HollandPTC is opgericht door Erasmus MC, LUMC, en TU Delft en vormt met deze centra een actief samenwerkingsverband in zorg, onderwijs en wetenschap.

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1 HollandPTC is opgericht door Erasmus MC, LUMC, en TU Delft en vormt met deze centra een actief samenwerkingsverband in zorg, onderwijs en wetenschap.

2 DISLCOSURE BELANGEN M. van Vulpen (Potentiele) belangenverstrengeling Geen Voor bijeenkomsten mogelijk relevante relaties met bedrijven (1) Geen a. Sponsoring of onderzoeksgelden (2) a. Geen b. Honoraria of andere (financiële) vergoeding (3) b. Geen c. Aandeelhouder (4) c. Nee d. Andere relatie, namelijk.. (5) d. Geen HollandPTC is opgericht door Erasmus MC, LUMC, en TU Delft en vormt met deze centra een actief samenwerkingsverband in zorg, onderwijs en wetenschap.

3 Biografie: Marco van Vulpen Tot 2017 UMC Utrecht Afdelingshoofd / Divisie leiding Oratie: Het einde van Radiotherapie Innovatie: MRI-linac Waardebepaling: ATLANTIC-consortium Vanaf 2017 Holland PTC Medisch directeur Hoogleraar: Erasmus, LUMC, TU Delft Innovatie: Protonentherapie Waardebepaling: HollandPTC-consortium Hoogleraar: MD Anderson, Houston MD Anderson, Houston HollandPTC is opgericht door Erasmus MC, LUMC, en TU Delft en vormt met deze centra een actief samenwerkingsverband in zorg, onderwijs en wetenschap.

4 Biografie: Marco van Vulpen Tot 2017 UMC Utrecht Afdelingshoofd / Divisie leiding Oratie: Het einde van Radiotherapie Innovatie: MRI-linac Waardebepaling: ATLANTIC-consortium Vanaf 2017 Holland PTC Medisch directeur Hoogleraar: Erasmus, LUMC, TU Delft Innovatie: Protonentherapie Waardebepaling: HollandPTC-consortium Hoogleraar: MD Anderson, Houston MD Anderson, Houston HollandPTC is opgericht door Erasmus MC, LUMC, en TU Delft en vormt met deze centra een actief samenwerkingsverband in zorg, onderwijs en wetenschap.

5 Protonentherapie Marco van Vulpen Medisch Directeur

6 Maatschappelijk debat Investering protonenkliniek: 100Mln E Zorg vanuit maatschappij: Wat is de klinische waarde van protonen therapie? Life magazine, May 5th, 1958 Proton therapy is the fresh hope on cancer

7 Fotonen Protonen

8 Fotonen plan Protonen plan 10 Gy 5 Gy 0 Gy Fotonen plan (IMRT, 6 bundels) CTV-PTV marge 2 mm Protonen plan (MFO, 2 bundels) Robuustheid 2 mm, 3.5%

9 Cranial irradiation compromises neuronal architecture Study on mice, 0Gy, 1Gy and 10Gy, effect 30 days post irradiation. Radiation-induced reductions in dendrite spine density. Representative images 3D reconstructed dendritic segments (green) containing spines (red). V.K. Parihar, C.L. Limoli. Proc Natl Acad Sci U S A Jul 30;110(31): Slide courtesy of D Grosshans, MDACC

10 Protonen therapie in HollandPTC Rationale protonen therapie: Sterke fysische rationale Minder dosis normale weefsels Klinische waarde: Tot op heden geen klinische waarde aangetoond Hoogste level of evidence: 4 Protonen centra zijn duur Doel van HollandPTC: Bepalen van de klinische waarde van protonentherapie Methode: Open werkplaats voor de radiotherapie gemeenschap: Zorg (detacheren) Onderwijs/opleiding en R&D Open kennis- en behandel centrum Alle patiënten behandelen in studieverband / cohort

11 Status protonentherapie in Nederland

12 Planningsbesluit Protonen Ministerie van VWS (WBMV) Kernpunten: Vergunningsplicht Maximaal patiënten/jaar Maximaal 4 centra ( patiënten/jaar) Looptijd tot 2020 Onderbouwing: Realistische capaciteit per centrum Optimale geografische spreiding (bereikbaarheid) Optimale regionale samenwerking Betere mogelijkheden voor klinische validatie

13 Stand van zaken PTC s UMC Groningen PTC Apparatuur: IBA Aantal: 600 patiënten per jaar Status: gestart (Q1-2018) Amsterdam PTC: VuMC / NKI/AVL / AMC Apparatuur: Pro Nova Aantal: 600 patiënten per jaar Status: on hold Holland PTC Delft: LUMC / Erasmus MC / TU Delft Aantal: 600 patiënten per jaar Apparatuur: Varian Status: gestart (Q3-2018) MAASTRO Maastricht: Apparatuur: Mevion Aantal: 400 patiënten per jaar Status: in aanbouw (Q4-2018)

14 HollandPTC Consortium Erasmus MC (AVA) TU Delft (AVA) LUMC (AVA) Amsterdam UMC VUmc AMC Onder andere: HMC, Den Haag ZRTI, Vlissingen Diverse buitenlandse centra Patienten: 600/jaar AvL/NKI

15 Protonentherapie Indicaties en aantallen Signalering Protonentherapie (Gezondheidsraad 2009) / Actualisatie NVRO

16 Model based indicaties, planvergelijking NVRO Consensus: drempels voor NTCP Fotonen Protonen 4-nov-18 16

17 Step 3: NTCP-profiles Protonen versus fotonen RT Side effects Acute toxicity Late toxicity W1 W2 W3 W4 W5 W6 W7 W12 M6 M12 M18 M24 SW-IMRT (PHOTONS) Dysphagia (grade 2) 5% 7% 15% 40% 55% 60% 60% 40% 25% 20% 18% 16% Tube feeding dependent 0% 0% 2% 10% 23% 30% 32% 20% 10% 5% 3% 3% Xerostomia (grade 2) 2% 5% 15% 25% 40% 50% 55% 40% 30% 28% 26% 26% Sicky saliva (grade 2) 2% 7% 20% 28% 45% 53% 57% 36% 28% 20% 15% 10% Loss of taste (grade 2) 0% 4% 15% 40% 45% 50% 55% 50% 30% 15% 8% 7% Oral mucositis (grade 3) 0% 0% 5% 20% 40% 45% 48% 6% Aspiration (grade 3) 0% 0% 1% 4% 6% 7% 7% 8% 7% 6% 3% 3% Osteoradionecrosis (grade 3) 2% 4% 5% 5% 3% Hypothyroidism (grade 3) 5% 10% 18% 23% SW-IMPT (PROTONS) Difference between RT technique 1 and RT technique 2 Dysphagia (grade 2) 2% 4% 5% 10% 20% 35% 45% 30% 15% 10% 6% 5% Tube feeding dependent 0% 0% 1% 3% 5% 14% 25% 10% 5% 3% 2% 2% Xerostomia (grade 2) 0% 0% 5% 12% 25% 30% 35% 24% 15% 12% 10% 9% Sicky saliva (grade 2) 0% 0% 8% 20% 40% 50% 53% 31% 24% 19% 15% 10% Loss of taste (grade 2) 0% 2% 10% 20% 40% 45% 45% 40% 30% 15% 8% 7% Oral mucositis (grade 3) 0% 0% 2% 17% 20% 25% 25% 2% Aspiration (grade 3) 0% 0% 0% 2% 4% 5% 7% 4% 5% 3% 1% 1% Osteoradionecrosis (grade 3) 0% 1% 2% 3% 3% Hypothyroidism (grade 3) 2% 5% 10% 15% NTCP-profile Dysphagia (grade 2) -3% -3% -10% -30% -35% -25% -15% -10% -10% -10% -12% -11% Tube feeding dependent 0% 0% -1% -7% -18% -16% -7% -10% -5% -2% -1% -1% Xerostomia (grade 2) -2% -5% -10% -13% -15% -20% -20% -16% -15% -16% -16% -17% Sicky saliva (grade 2) -2% -7% -12% -8% -5% -3% -4% -5% -4% -1% 0% 0% Loss of taste (grade 2) 0% -2% -5% -20% -5% -5% -10% -10% 0% 0% 0% 0% Oral mucositis (grade 3) 0% 0% -3% -3% -20% -20% -23% -4% Aspiration (grade 3) 0% 0% -1% -2% -2% -2% 0% -4% -2% -3% -2% -2% Osteoradionecrosis (grade 3) -2% -3% -3% -2% 0% Hypothyroidism (grade 3) -3% -5% -8% -8% Courtesy J Langendijk

18 Landelijke spelers DUPROTON Samenwerkingsverband tussen 4 initiatieven / 7 betrokken centra Taken: Richtlijnen Uniforme behandelprotocollen en workflows Landelijke database voor prospectieve dataregistratie Gezamenlijk wetenschappelijk onderzoek LPPT: Landelijk Platform Protonen Therapie Vertegenwoordiging vanuit alle radiotherapie afdelingen in Nederland Taken: Indicatieprotocollen Verwijslogistiek 18

19 Implementatie Expert Groep Protonen ZiN Leden: ZiN, DUPROTON, NVRO, ZN, NZA, ZonMw, VWS, LPPT, NFK Toezicht op klinische implementatie van protonentherapie Landelijke database ProTRAIT (Proton Therapy IT ReseArch InfrasTructure) WP2 registratie bepaald door: Nationale Indicatie Protocollen (LPPT) Uniforme richtlijnen uitvoering (DUPROTON) Commissie Toxiciteit (NVRO) Kanker Registratie (IKNL) (Sustainability) Rol IKNL: Datamanagement registraties Epidemiologie / statistiek (THINC) Quality assurance 19

20 Clinical implementation Rapid learning health care system Multivariable NTCP model Most relevant dose Volume factors Prospective data registration Model-based validation IMPT dose optimisation IMRT dose optimisation IMPT protons IMRT photons Decision Support System National indication protocol Web-based NTCP model library Courtesy J Langendijk

21 HollandPTC uitgangspunt: ja, RCT noodzakelijk Maar: Hoe patient selectie na model-based inclusie? Hoe financieren bij model-based selectie? Discussie: ALARA-principe: minder dosis is altijd beter. Moet je dat bewijzen? Wat is de waarde van minder dosis?

22 Bepalen klinische waarde

23 Demands: current versus past Physics role last decade was to translate industry products to clinical practice Society demands changed: currently clinical value is demanded. Earlier physicist could innovate relatively freely, without the value demand of society This made some physicist develop into famous long haired rock stars Medical???

24 Brain radiotherapy end 90 s

25 Fotonen plan Protonen plan 10 Gy 5 Gy 0 Gy Fotonen plan (IMRT, 6 bundels) CTV-PTV marge 2 mm Protonen plan (MFO, 2 bundels) Robuustheid 2 mm, 3.5%

26 Technology Advances 1980 s 1990 s 2000 s D-CRT X-RAYS IMRT X-RAYS VMAT X-RAYS PASSIVE PROTONS IMPT PROTONS HEART DOSE (cgy): LUNG DOSE (cgy): LIVER DOSE (cgy):

27 ELIMINATION OF UNNECESSARY RADIATION Proton Therapy (IMPT) X-Ray Therapy (IMRT) Added Radiation w/ IMRT (X-Rays) *25 Gy (25 Sv) of Unnecessary Radiation

28 ELIMINATION OF UNNECESSARY RADIATION Added Radiation w/ IMRT (X-Rays) *25 Gy (25 Sv) of Unnecessary Radiation = 12,500 H&N CTs (2 msv) 5,000,000 Intraoral X-Rays (0.002 msv) 25,000x General Public Annual Limit (1.0 msv)

29 PT for Nasopharynx/Oropharynx Ca 50%+ reduction in feeding tubes Proton Therapy (IMPT) Frank SJ et al. IJROBP 2014 Thaker N et al. Oncology Payers 2014

30 Future Potential of Proton Therapy Proton Therapy Development Lag = ~17 Yrs. 75% of RO using IMRT (2002) CBCT & VMAT Growth (2010) kv Imaging VMAT Implementation (2006) VMAT Maturation (2014 ) 1 st Linac (1960) 2-D Planning & MV Port Films (1970) 3-D Planning (1990) CT-Based Planning (1987) IMRT Implementation (1992) LLUMC (#1) (1990) UCSF (#2) (1994) 1 st USA IMPT (MDACC)* (2009) MGH (#3) (2001) 7 w/ Spot Scanning & 0 w/ CBCT (2014) MDACC (#5) (2006) 39 New PT Centers (45%) ( ) 1 st USA Spot Scanning (2008) Single Room PT Growth (2018) Courtesy SJ Frank

31 Roadblocks for Proton Therapy 1. A limited number (14) of proton therapy centers to publish data and average time to publication (6,75 year) 2. Varying Definitions of Medical Necessity 3. Lack of Validity and Accuracy in Insurance Companies Medical Policies 4. Only a few randomized studies 5. Required resources and cost of treatment Courtesy SJ Frank

32 Various definitions of value: Profit Survival Side effects Patient satisfaction PROMS & PREMS Patient throughput Linear accelerator capacity Value and Money QUALY: 1 QoL corrected life year in NHS: (Claxton et al. HTA 2015;19:1-503) Repression: 1 QUALY for a treatment of means saving on other treatments (which might produce e.g.10qualy s for the amount of

33 Introduction of advanced technologies ESTRO and ASTRO have no formal guidelines for the introduction of advanced technologies The course material of the ESTRO advanced Technology course does not provide advises on approach Dutch Society for Radiotherapy note 2010: Goals new technique: improve local control, reduce side-effects, improve survival Randomized trial: preferred method, but many difficulties Alternative: model-based indications (NTCP / TCP) + planning studies, followed by clinical validation

34 Upcoming society based approaches to determine value Model base value proposition Data learning New trials like Cohort Multiple Randomized Controlled Trial

35 Innovations and costs Current examples in Radiotherapy MRI linear accelerator Proton therapy Questions: IDEAL: 1. Innovation stage: First-in-man innovation 2a. Development stage: Prospective development studies. Outcome: safety and technical success 2b. Exploration stage: Prospective cohorts Short term clinical outcome, feasibility, PROs 3. Assessment stage: Formal comparative studies Clinical outcomes, PROs, cost-effectiveness 4. Long term evaluation: Rare events, long term outcomes How does society evaluate which innovation to invest in? Proposal: R-IDEAL (Verkooijen et al. R-IDEAL: a framework for systematic clinical evaluation of technical innovations in radiation oncology. Front. Oncol. 2017;7;59)

36 MRI linac Comparing radiotherapy innovations GOAL: ABLATE THE TUMOR Optimal soft tissue contrast Optimal normal tissue sparing Optimal on-line adaptation, intra-fraction But, Complex, difficult, dangerous, relative measures Electron return effect Estimated cost of treatment 2x photon? Cost equipment: app. 10M Protons GOAL: NO DOSESURROUNDING TISSUE Less integral dose Optimal normal tissue sparing Optimal dose deposition using the bragg peak But, Range uncertainty Dose degradation by movement, tissues, gas, changing anatomy Estimated cost of treatment 2x photon? Cost equipment: app. 100M

37 Technology Development Lifecycle Courtesy SJ Frank

38 Rapid Adoption of Proton Therapy is Close Collective Industry Developments will Break the Financial-Viability Threshold with Support Gantry Design Floor Plan Design Vault Design Shielding Design Accelerator Design -28% -46% -33% -36% -20% System Design Proton Source Power Supply -59% Image Courtesy of HIL Applied Medical Courtesy SJ Frank Construction Time months

39 Samenwerken in bepalen waarde

40 Need to collaborate Clinical collaboration in a consortium: Benefits collaboration: proof clinical benefit /faster accrual, set standards on quality, larger patient numbers Collaboration will not happen automatically: big centers, many people, many interests Primary goal: value proposition Evaluate and compare innovations MRI-linac and proton therapy definitively can live besides Each potential benefits for specific patients / goals