Proton therapy for prostate cancer

Transcription

1 Proton therapy for prostate cancer Shafak Aluwini Radiation oncologist UMCG Protons versus photons Superior beam properties Advantage of protons 160 Photons Spread out Bragg Peak Tumor MV photons Protons Bragg Peak Organ at risk Skin Depth (cm) 30 1

2 Photons vs protons bundles 1 bundle 2 bundles 4 bundles Protons Photons Protons therapy technique Passive scattering technique Most used so far Pencil beam scanning technique (PBS) or spot scanning technique New facilities 2

3 Proton techniques Passive scattering Scattering Spread Out Bragg Peak Protonenbundel Proton techniques Pencil Beam Scanning (PBS) Magnets advantages: Less secondary neutrons Superior dose distribution 3

4 Uncertainties in Proton Therapy 1. The potential effects of calculation uncertainties 2. The potential effects of motion based uncertainties R hom Soft tissue bone R hom Soft tissue Setup error Soft tissue Underdosed area AJ Lomax, Phys. Med. Biol. 53 (2008) ,

5 IMPT Planning Techniques The lateral dose distribution is determined by the placement and weights of the spots on each energy layer. Spot weights are optimized for each beam direction using inverse planning techniques => beam weight maps for different energy layers. Kirk & Both, Penn Course 2014 Treatment Planning It is common for Inverse planning to require that any margins for set-up or range be incorporated into a structure which can be used to optimize the dose distribution. Standard PTV Additional margin for range uncertainty Beam 1 Beam 2 Kirk & Both, Penn Course

6 Photons vs Protons Dose reduction in several organs Photons Protons Intestine Intestine Widesot et al, Int J Radiat Oncol Biol Phys 2011 Prostate RT sparing rectum and bladder VMAT IMPT IMPT VMAT Virtueel Protonen Centrum GPTC - November

7 Prostate N+ sparing intestine VMAT IMPT VMAT IMPT Virtueel Protonen Centrum GPTC - November 2016 Bundles characteristics translated to patient advantage Tumor control Complications Probability (%) Improvement local control Prevention of complications 10 0 Current photons standard (IMRT photons) Complications Local tumour control Protons 7

8 Horizon Scanning Report Report of the Dutch Health Council (2009) 0% 10% 20% 30% 40% 50% 60% 70% Preventie Prevention ongewenste of neveneffecten complications 4,824 Verbetering Target dose lokale escalation controle Prevention Preventie van secundaire secondary tumoren tumours Standaardindicaties Standard indications ,215 Total number with expected benefit: 7,098 patients per year (based on Cancer Registry in 2005) Advice: Keep initial capacity below 4,000 patients per year Indications for proton therapy (4 categories) Proton therapy licenses (2013) Planned capacity: 2,200 patients per year Groningen (GPTC) Treatment rooms: 2 Capacity: 600 patients Vendor: IBA Operational: Q Amsterdam (APTC) Treatment rooms: 3 Capacity: 600 patients Status: On hold Delft (HollandPTC) Treatment rooms: 3 Capacity: 600 patients Vendor: Varian Operational: Q Maastricht (ZonPTC) Treatment rooms: 1 gantry Capacity: 400 patients Vendor: Mevion Operational: Q

9 Planned capacity In relation to total number of RT treatments Number per year Number of photon therapy treatment per year Assumed ramp up of 30%-60%-90%-100% % 0.8% 1.9% 2.8% 3.3% 3.4% Evidence-based medicine Gold standard RCT (Randomised Controlled Trial) Randomisation Standard treatment e.g. IMRT (photons) Experimental treatment e.g. IMPT (protons) Standard for introducing new curative methods with unpredictable outcome Not standard for introducing new technology with predictable outcome 9

10 Royal Dutch Academy of Arts and Sciences Most important scientific body in the Netherlands RCT s mostly not suitable / feasible for testing new technologies Alternative evidencebased methods needed and available No standard solution for all technologies But if we still need an RCT? 0 Individual patients -5 NTCP (%) Patients that would not benefit Patients that would benefit -25 Say, we include all patients. If the study is Negative Don t treat any patient with protons Not fair to the patients that would benefit Positive Treat all patients with protons Not efficient 10

11 Insurance report (2011) p. 6 NVRO consensus (2015) Thresholds for NTCP Thresholds for 1 complication CTCAE Grade I II 10% III 5% IV-V 2% Threshold for NTCP No indication NOTE: Special rules in case of multiple complications 11

12 What should we spare? It is impossible to spare all organs and tissues associated with toxicities We need to find the right priorities and even better, the right balance This depends on The impact of toxicity on quality of life Dose limits to avoid severe complications The relation between dose and complication probability We need NTCP models! Model-based approach 4 steps Selection STEP 1: NTCP model Multivariable NTCP-models, which patients have high risk op complications STEP 2: Individual dose comparison Dose reduction with protons? ( Dose): relevant DVH parameters STEP 3: Estimate NTCP reduction ( NTCP) Translate Dose to NTCP STEP 4: Validation and selection Validation External validation NTCP-model with new technology Langendijk, et al. Radiother Oncol

13 Prostate cancer Complications radiotherapy and organ at risk bladder Urethra Rectum Anus penis testis prostate Radiotherapy prostate Complications acute General Lethargy local Skin reaction Intestinal discomfort/cramps Urge/incontinence Diarrhea/obstipation polyuria hematuria Rectal bleeding Late Increase stool freg/ Diarrhea Urge/Obstipation Blood/mucous loss Incontinence Polyuria/urge/pain Nacturia incontinence Erectile dysfunction 13

14 Prostate cancer Example of organ at risk for radiotherapy complications Musculus levator ani Musculus puborectalis Externe anale sphincter Interne anale sphincter Smeenk et al, Int J Radiat Oncol Biol Phys Step 1: predictive model fecal incontinence (mean anal wall dose) 25% Kans NTCP op complicatie 20% 15% 10% History of abdominal surgery No surgery 5% 0% Mean Gemiddelde dose anal dosis wall (Gy) (Gy) 50 14

15 Model-based approach 4 steps STEP 1: NTCP model Selection Multivariable NTCP-models, which patients have high risk op complications STEP 2: Individual dose comparison Dose reduction with protons? ( Dose): relevant DVH parameters STEP 3: Estimate NTCP reduction ( NTCP) Translate Dose to NTCP STEP 4: Validation and selection Validation External validation NTCP-model with new technology Langendijk, et al. Radiother Oncol 2013 Stap 2: Dose comparison Mean anus dose: Photons vs protons Photons Protons Mean anus dose 45 Gy Mean anus dose 27 Gy Van der Laan et al, Virtueel Protonen Centrum UMCG 15

16 Model-based approach 4 steps Selection STEP 1: NTCP model Multivariable NTCP-models, which patients have high risk op complications STEP 2: Individual dose comparison Dose reduction with protons? ( Dose): relevant DVH parameters STEP 3: Estimate NTCP reduction ( NTCP) Translate Dose to NTCP STEP 4: Validation and selection Validation External validation NTCP-model with new technology Langendijk, et al. Radiother Oncol 2013 Step 3: Risk reduction Plan comparison + predictive model 25% Kans NTCP op complicatie 20% 15% 10% Risk-reduction History of Surgery Fotonen (45 Gy) 5% 0% Dose-reduction Mean Gemiddelde dose anal dosis wall (Gy) (Gy) 50 Protonen (27 Gy) Van der Laan et al, Virtueel Protonen Centrum UMCG 16

17 Step 3: Risk reduction Plan comparison + predictive model 25% Kans Kans op op complicaties 20% 15% 10% 5% 0% Risicoverminderin g No surgery Dosisreductie Gemiddelde Gemiddelde dosis dosis anal(gy) wall (Gy) 50 Fotonen (45 Gy) Protonen (27 Gy) Van der Laan et al, Virtueel Protonen Centrum UMCG Step 2: Dose comparison Mean anus dose: Photons vs protons Photons Protons Mean dose anal wall 32 Gy Mean dose anal wall 22 Gy Van der Laan et al, Virtueel Protonen Centrum UMCG 17

18 Step 3: Risk reduction Plan comparison + predictive model 25% Kans Kans op op complicaties 20% 15% 10% 5% 0% Risicoverminderin g Dosisreductie History of surgery Gemiddelde Gemiddelde dosis dosis anal(gy) wall (Gy) 50 Fotonen (32 Gy) Protonen (20 Gy) Van der Laan et al, Virtueel Protonen Centrum UMCG Model-based approach 4 steps Selection STEP 1: NTCP model Multivariable NTCP-models, which patients have high risk op complications STEP 2: Individual dose comparison Dose reduction with protons? ( Dose): relevant DVH parameters STEP 3: Estimate NTCP reduction ( NTCP) Translate Dose to NTCP STEP 4: Validation and selection Validation External validation NTCP-model with new technology Langendijk, et al. Radiother Oncol

19 Numbers of patients with 6-month and 12-month toxicity and odds ratios (ORs) for patients receiving proton radiotherapy (PRT) and a matched intensity-modulated radiotherapy (IMRT Gray et al, Cancer 2013 Propensity Score Matched Rates of Additional Cancer Treatment for Patients Treated With Intensity- Modulated Radiation Therapy vs Proton Therapy 19

20 Patient reported outcomes after 3 dimensional conformal, intensity modulated, or proton beam radiotherapy for localized prostate cancer PT IMRT 3DCRT Cancer Volume 119, Issue 9, pages , 22 FEB 2013 DOI: /cncr The Model Based Approach How to trust models 20

21 Minimal requirements for high quality models Prospective data collection of toxicity Sufficient number of patients /events Multivariable analysis Clinical Decision Rule Formula, nomogram or graph Model performance Minimal requirements for high quality models Test generalizability External validation TRIPOD Type Type 4 Type 3 Type 2b Type 2a Type 1b Type 1a Description External validation of published High quality NTCP-model in separate dataset in other institution Development and external validation of High quality NTCP-model using one data set for development and a separate dataset for validation Non-random split-sample development and external validation Random split-sample development and validation Development and validation using resampling Development only Derived from: Collins, et al. Ann Int Med

22 What determines NTCP? Patient Disease Treatment Dose distribution Reserve capacity Substructure Organ at risk Risk factors Organ at risk NTCP Tissue damage Inflammation Radiobiological processes Repair Cell loss Fibrosis TOO MANY UNKNOWN DETAILS Model-based enrichment (RCT) Multivariable NTCP model Most relevant dose Volume factors Prospective data registration IMPT dose optimisation IMRT dose optimisation IMPT protons IMPT protons IMRT photons R IMRT photons Based on: Lambin, et al. Acta Oncol

23 Conclusions Bundle characteristic's of P are superior Always lower dose in OAR But, Not always translated in less toxicity for patients Selection is needed Model-based approach Personalized medicine Only patient with relevant advantage Cost effective Conclusions Proton RT is a technique in development. Expecting fast improvement Clinical validation Model-based approach is applicable as alternative for CRT. CRT is still needed for validation of dose escalation or hypofractionation with end point improvement tumor control. 23