21 st Century Radiotherapy: State-of-the-art and predicting the future. Clinical applications of PET. PET Imaging

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1 21 st Century Radiotherapy: State-of-the-art and predicting the future Clinical applications of PET Pat Price Ralston Paterson Professor of Radiation Oncology Christie Hospital Manchester UK Mayneord-Phillips Summer School Oxford July 2009 PET Imaging Cyclotron Chemistry Hot Cell PET Scanner Image A Modern Cyclotron Result Kinetics 1

2 Royal Postgraduate Medical School 1955 First Hospital Based Cyclotron Hammersmith-London Home Built Medical Research Council Cyclotron Unit CYCLOTRON PRODUCED POSITRON EMITTING ISOTOPES Oxygen-15 Nitrogen-13 Carbon-11 Fluorine- 2.1 min T½ 10 min T ½ 20.1 min T ½ 1.7 hr T ½ WELLCOUNTER Count/sec/ml PET SCANNER Picture element counts/sec. aliquot phantom 2

3 PET The most specific and sensitive means for imaging molecular pathways and molecular interactions in man. FDG imaging of cancer F Glut-1 O-P Hexokinase F P-FDG accumulates proportional to MR glu 3

4 Flat bed insert on scanner couch PET-CT images from radiotherapy planning patient Problems with Accurate Delineation of Target Volumes Based on Thresholding of PET Images Threshold at 40% of max SUV Threshold at 30% of max SUV Ref: Bradley J et al, JNM 2004, 45:96S PET Molecular Imaging of target volume definition: current status Definition of Treatment Volume GTV CTV Target volume definition Lung 35 publications since 1996 Planning with multi-modality image processing possible 15 30% reduction in G.T.V./P.T.V. Useful with tumour associated atelectasis using FDG PET Improved intra-clinician variability 4

5 Target volume definition Brain 25 Publications since 1998 CT/MRI non-specific sign of blood brain barrier breakdown PET volume < MRI T 1 Add modality, add up to 10% to Volume 80% recurrences still within 2cm of PTV FDG PET problems lower resolution, insufficient differentiation in grey matter Target volume definition Target volume definition IAEA expert report MacManus et al Radiotherapy and Oncology 91 (2009) Reviewed data up till 2006 FDG most useful tracer PET CT data best Best to acquire in a standard fashion in RT treatment position Care with contouring rules Evidence of utility in lung, and emerging evidence in head and neck, oesophagus, lymphoma. No data on improved outcome. But should use most accurate-which is PET Head and Neck Largest series so far 78 pt FDG scans co-registered with CT and compared. Results largely dependent on the PET segmentation tool used. FDG-PET not recommended for target volume definition of metastatic lymph nodes in routine practice Schinagl et al Radiotherapy and Oncology 91 (2009) Target volume definition Astrocytoma WHO III Oesophagus Zhong et al Int J Radiation Oncology Biol.Phys Vol 73 no (2009) 36 patients compare FDG PET (visual/suv 2.5/40% SUV max) with surgical length Optimal PET method varied with tumour length & SUV SUV cut off of 2.5 provided closest estimate. MRI (T2) FDG-PET Methionine-PET 5

6 MET-PET for GTV Definition in Gliomas MRI (T1, Gd-DTPA) Methionine-PET image fusion Glioblastoma MRI and PET (Jacobs et al, 2002) Grade IV (Patient 6 CK) MRI-T1+Gd [ F]FDG GTV: 4 ml GTV: 72 ml [ 11 C]MET [ F]FLT Planning using PET-CT - Erdi et al Cervix carcinoma Para Aortic Lymph Nodes. CT/PET Fusion. IMRT: GTV 1.8 Gy/d, CTV 1.53 Gy/d Mutic et al IJROBP 2003 FDG PET For Target Volume Definition Truths so far interobserver variability in TVD Complex relationship with pathology 1 and 2 detection different related to site Lung GTV definition: can reduce normal tissue outlined Lung / Oesophagus / Lymphoma increases nodes in CTV Rest insufficient data FDG PET For Target Volume Definition Myths-lots of them Sensitivity and Specificity > CT but not 100% Does not detect sub-clinical disease Low inherent spatial resolution Visual delineation poor thresholding software Motion during acquisition Evidence that PET/CT can misalign in 5-40% cases 6

7 PET Molecular Imaging of target volume definition: current status Imaging the tumour phenotype Biological Image-guided dose escalation Dose painting PET Hypoxia and GTV delineation Comparison of CT and FDG-PET based isodoses for carcinoma of tongue (Chao 2001) CT-defined target volumes are on the left. FDG-PET/CT-defined CTV is on the right High dose CTV (magenta) and prophylactic dose (clinical target volume) (yellow). GTV is shown in light green (Schwartz 2005) Tumor Heterogeneity - Dose Painting Current status of Biological image guided RT Dose painting Christian et al radiotherapy and Oncology 91 (2009) Care is needed Discrepancies between PET image and microscopy Due to finite resolution of PET (W. Müller-Klieser/Mainz) Biological Image Guided dose escalation Sovik et al Int J radiation Oncology Biol Phys Vol 73 no (2009) Clinical verification is needed Complex relationship with pathology only done in head and neck Daisu et al. J Nucl Med = PET underestimate mucosal infiltration 7

8 Functional normal tissues Triple scanning metabolism, blood flow, proliferation Transitional metabolic post irradiation changes in spinal cord Transitory increased FDG uptake and perfusion but no changes in proliferation Due to mild inflammatory and regenerative processes Finding consistent with the expected spinal cord recovery by 3 yrs Esik et al 2004 Outcome of using PET for RTX planning Insufficient data to conclude improved outcomes Stage Migration 10 26% Lung Radical to Palliative Selecting the tumour phenotype Cf. DVH / NTCP ± PET Lung (Erdi et al. 2007) no change Brain boost 11C-Methionine Hypoxia Hypoxia F-FMISOFMISO Hypoxic: Cis-Tpz F-FMISO fluoromisonidazole 64 Cu-ATSM diacetyl-bis(n4- methylthiosemicarbazone F-FETNIM fluoroerythronitroimidazole F-FETA fluoroetanidazole Hypoxic: Cis-FU F-FAZA fluoroazomycinarabinofuranoside 16 HNSCC F-EF5 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3- pentafluoropropyl) acetamide F-PIMO pimonidazole Gagel et al 2004 Copyright American Society of Clinical Oncology Rischin, D. et al. J Clin Oncol; 24:

9 * * * Pre treatment Post-treatment with temozolomide Quantitation and response assessment CT PET CT PET CT changes at 2 months; PET response at 7 days Esophageal cancer responding to therapy Value of a pre-therapeutic PET scan FDG-PET Low FDG-uptake prior to therapy (Mucinous adenocarcinoma) Radiation induced esophagitis 0 SUV 10 day 0 day 14 0 SUV 9 Comparison of pre- and post-therapeutic PET scans reduces: false-negative findings (tumours with low baseline FDG-uptake) false-positive findings (tumour vs. therapy induced inflammation) Ott et al. World J Surg, 2001; Hicks et al., Int J Rad Oncol Biol Phys, 2004 Treatment responsefdg Changes in FDG uptake before, during and after RT N=23 x 4 FDG NSCLC SUVmax Large intra-patient heterogeneity High=poor prognosis & non responders Little change=responders maximal SUV (mean +/- SE) Time trends (responders vs non-responders) metabolic response metabolic responders non-responders metabolic non-responders responders 4 2 Baardinjk et al 2007 before start of RT (n=11 n=9) day 7 of RT (n=10 n=9) time day 14 of RT (n=9 n=8) Van Baardwijk et al. Radiother Oncol days after RT (n=10 n=9) 9

10 FDG for RTX response assessment Clinical significance of post RT FDG Charnely et al IJROBP patients high grade glioma Primary: Temozolomide + 60Gy/30# Recurrent: Temozolomide Results: Early changes in MRGlu predict response to chemotherapy, but not chemotherapy plus RTX Yao et al Int J Radiation Oncology Biol.Phys Vol: 74 No Retrospective study 8 patients head and neck cancer Pretreatemnt FDG and post treatment FDG (within 12months) Patients with positive post treatment FDG findings had significantly worse 3-year overall and disease free survival. FLT for RTX response assessment Esther et al J Nucl. Med 2007 Nijmegan Head and Neck Biocare: Framework 6 EU Programme Imaging apoptosis- 99 m Tc-Annexin Clinical Applications of PET The Future Patients with recurrent follicular lymhoma Imaged before and after 2x 2 Gy radiotherapy Annexin uptake increased following radiotherapy. Concordant with cytology Uptake on day 4 predicted complete remission at 1 week? Predictive test for treatment response Haas

11 Permeability vs freely diffusible and inert radioligand Tumour Perfusion and Survival 32 liver metastases 100 Low blood flow High blood flow 100 Low Vd High Vd Normally perfused tissue. Overall survival by blood flow (%) p=0.529 Overall survival by Vd (%) p= Time from PET scan (months) Time from PET scan (months) Abnormally perfused tissue. Perfusion Vd Perfusion varies x5 between metastases in same patient Trend for longer survival with higher plasma exchangeable volume -improved tumor access for systemic therapy -less tumor necrosis/hypoxia. Exchangeable tissue volume (Vd), may be a useful biomarker PET Imaging Improving Radiation Chemotherapy -knowledge of in vivo chemotherapy Modulation of Blood Flow and Chemotherapy Delivery 6 patients 10 colorectal metastases > 3cm Nicotinomide 60mg/kg 2 hours prior Carbogen (95% Oxygen/5% Carbondioxide) for 10 mins during BFI (AUC 10) 5FU(SUV 3 ) In beam PET for radiotherapy monitoring Tumour +61% (19-149%) +52% (11-196%) (P=0.002) (P=0.02) Normal Tissue +15% (10-40%) +2% (38-42%) (Spleen) (P=0.3) (P=0.6) Gupta et al Clin Cancer Res (10):

12 Clinical application of in-beam PET at the carbon ion therapy facility at GSI Darmstadt. Irradiation of a chondrosarcoma of the skull base. The comparison of the predicted (middle) with the measured (right) b+-activity distributions Enghardt et al 2007 Depth distributions of calculated dose (blue, dashed) and measured+-activity (red, solid) induced by beams of protons as well as 3He, 12C and 16O ions in thick targets of polymethyl methacrylate. Enghardt et al 2007 How useful is trajectory information? Only useful for Carbon ions- activation close to the Bragg peak? Limited spatial resolution of PET Image late to get maximum effect after decay of short lived sharpen up curvefluorine is activated nearer the bragg peak? Is this a crude QA tool? Can it define the treated volume accurately? Can we convert the measure of induced radioactivity to a dose and a measurement of Radiation damage? Radioactivity induced depends on energy of beam, nature of particle, and tissue Andreo PMB 54 (2009) May 13 th Nuclear event vs DNA strand breaks-chemical event what is the relationship How relate quantitative signal to radiobiological damage ie effective dose?the new Gy Looks promising-dose painting in vivo-true in vivo dosimetry. High risk high pay of research area Conclusions PET is the most sensitive and Specific Imaging tool for use in man-true molecular imaging Advantages Flexibility of ligands Absolute quantitative physiological measurements Multiple measurements Disadvantages Underused as seen as an anatomical tool Underachieved now few methodology development centres Lack of critical mass of experts 12