A. et al. OncoImmunology 2016

Twyman-Saint Victor et al. Nature 2015

Maximum clonal frequency in post-treatment blood of the most frequent TCR clonotypes found in TILs.

Wang et al. Cancer Res 2016

Resistance for anti-PD1 can be overcome by radiation

Radiotherapy primary tumour 5x4 Gy, followed by selectikine

2/13 (15 %) patients no progression after 4 years!

Rekers N et al. Nature Comm 2015

Abscopal effect of L19-IL2 and radiation

Subgroup analysis of KEYNOTE-001 phase I trial

Shaverdian et al. Lancet Oncol 2017

Primary endpoint: Grade ≥3 pneumonitis (CTCAE V4.0) up to 6 months post-radiotherapy

Secondary endpoints: Time to first grade ≥3 pneumonitis; PFS, OS; objective response (RECIST 1.1); time to treatment failure; Adverse events by CTCAE 4.0

ETOP 6-14 NICOLAS

Phase II trial stage III non-small cell lung cancer "ETOP- NICOLAS"

Screening, eligibility

and enrolment

Nivolumab:

480mg every

4 weeks

up to 1 year

Stage

IIIA / B

NSCLC

chemo

cycle 1

chemo

cycle 2

chemo

cycle 3Radiotherapy

Radiotherapy

chemo

cycle 3

chemo

cycle 1

chemo

cycle 2

Investi-

gator‘s

choice

until progression

Whole body

FDG-PET

CT scans year 1: every 9 weeks, year 2: every 12 weeks, beyond 2 years: every 6 months

Nivolumab: 360 mg every 3 weeks, 4 doses

Nivolumab: 240mg every 2 weeks, 8 doses

ETOP 6-14 NICOLAS

Phase I trial SBRT + L19-IL2

• 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)

NCT02086721

Randomised phase II trial in stage IV NSCLC: HORIZON 2020

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

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