Lots of technology. Improved Targeting. Improved Delivery. Adapting radiotherapy using patient-specific biological imaging

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1 Lots of technology Adapting radiotherapy using patient-specific biological imaging Mike Partridge Associate Professor Linacs with on-board imaging Cone beam Tomotherapy, Cyberknife, Vero Fluoroscopy 4D Surrogates for breathing / implanted fiducial markers Gating, tracking, ABC Functional imaging PET, SPE, MRI Ultrasound Translational Techniques: Up and coming techniques in Medical Physics translated into preclinical and clinical practice. IoP, 80 Portland Place, London Monday 1st December 2014 Personalized Radiotherapy Radiotherapy Today The fundamental aims of radiotherapy are independent of the technology we use: to deliver a high enough dose to control local tumour growth, to keep normal tissue toxicity within reasonable limits. Jaffray, D. A. Nat. Rev. Clin. Oncol. 9, (2012); Improved Targeting Pre-treatment we can use imaging to: During treatment we can use imaging to: Better identify the target volume (18FDG PET, MRI, 4D ) Better identify radiosensitive normal tissues Improved Delivery Improve day-to-day setup and delivery accuracy Measure (and correct for) systematic changes in anatomy 1

2 Target Definition: Head & Neck FDG PET for volume delineation in non-small-cell lung cancer T1N0M0 stage from Fig 2, 3 T1N2M0 stage from PET PET Fusion I. J. Radiation Oncology Biol. Phys (2004) Int J Radiation Oncology Biol Phys (2004) Volume Definition In radiotherapy planning we define a number of volumes to account for uncertainties in the planning process: Where next? Use on-line imaging to reduce margins more and more to allow dose escalation and normal tissue sparing. Yes, but with caution Int. J. Radiat. Oncol. Biol. Phys. 74, (2009). Gross Tumour Volume Continue to increase PTV dose with protons & carbon ions. Clinical Target Volume every patient with every modality as many times as we can. Yes, but physical dose is not always the limiting factor. Probably not V PTV ning Target Volume But tumours are heterogeneous Visible tumour mass PET SPE? Move away from delivery of a uniform populationderived dose to a (deliberately non-uniform) patientspecific prescription: Individualised iso-toxic dose Biologically-guided using functional imaging Necrotic core Stratified using gene expression profile Oedema Linac Where next? Hypoxic region Microscopic extension MRI Monitor patient response during treatment to create biologically adaptive plans: Boost dose to non-responding sub-regions of tumours Reduce dose to well-responding areas Early prediction (& reduction) of normal tissue toxicity Intervene with radiosensitivity modulating drug 2

3 Imaging in Radiation Oncology Anatomical IGRT Functional Biologically adaptive Before Diagnosis & Staging During The challenge? [Gy] After Early Late Target definition Adapted from a slide by Robert Jeraj 18F-FDG for boost target definition in locally-advanced pancreatic cancer How could we use functional data for dose prescription? i. don t dose escalate to a fixed (or iso-ntcp) level with an anatomically-defined target ii. dose escalate to a fixed level with a single functional image defined target iii. dose escalate to a fixed level with a multiple functional image defined targets iv. optimise plan using explicit radiobiological objective function MR-guided intraprostatic boost Post90% Pre40% Post80% Post70% Post60% H&E stained section Central gland (red) Tumour (yellow) Prostate (blue) Courtesy James Wilson and Maria Hawkins MR-guided intraprostatic boost Challenges: Optimisation & validation of imaging (2 different clinical trials) Elastic matching of images pre/post hormone and with/without endorectal probe (developed in-house software) Developing optimum model to segment tumours (developed in-house software) Importing segmented template and matching with planning (fiducial markers and in-house software) Integrated area under gadolinium uptake curve Fresh slice + outline T2 MR + outline Diffusion coefficient map Dynamic coefficient Ktrans Spectroscopy voxels Dynamic coefficient Kep Courtesy Sophie Riches, ICR MR-guided intraprostatic boost T2W ADC T2map Cho+Cr/Cit Ktrans IAUGC Br J Radiol 2014;87:

4 MR-guided intraprostatic boost ADC T2W FDG-PET guided boost T2map IAUGC Br J Radiol 2014;87: FDG-PET guided boost In radiotherapy planning we define a number of volumes to account for uncertainties in the planning process: BTV BTV PTV PTV Imaging Protocol & QA To ensure that images are consistent, careful protocols should be followed for: Patient immobilisation Time from injection to imaging (for PET) acquisition protocol processing Segmentation These should be regularly checked using phantom measurements. Nuklearmedizin 2012; 51: Same mean dose to PTV Acquisition Protocol PET image contrast changes as a function of time after injection. Different types of lesion show different kinetic behaviour. A well-defined protocol is essential for accurate outlining. H. Zhuang et al J. Nucl Med (2001) So which one is the target? DCE MR DW MR FDG PET T2 MR Courtesy Ceri Powell & Kate Newbold 4

5 Histopathological correlation Histopathological correlation Study of 12 patients with head and neck cancer with 28 metastatic lymph nodes eligible for therapeutic neck dissection who underwent preoperative FDG PET/. Eur J Nucl Med Mol Imaging (2013) 40: Daisne Radiology (2004) 223, 93 Biological Adaptation Early assessment of response Pre-treatment Use the imaging to measure biological response to treatment and adapt individual patient treatments according to response: Post-treatment DW-MRI ADC changes at 2 weeks predicts response 18FLT DCE MR DW MR FDG PET T2 MR as a predictor of response baseline baseline Median ΔADC in poor responders was significantly lower than in good responders 2 weeks into treatment (7% vs. 21%; p < 0.001). Lambrecht et al.radiotherapy and Oncology (2013) week 2 Stratify by 45% decrease in SUVmax between baseline and week 2 (patients treated with radiotherapy) Hoeben et al JNM 54 (2012) baseline week 2 week 4 5

6 18FMISO PET as a predictor of response The RHYTHM trial as an example of imaging biomarker development RHYTHM: modulation of Radiotherapy according to HYpoxia: exploiting changes in the Tumour Microenvironment to improve outcome in rectal cancer. Objectives: To define the best method of detecting hypoxia in rectal cancer and to develop a method of detecting changes in rectal tumour oxygenation during preoperative chemoradiotherapy Zips et al Radiotherapy and Oncology 105 (2012) RHYTHM-I: Group B Biopsy Biopsy Blood sample Blood sample FMISO PET FMISO-PET p p Daily radiotherapy dce-mri rectum and capecitabine dce-mri rectum treatment (Mon-Fri) s before and after 10# RT Restaging dce-mri rectum Resection MRI FMISO PET / FMISO PET / MRI Radiotherapy planning feasibility study Day 7: weeks 8 weeks Histologically confirmed locally advanced adenocarcinoma of the rectum: CRM threatened/involved s courtesy of James Wilson Compare images or doses? Picking a single fixed threshold to define a biological target volume is hazardous: Different thresholds give different volumes! Threshold value changes with object size Patters of uptake vary with time Compare images or doses? Solution use doses not images DCE MRI-derived po2 Optimal dose distribution given the above po2 Spontaneous canine head and neck tumour treated with 3.0 Gy per fraction. Søvik Semin Radiat Oncol (2010) Søvik Semin Radiat Oncol (2010) 6

7 PET / MRI Summary I Biological information already plays an important role in radiotherapy in staging It is playing an increasing role in assisting definition A number of clinical trials are in progress testing functional image-guided boosting or dose redistribution. Challenges Knowing the best imaging modality to use and the best time point to observe response (but still have time to intervene) for a particular disease and site needs more work. The link between functional image signal and dose-response is still largely unknown and raises both physical challenges (absolute image quantification, standardisation and QA) and biomedical challenges (clinical dose-response studies using heterogeneous prescriptions). There are safe and pragmatic ways to get started without the above MRI / linac Crijns & Raaymakers PMB (2014) Summary II Through observational trials we are learning how to use functional imaging as a quantitative and standardised biomarker of response to treatment. This will allow patient-specific adaptation of treatment according to response to therapy. The advent of the PET/MRI and the MR-LINAC offer the opportunity to get more and more patient-specific biological information during treatment. Acknowledgements Tim Maughan Maria Hawkins James Wilson RHYTHM trial group Samantha Warren 7