International Conference on Modern Radiotherapy: Advances and Challenges in Radiation Protection of Patients Advances in external beam radiotherapy New techniques, new benefits and new risks Michael Brada The Institute of Cancer Research & the Royal Marsden Hospital London & Sutton Versailles, 2 December 2009 Versailles, France December 2 4, 2009
Particle RT IGRT IMRT SRT CRT RT DXT New radiotherapy technology
Advances in technology Radiotherapy Imaging Systemic therapy Surgery Biomarkers etc Advances in oncology
Modern technology of radiotherapy delivery Conformal radiotherapy IMRT (intensity modulated radiotherapy) Protons, Heavy ions Image guided radiotherapy 4D radiotherapy External beam radiotherapy technology
Modern technology of radiotherapy delivery Conformal radiotherapy IMRT Protons, Heavy ions Image guided radiotherapy 4D radiotherapy multi-leaf collimator External beam radiotherapy technology
Modern technology of radiotherapy delivery Conformal radiotherapy IMRT (intensity modulated radiotherapy) Protons, Heavy ions Image guided radiotherapy 4D radiotherapy multi-leaf collimator altering the beam intensity External beam radiotherapy technology
Clinical application of IMRT avoidance of critical structures target dose inhomogeneity concomitant boost within target boost Intensity Modulated Radiotherapy (IMRT)
Clinical application of IMRT avoidance of critical structures target dose inhomogeneity concomitant boost within target boost examples: spinal cord avoidance parotid sparing Intensity Modulated Radiotherapy (IMRT)
Clinical application of IMRT avoidance of critical structures target dose inhomogeneity concomitant boost within target boost Intensity Modulated Radiotherapy (IMRT)
Clinical application of IMRT requiring proof of benefit avoidance of critical structures target dose inhomogeneity concomitant boost within target boost Intensity Modulated Radiotherapy (IMRT)
Modern technology of radiotherapy delivery Conformal radiotherapy IMRT Protons, Heavy ions Image guided radiotherapy 4D radiotherapy IMRT Protons External beam radiotherapy technology
Modern technology of radiotherapy delivery Conformal radiotherapy IMRT Protons, Heavy ions Image guided radiotherapy 4D radiotherapy External beam radiotherapy technology cone beam CT RT room scanner
Modern technology of radiotherapy delivery Conformal radiotherapy IMRT Protons, Heavy ions Image guided radiotherapy 4D radiotherapy External beam radiotherapy technology
Changes over a course of radiotherapy - adaptive RT 4D radiotherapy
Radiotherapy to a moving target 4D radiotherapy
Radiotherapy to a moving target - gating 4D radiotherapy for non-small cell lung cancer
Radiotherapy to a moving target - tracking 4D radiotherapy for non-small cell lung cancer
Radiotherapy to a moving target tracking tracking with MLC 4D radiotherapy for non-small cell lung cancer
Technology Radiotherapy Imaging Systemic therapy Surgery Biomarkers etc Advances in oncology
Modern imaging CT MRI Functional Imaging Advances in imaging
Modern imaging CT MRI Functional Imaging Advances in imaging
Particle RT IGRT IMRT SRT CRT RT DXT New radiotherapy technology
Introduction into clinical practice benefits radiotherapy process clinical benefit New radiotherapy technology
Introduction into clinical practice requirements: technical benefit in clinical setting representative series of patients clinically relevant endpoint clinical benefit surrogate endpoint (tumour control and toxicity) survival and quality of life Evaluating new radiotherapy technology
Introduction into clinical practice technical benefit in clinical setting representative series of patients clinically relevant endpoint clinical benefit surrogate endpoint (tumour control and toxicity) survival and quality of life Evaluating new radiotherapy technology
Robotic arm mounted linac (Cyberknife) Modern technology of radiotherapy delivery
Comparison of techniques of high precision localised RT Cozzi et al 2006
Planning Target Volume (PTV) dose distribution 100 ideal % volume 80 60 40 IMRT cyberknife helical tomotherapy (HT) 20 90 100 110 dose (%) Comparison of techniques of high precision localised RT Cozzi et al 2006
Normal CNS dose distribution (organs at risk) Comparison of techniques of high precision localised RT Cozzi et al 2006
Proton therapy
Bragg peak protons Depth dose distribution of photons and protons
protons modulated protons Depth dose distribution of photons and protons
spread out Bragg peak Depth dose distribution of photons and protons
spread out Bragg peak multiple photon (Xray) beams Depth dose distribution of photons and protons
Introduction into clinical practice technical benefit in clinical setting representative series of patients clinically relevant endpoint clinical benefit surrogate endpoint (tumour control and toxicity) survival and quality of life Evaluating new radiotherapy technology
Introduction into clinical practice technical benefit in clinical setting representative series of patients clinically relevant endpoint clinical benefit surrogate endpoint (tumour control and toxicity) survival and quality of life Evaluating new radiotherapy technology
IMRT Prostate radiotherapy
introducing protons IMRT IM protons (IMPT) conformal protons Trofimov et al IJROBP (69), 444, 2007 Prostate radiotherapy
1 IMRT Mean SD Rectal sparing IMRT % dose Protons conformal protons IM protons (IMPT) Trofimov et al IJROBP (69), 444, 2007 Prostate radiotherapy
1 IMRT Mean SD Bladder sparing IMRT % dose IM protons (IMPT) Protons conformal protons Trofimov et al IJROBP (69), 444, 2007 Prostate radiotherapy
Introduction into clinical practice protons technical benefit in clinical setting representative series of patients clinically relevant endpoint clinical benefit surrogate endpoint (tumour control and toxicity) survival and quality of life Evaluating new radiotherapy technology
Clinical evidence for efficacy of protons Tumour control Tumour % 5yr local control best conventional protons* treatment chordoma 65 60 chondrosarcoma 95 95 * weighted mean of published studies Brada et al 2007 JCO, 25 (8), 965-970 Protons in chordoma and chondrosarcoma
Clinical evidence for efficacy of protons compared to best conventional treatment Tumour site tumour control survival toxicity Head and neck tumours Prostate cancer Ocular tumours Gastrointestinal cancer Lung cancer CNS tumours Sarcomas Paediatric tumours Protons in other tumours
Clinical evidence for efficacy of protons compared to best conventional treatment Tumour site tumour control survival toxicity Head and neck tumours Prostate cancer Ocular tumours Gastrointestinal cancer Lung cancer CNS tumours Sarcomas Paediatric tumours Protons in other tumours
Introduction into clinical practice technical benefit in clinical setting representative series of patients clinically relevant endpoint clinical benefit surrogate endpoint (tumour control and toxicity) survival and quality of life Evaluating new radiotherapy technology
Conventional design Phase I to evaluate Phase II Phase III model of drug testing Evidence based medicine
Conventional design to evaluate Phase I clinical pharmacology & toxicity Phase II Phase III model of drug testing Evidence based medicine
Conventional design to evaluate Phase I feasibility & toxicity Phase II Phase III model of drug testing Evidence based medicine
Conventional design to evaluate Phase I feasibility & toxicity Phase II initial investigation of activity no information on comparative efficacy Phase III model of drug testing Evidence based medicine
Problems of Phase II studies study design (prospective/retrospective; statistics) patient selection (performance status, disease status etc) new staging & other treatments comparative control group endpoints and methods of assessment.. Evidence based medicine
Conventional design to evaluate Phase I clinical pharmacology & toxicity Phase II initial investigation of activity Phase III comparative efficacy model of drug testing Evidence based medicine
Introduction of protons into clinical practice technical benefit in clinical setting representative series of patients clinically relevant endpoint clinical benefit surrogate endpoint (tumour control and toxicity) survival and quality of life Evaluating new radiotherapy technology
Radiotherapy in non-small cell lung cancer implementation of novel techniques assumes a dose response relationship Evaluating new radiotherapy technology
Summary of published phase II studies (1201 patients, 8 publications) 2 year local progression free survival 1 Progression-free survival [2 yr] 0.8 0.6 0.4 0.2 Martel model Fenwick model Clinical data 0 40 60 80 100 120 BED [Gy] Dose response in non-small cell lung cancer (NSCLC) Ramos, Partridge et al 2009 (unpublished)
Introduction into clinical practice technical benefit in clinical setting representative series of patients clinically relevant endpoint clinical benefit surrogate endpoint (tumour control and toxicity) survival and quality of life Evaluating new radiotherapy technology
Radiotherapy to a moving lung tumour Evaluating new radiotherapy technology in NSCLC
Radiotherapy to a moving target respiratory volume BEAM ON time Conventional radiotherapy for non-small cell lung cancer
technology intensive real time tracking predictive tracking regular breathing tracking normal unregulated breathing voluntary breath hold imposed breath hold gating gating with free breathing or breath hold sedation anaesthaesia standard fixed delivery conventional treatment patient intensive Solutions to tumour motion in NSCLC RT
Radiotherapy to a moving target active breathing control (ABC) 4D radiotherapy for non-small cell lung cancer
respiratory volume Radiotherapy to a moving target active breathing control (ABC) BEAM ON time 4D radiotherapy for non-small cell lung cancer
Radiotherapy to a moving target active breathing control (ABC) 4D radiotherapy for non-small cell lung cancer
Introduction into clinical practice technical benefit in clinical setting representative series of patients clinically relevant endpoint clinical benefit surrogate endpoint (tumour control and toxicity) survival and quality of life Evaluating new radiotherapy technology
Change in mean lung parameters Mean Lung Dose (MLD) 15 MLD (Gy) 10 5 8% 20% 0 free breathing FB1 free breathing FB2 ABC larger margin smaller margin active breathing control 4D gated radiotherapy with ABC for NSCLC Panakis et al 2008
Introduction into clinical practice technical benefit in clinical setting representative series of patients clinically relevant endpoint clinical benefit model potential benefit surrogate endpoint (tumour control and toxicity) survival and quality of life Evaluating new radiotherapy technology
Change in tumour control probability (TCP) for iso-ntcp plan (max dose 84Gy) 0.5 TCP at 30 months 0.4 0.3 0.2 0.1 0.15 0.3 0 original plan dose escalated plan (25 patients) Partridge et al 2009 4D gated radiotherapy with ABC for NSCLC (NTCP normal tissue complication probability)
Comparison of techniques Volumetric intensity modulated arc therapy (VMAT) Brock et al 2008
Volumetric intensity modulated arc therapy (VMAT)
Stereotactic body radiotherapy (SBRT)
Introduction into clinical practice technical benefit in clinical setting representative series of patients clinically relevant endpoint clinical benefit surrogate endpoint (tumour control and toxicity) survival and quality of life Evaluating new radiotherapy technology
Systematic review of published literature (15 studies, 880 patients) at 2 years local progression free survival 89% survival 65% Brock et al Clin Oncol, 20, 666-676, 2008 SBRT stereotactic body radiotherapy High dose RT for localised NSCLC (SBRT)
Summary of published phase II studies (including SBRT) 2 year local progression free survival 1 2 year local progression free survival Disease-free survival [2 yr] 0.8 0.6 0.4 0.2 early stage disease advanced stage disease Fenwick model (solid curve) 0 40 60 80 100 120 BED [Gy] conventional fractionation hypofractionated SBRT Dose response in non-small cell lung cancer (NSCLC) Partridge, Ramos et al 2009 (unpublished)
Introduction into clinical practice technical benefit in clinical setting representative series of patients clinically relevant endpoint clinical benefit surrogate endpoint (tumour control and toxicity) survival and quality of life Evaluating new radiotherapy technology
Risks from introduction into clinical practice system problems and complexity system errors demands on under resourced service individual patient risks reliance on image interpretation clinical expertise vs technical prowess commercial interests & direct to patient marketing Evaluating new radiotherapy technology
Conventional design to evaluate Phase I clinical pharmacology & toxicity Phase II initial investigation of activity Phase III comparative efficacy model of drug testing Evidence based medicine
New technology trial Localised NSCLC conventional dose RT novel technology (gating/tracking/imrt/vmat..) Evaluation of new technology of RT delivery in NSCLC
New technology trial Localised NSCLC randomise conventional dose RT conventional technology conventional dose RT novel technology (gating/tracking/imrt/vmat..) Evaluation of new technology of RT delivery in NSCLC
Combination of dose escalation with new technology Localised NSCLC randomise conventional dose RT conventional technology high dose RT novel technology (gating/tracking/imrt/...) Evaluation of new technology of RT delivery in NSCLC
Introduction into clinical practice benefits radiotherapy process clinical benefit New radiotherapy technology
International Conference on Modern Radiotherapy: Advances and Challenges in Radiation Protection of Patients Advances in external beam radiotherapy New techniques, new benefits and new risks Academic Radiotherapy Unit, Joint Department of Physics, Neuro-oncology Unit Lung Unit, Radiotherapy Department Michael Brada Work supported by: NHS Executive Cancer Research UK Neuro-oncology Research Fund Versailles, France December 2 4, 2009