(Radiation) Therapy

10/31/2012Image quantification in (radiation) therapyRobert Jeraj Associate Professor of Medical Physics, Human Oncology, Radiology and Biomedical Engineering Translational Imaging Research Program University of Wisconsin Carbone Cancer Center [email protected] Biomarkers and surrogate endpoints Biomarkers are characteristics that can be objectively imaged as indicators of normal biological processes, pathogenic processes, or pharmacologic responses to therapeutic interventions. Biomarkers as surrogate endpoints are biomarkers that are intended to substitute for clinical endpoints. Surrogate endpoints are expected to predict clinical benefit (or harm or lack of benefit or harm) based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence. 1 10/31/2012Imaging as a <a href="/tags/Biomarker_(medicine)/" rel="tag">biomarker</a>Tumor effects ManifestationTarget effect Tumor effect Clinical outcomeIMAGINGImaging biomarker as <a href="/tags/Imaging_biomarker/" rel="tag">Imaging biomarker</a> a <a href="/tags/Surrogate_endpoint/" rel="tag">surrogate endpoint</a>Imaging as a biomarkerImaging as a biomarkerNormal tissue effects ManifestationLocal Resolution Subclinical tissue damageOrgan dysfunction ClinicalIMAGINGImaging biomarker as Imaging biomarker a surrogate endpoint Imaging as a biomarker Jeraj et al 2010, Int J Rad Oncol Biol Phys, 76(3): S1402 10/31/2012Prentice’s criteria For a given treatment (Z) , a surrogate (S) may be validly substituted for a true endpoint (T) if and only if: 1. P(S|Z) ≠ P(S) 2. P(T|Z) ≠ P(T) 3. P(T|S) ≠ P(T) 4. P(T|S,Z) = P(T|S) Entire treatment effect Z on true endpoint T is captured by surrogate S (100% explained) – A valid surrogate is defined as a response variable for which a test of the null hypothesis of no relationship to the treatment groups under comparison is also a valid test of the corresponding null hypothesis based on the true endpoint Prentice, 1989Prentice’s criteria vs. Real worldInterventionClinically <a href="/tags/Disease/" rel="tag">Disease</a> Surrogate Meaningful Endpoint3 10/31/2012Prentice’s criteria vs. Real worldOther Causal Factors Unintended intervention consequencesInterventionClinically Disease Surrogate Meaningful EndpointOther Causal Factors Disease related Other Causal Factors “Noise”Real world biomarkers Proportion of treatment effect explained (PE): PE = (β�βs)/β = 1� βs/β Relative effectiveness (RE): RE = β/αZ: Treatment S: Surrogate T: Endpoint4 10/31/2012Biomarker characteristics Clinical relevance: Existence of a strong mechanistic molecular or biochemical basis for the biomarker to be influenced by exposure to treatment Sensitivity and specificity: Ability to detect the intended measurement or change in target population via a given mechanism Reliability: Ability to measure the biomarker with accuracy, precision, robustness, and <a href="/tags/Reproducibility/" rel="tag">reproducibility</a> Practicality: Ability to measure the biomarker in a minimally invasive way Simplicity: Feasibility of widespread clinical adoptionBiomarker validation/qualification Individual validation (measurement) – Successfully measures a quantifiable characteristic both objectively and reproducibly Internal validation (study) – Correlates with <a href="/tags/Clinical_endpoint/" rel="tag">clinical endpoint</a>, adds accuracy to precision and reproducibility External validation – Demonstrates similar predictive power in other populations or in other related treatment studies Broad qualification – Can be used as a surrogate in evaluating other classes of disease5 10/31/2012Imaging biomarkers Imaging biomarker validation – What imaging biomarkers are available? – What is uncertainty of imaging biomarkers? Imaging biomarker qualification – What should be correlated to the clinical events? – How far in biomarker qualification are we?Imaging biomarkers Imaging biomarker validation – What imaging biomarkers are available? – What is uncertainty of imaging biomarkers? Imaging biomarker qualification – What should be correlated to the clinical events? – How far in biomarker qualification are we?6 10/31/2012MICAD: <a href="/tags/Molecular_imaging/" rel="tag">Molecular Imaging</a> and Contrast Agent Database1260 agents listed (July 2012)But can we really use them all?11. Credentialing2. Modality creation 3 3. Supporting tools 2 100% 4. Development Regulatory approval (eIND, RDRC) 5. Clinical trials 4 10%Regulatory approval (full IND) <a href="/tags/Multicenter_trial/" rel="tag">Multicenter trial</a> infrastructure (NCI CIP, ACRIN) 5 1%7 10/31/2012What do biomarkers really show?What does the FDG show?5 Pre Cu-ATSM SUV 4 5.000 4.500 3 3.500 2.5002 1.500 0.5000Pre Pre FDG SUV 10 0 2 4 6 Pre FLT SUV Proliferation Hypoxia InflammationSpecificityProliferation [18 F]FLTProliferative and hypoxicProliferative Hypoxia Hypoxic [64 Cu]Cu�ATSM8 10/31/2012Sensitivity and specificity HIGH HIGH sensitivity LOW specificity LOW sensitivity LOW HIGH specificity HIGH Weissleder 2001, Radiology 219, 316Extraction of biological information1 min15 min60 minFLT PET/CT9 10/31/2012PET imaging uncertainties Technical factors – Relative calibration between PET scanner and dose calibrator – Residual activity in syringe – Incorrect synchronization of clocks – Injection vs calibration time – Quality of administration Physical factors – Scan acquisition parameters – Image reconstruction parameters – Use of contrast agents Analytical factors – Region of interest (ROI) definition – Image processing Biological factors – Patient positioning – Patient breathing – Uptake period – Blood glucose levels Jeraj et al 2011, in Uncertainties in ext. beam RT Boellaard et al 2009, J Nucl Med 50: 11S PET imaging uncertainties Technical factors – Relative calibration between PET scanner and dose calibrator ( 10% ) – Residual activity in syringe ( 5% ) – Incorrect synchronization of clocks ( 10% ) – Injection vs calibration time ( 10% ) – Quality of administration ( 50% ) Physical factors – Scan acquisition parameters ( 15% ) – Image reconstruction parameters ( 30% ) – Use of contrast agents ( 15% ) Analytical factors – Region of interest (ROI) definition ( 50% ) – Image processing ( 25% ) Biological factors – Patient positioning ( 15% ) – Patient breathing ( 30% ) – Uptake period ( 15% ) – Blood glucose levels ( 15% ) Jeraj et al 2011, in Uncertainties in ext. beam RT Boellaard et al 2009, J Nucl Med 50: 11S 10 10/31/2012Efforts in quantitative imaging Organized efforts started on behalf of pharma, FDA Initial efforts started within professional societies: RSNA, AAPM, ACR, SNM, ISMRM 2004: Image Response Assessment Teams (IRAT): first organized initiative by NCI/AACI 2006: Imaging as a biomarker: large workshop at NIST including pharma, FDA, NIH, academia, societies 2008: Quantitative Imaging Biomarkers Alliance (QIBA): drug and equipment industries, imaging, societies focusing on CT, PET, MRI 2008: Clinical Translational Science Awards Imaging Working Group (CTSA IWG): initiatives like UPICT 2008: Quantitative imaging for evaluation of responses to cancer therapies: funding initiative (U01 RFA�08�255) 2010: Coming to Consensus on Standards for Imaging Endpoints: NIH workshop between FDA, SNM, RSNA 2010: ITART 2010: Specialized conference on treatment assessment and quantitative imaging (AAPM, ASTRO, ESTRO, RSNA, NCI)Repeatability• Repeatability results of double baseline 18 F�FDG PET scans were similar for all SUV parameters assessed• Centralized QA and centralized data analysis improved intra�subject CV from 15.9% to 10.7% for averaged SUV maxVelasquez et al 2009, J Nucl Med 50: 1646 11 10/31/2012Imaging biomarkers Imaging biomarker validation – What imaging biomarkers are available? – What is uncertainty of imaging biomarkers? Imaging biomarker qualification – What should be correlated to the clinical events? – How far in biomarker qualification are we?PET�based response assessment EORTC, NCI Recommendations (1999, 2005) 1,2 – SUV�based approach – SUV mean and SUV max – Response categories with thresholds ( CR , PR , SD , PD ) – Problems • SUV mean – collapse information, sensitivity issues • SUV max – noise contamination • fails to use all available functional data • distribution • heterogeneity • no response threshold validation • few sensitivity studies • alternative measures PET Response Criteria in Solid Tumors (PERCIST) (2009) 3 – SUV peak1Young et al 1999, 2Shankar et al 2006, 3Wahl et al 200912 10/31/2012Definition of the measures1.4 circle, center on SUV max circle, highest uptake region 1.2 circle, center on SUV max sphere, center on SUV max circle, highest uptake region sphere, highest uptake region sphere, center on SUV max 1.2 sphere, highest uptake region 1.11.0 peak1.0SUV 0.8 0.9 Tumor Response 0.6 0.8 7.5 10.0 12.5 15.0 17.5 20.0 7.5 10.0 12.5 15.0 17.5 20.0 Diameter (mm) Diameter (mm)Vanderhoek et al 2012, J Nucl Med 53: 4�11Images are more than just one number! Size measures SUV peak SUV max – Volume SUV mean SUV total – 1D size (axial) Standardized Uptake 1D Size (axial) Value (SUV) measures:– SUV mean– SUV total– SUV max– SUV peak 250 Uptake Non�uniformity 200 SUV sd measure: Volume 150– SUV sd 100 � 50 Number of Voxels 0 0 5 10 15 20 Standardized Uptake Value13 10/31/2012Ambiguity of responsePre�treatmentPost�treatment SUV 180 FLT PET/CTAmbiguity of response140 120 SUVmean ambiguous SUVmax response 100 SUVpeak SUVtotal 80 Progressive 60 Disease 40 20Stable 0 Disease �20Response (%) �40 �60 Partial Response �80 �100 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 Tumor14 10/31/2012FDG PET as a potential biomarker HNSCC: Negative FDG PET results post chemoRT have a high NPV (95%), but low PPV (50%) (Schöder et al 2009, J Nucl Med, 50:74S) NSCLC: 80% decrease in FDG PET SUV max post chemoRT has 90% sensitivity, 100% specificity, and 96% accuracy for predicting pathologic response (Cerfolio et al 2004, Ann Thorac Surg, 78:1903)Except of FDG PET (still debatable) no other imaging biomarkers has Rectal cancer: 70% decrease in FDG PET SUV max post chemoRTgot has far 79% in specificity, qualification 81% sensitivity, process 77% PPV, 89% NPV and 80% accuracy for predicting pathological response (Caprici et al 2007, Eur J Nucl Med Mol Imaging, 34:1583) Esophageal cancer: Mixed results � in adenocarcinomas negative FDG PET post chemoRT has a high PPV, elsewhere inconclusive (Krause et al 2009, J Nucl Med, 50:89S)FDG PET vs Time�to�progressionFDG SUV Pre�treatment 3 months post RT 6 months post RT measure p�val (N=19) p�val (N=16) p�val (N=11) SUVmean 0.94 0.005 0.0002 SUVmax 0.86 0.017 0.003 SUVpeak 0.90 0.046 0.004 SUVtotal 0.51 0.047 0.006Pre�treatment 3 months post RT 6 months post RT400 400 400300 300 300200 200 200 100 100 Days toDays Progression DaysProgression to 100 0 Progression toDays 1 2 3 4 1 2 3 1 2 3 Pre FDG SUVmean 3 mo FDG SUVmean 6 mo FDG SUVmean15 10/31/2012Imaging normal tissue Anatomical imaging of structural changes (e.g., CT): – Often identified months to years following RT – too late to ameliorate effects of radiation injury – Even then often not related to symptomatic injury Functional imaging of organ function (e.g., DCE�MRI): – Evaluation of the organ function, or reduction in response to radiation therapy – Many organ specific choices (e.g., brain, heart), but not much used Molecular imaging of cellular processes (e.g., FDG PET): – Reflects pathophysiological processes – Early detection of normal tissue injury, which would allow further intervention to ameliorate radiation injuryImaging normal tissue damageHart et al 2008, Int J Rad Oncol Biol Phys, 71: 967.16 10/31/2012Conclusions Imaging biomarkers are not to be taken easy!!! – They should be subject to the same stringent criteria as other biomarkers We are just at the beginning of biomarker validation: – Large uncertainties of the molecular imaging assays: • Scanner harmonization • Uniform protocols and definition of assays • Central review • Extensive test/retest studies – Poor exploration of available imaging information: • Comprehensive imaging metrics • Multiple molecular imaging agents/modalities – Need randomized Phase III studies with imaging endpoints “A correlate does not a surrogate make” – Complexity of correlations (e.g., histology)17

(Radiation) Therapy

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