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ROBERTO GARCÍA FIGUEIRAS, MD, PhD DECISIONS IN ONCOLOGY BLOOD and URINE PATHOLOGIC CIRCULATING Cells PROTEOMICS PHYSIOLOGIC RADIOMICS GENOMICS EVALUATING RENAL CANCER Imaging Technology: The perfection of anatomic imaging RADIOGENOMICS – CONVENTIONAL IMAGING Associations between CT Imaging Features and Mutations NECROSIS 1. Understanding the biological correlates behind image phenotypes. VEIN INVASION ILL-DEFINED MARGIN NODULAR ENHANCEMENT 1. Understanding how a biological process is reflected in imaging. 1. Defining clinical biomarkers or biological surrogates. CALCIFICATION MULTICYSTIC GROSS VESSELS COLLECTING SYSTEM INVASION Karlo CA, et al. Radiogenomics of Clear Cell Renal Cell Carcinoma: Associations between CT Imaging Features and Mutations. Radiology. 2014 Feb;270(2):464-71. DECISIONS IN ONCOLOGY Looking for non-responders and early progressors BIOLOGY-MOLECULAR ProteIns GROUP A RESPONDER TO DRUG Increased TTP and OS GROUP B IMAGING FEATURES IMAGING ANALYSIS NON-RESPONDER Short TTP and OS CLINICAL DECISIONS IN ONCOLOGY Looking for non-responders and early progressors Is there any imaging finding that may suggest risk for early tumor progression and, as a result, changing patient management? Metastatic Renal Cancer A GREAT CHANGE IN THE NATURAL HISTORY 10/07 09/08 03/09 IL-2 From 2005… to 04/2009 09/09 08/10 SORAFENIB From 04/2009 to 02/2011 03/11 06/11 05/12 09/13 SUNITINIB From 02/2011 to 11/2014 WHAT´S YOUR FEELING CONCERNING THE EVOLUTION OF THIS PATIENT? 10/14 EVALUATING RENAL CANCER Technical Features The use of an adequate imaging protocol, which must include an arterial phase, is a key point to for the right evaluation of patients. Arterial phase Portal phase WHAT´S YOUR OPINION CONCERNING THIS CT IMAGE IN A PATIENT WITH RENAL CANCER? RECIST (Response Criteria in Solid Tumors) CASE 1 PRE POST CASE 2 PRE POST RECIST 1.1 is simple, objective, and reproducible. GOOD REASONS FOR USING RECIST. EVALUATING RENAL CANCER RECIST – LYMPH NODES SHORT AXIS HOW MUST WE MEASURE LYMPH NODES IN RECIST EVALUATION? EVALUATING RENAL CANCER RECIST – BONE LESIONS CAN WE USE BONE LESIONS AS TARGET LESIONS IN RECIST EVALUATION? EVALUATING RENAL CANCER RECIST – SIZE IS MY ONLY REASON Baseline Post-therapy with Sunitinib Follow-up CT 04/12 07/12 02/13 WHAT´S YOUR OPINION ABOUT THE EVOLUTION OF THIS TUMOR UNDER THERAPY? WHICH ARE THE RELEVANT QUESTIONS EVALUATING TARGETED THERAPIES? POST-TKIs THERAPY EVALUATING RENAL CANCER RECIST – IS SIZE THE KEY FEATURE? - RECIST criteria had sensitivity of 16% for predicting favorable PFS (Smith et al, AJR ‘10) - Response rates by RECIST did NOT PREDICT SURVIVAL *Sunitinib 31% (Motzer et al, NEJM 2007) *Sorafenib 10% (Escudier et al, NEJM, 2007) *Sunitinib or cediranib 25% (Nathan et al, CBT, 2010) EVALUATING RENAL CANCER RECIST limitations 1 2 3 4 5 The assessment of response to treatment in patients with mRCC has been carried out using RECIST as the primary criteria. Available data supported the implementation of RECIST 1.1 not only in clinical research but also in clinical practice in many tumor types. However, RECIST criteria have some limitations in the evaluation of patients treated with molecular targeted therapies. These therapies apparently lead to disease stabilization rather than to substantial tumor regression. Such limitations in RECIST criteria have encouraged the development of new response evaluation criteria, which are more specific criteria to cancer type and oncology treatment. TUMOR GROWTH RATE (TGR) TGR estimates the increase of the tumor volume over time. It incorporates the time between the imaging examinations, allowing for a quantitative and dynamic evaluation of the tumor response. Tumor growth rate (TGR) is associated with prognosis (PFS and OS) independent of the Memorial Sloan-Kettering prognostic score. The use of TGR allows for early and precise evaluation of drug activity compared with RECIST evaluation. TGR suggests interesting drug-specific profiles at treatment discontinuation. PRE DRUG TRIAL PD TG = 3 log(Dt / D0) / t (Dt) the sum of the longest diameters of the target lesions at time t per RECIST (D0) the sum of the longest diameters of the target lesions at baseline per RECIST Tumor growth rate (TGR) across specific treatment periods Ferté Ch et al. European Urology 2014; 6 5 :713 – 20. EPTIC (Early Posttherapy Imaging Changes) Early size change > 10% = RESPONDER 14 days post-therapy with Sunitinib -66 mRCC patients with 165 lesions on clinical trials of VEGF-targeted agents Krajewski KM, et al. Eur Urol. 2011; 59(5):856-62. Krajewski KM, et al. Oncologist 2014: 19(5):207-14 -More than -10% SLD significantly differentiated responders from nonresponders (median TTF 8.4 vs. 4.1 months, p = .001), whereas partial response by RECIST did not). -10% SLD was also significantly predictive of OS (median OS 35.1 vs. 15.0 months in responders vs. non-responders, p = .003). EVALUATING RENAL CANCER RECIST – IS SIZE THE KEY FEATURE? Pre 1m 4m Courtesy MC Sebastiá, H Clínic WHAT´S YOUR OPINION ABOUT THE EVOLUTION OF THIS TUMOR UNDER THERAPY? - Tumor size is a late and inaccurate measurement. - Non-measurable disease eg: bone mets. - Key biological tumor hallmarks are not considered. Choi Criteria size >10% OR a decrease in tumor attenuation (HU) >15% on CT Choi criteria defined more patients as responders than RECIST. However, they did not differentiate between patients who did and those who did not have therapeutic improvements in PFS or OS (*different data depending studies) PROBLEMS WITH DENSITY BASE CRITERIA • The reliability of Choi criteria decreases when fewer lesions are included for analysis. • The attenuation of heterogeneous lesions may be assessed inaccurately, as the mean value is calculated in one region of interest in one slice. • Measurements of relatively hypodense lesions at baseline may be less reliable, because a 15% decrease in attenuation is less accurate than measurements in lesions with higher pretreatment attenuation values. • Attenuation measurements are not possible in lesions with sunitinib-induced cavitations EVALUATING RENAL CANCER Beyond RECIST Qualitative changes = density changes (necrosis) may precise normalization of the enhancement Choi, Nathan, SACT, and MASS criteria 132 UH (mass): 283 UH (aorta) 119 UH (mass): 245 UH (aorta) Choi modified/Nathan Criteria size >10% AND a decrease in tumor attenuation (HU) >15% on CT • Neither the RECIST or CHOI criteria were able of effectively discriminating between patients treated with sunitinib or cediranib with short or long term clinical benefits. Patients who had a PR according to the modified Choi criteria had a statistically significant longer TTP • The response analysis, according to this study, combining both size reduction and arterial phase density of the tumor in the mRCC treated with Tyrosine Kinase Inhibitors (TKIs), can be correlated with TTP of the illness. RECIST and CHOI criteria were apparently inferior to NATHAN 1. Shinagare AB, et al. Am J Roentgenol. 2012; 199(5):W554-64. 2. Smith AD, et al. Am J Roentgenol. 2010; 194(1):157-65. 3. Nathan PD, et al. Cancer Biol Ther. 2010; 9(1):15-9. 4. Krajewski KM, et al. Eur Urol. 2011; 59(5):856-62. 5. Smith AD, et al. Am J Roentgenol. 2010; 194(6):1470-8. 6. Fournier LS, et al. Radiology. 2010; 256(2):511-8. 7. Van der Veldt AA, et al. Target Oncol. 2010; 5(2):95-112. EVALUATING RENAL CANCER RECIST – MUST BE SIZE MY ONLY REASON Baseline Post-therapy with Sunitinib Follow-up CT 01/12 04/12 10/12 WHAT´S YOUR OPINION ABOUT THE EVOLUTION OF THIS TUMOR UNDER THERAPY? SACT Criteria - Size decrease ≥ 20% - Size decrease ≥ 10% and average attenuation of ≥ 20 UH in over half of the non-pulmonary treated lesions - Decrease in average attenuation of ≥ 40 UH in at least one nonpulmonary treated lesion Marked central necrosis was defined as more than 50% of the enhancing central portion of a predominantly solid enhancing mass subjectively changing to near fluid attenuation (necrosis) after treatment • Improved response assessment by changes in tumor SCAT criteria using CT after target therapy for mRCC. They can suggest EARLY PD (<250d). However: • Need for contrast-enhanced CT evaluation in arterial phase and 3D volumetric assessment. • Time consuming, Complex criteria. N Favorableresponse SCAT criteria Partial-response RECIST Good-response Modified Choi Criteria PFS >250d 44 75% 16% 93% Early PD <250d 9 0% 0% 56% <0.0001 0.33 0.012 Disease Status P value MASS Criteria • The MASS “Morphology, Attenuation, Size and Structure” criteria was created to compensate for some of the limitations of the evaluation criteria, such as not taking into account specific morphological or structural changes in the treated cases. However • Need for contrast-enhanced CT evaluation in portal phase. • Complex parameters for indeterminate or unfavorable response. MASS criteria are more reliable and may predict the response of the illness measured as PFS Qualitative evaluation Central fill-in EVALUATING RENAL CANCER Beyond RECIST – Different response criteria Partial response (PR) Stable disease (SD) Progressive disease (PD) RECIST Version 1.1 Choi Criteria CLASSIC CATHEGORIES OF RESPONSE CRITERIA Modified Choi criteria (Nathan) SACT criteria MASS criteria PROGNOSTIC VALUE CRITERIA EPTIC RECIST Response Evaluation Criteria in Solid Tumors, SACT evaluation criteria of size and attenuation EPTIC Early Posttherapy Imaging Changes MASS Morphology, Attenuation, Size and Structure 1. Shinagare AB, et al. Am J Roentgenol. 2012; 199(5):W554-64. 2. Smith AD, et al. Am J Roentgenol. 2010; 194(1):157-65. 3. Nathan PD, et al. Cancer Biol Ther. 2010; 9(1):15-9. 4. Krajewski KM, et al. Eur Urol. 2011; 59(5):856-62. 5. Smith AD, et al. Am J Roentgenol. 2010; 194(6):1470-8. 6. Fournier LS, et al. Radiology. 2010; 256(2):5118. 7. Van der Veldt AA, et al. Target Oncol. 2010; 5(2):95-112. EVALUATING RENAL CANCER Imaging-based evaluation criteria of the mRCC response Criteria RECIST Version 1.1 Target lesions Complete response Tumor size ≥10mm per CT Disappearanc Size decrease ≥30% e of all lesions Tumor size ≥15mm per Chest X-ray Maximum 5 target lesions No new lesions Choi Criteria Tumor size ≥15mm Disappearanc Size decrease ≥10% OR attenuation e of all lesions decrease in the tumor (UH) ≥15% in CT No new lesions No new lesions Maximum of 10 target lesions Tumor size ≥15mm Modified Choi criteria Maximum of 10 target (Nathan) lesions SACT criteria MASS criteria EPTIC (Early Posttherapy Imaging Changes) Partial response (PR) Disappearanc Size decrease ≥10% AND attenuation e of all lesions decrease in the tumor (UH) ≥15% in CT No new lesions No new lesions Tumor size Arterial phase ≥10mm Volumetric measurements Maximum of 10 Portal phase target lesions FAVOURABLE RESPONSE Size decrease ≥20% Size decrease ≥10% and average attenuation of ≥20 UH in over half of the non-pulmonary treated lesions Decrease in average attenuation of ≥40 UH in at least one non-pulmonary treated lesion RESPONDERS - Decrease in size ≥10% Stable disease Progressive disease (PD) Does not comply with criteria of PR or PD Increase in tumor size ≥20% (the sum should show an absolute increase in size of at least 5mm) Appearance of new lesions Does not comply with criteria of CR, PR or PD Increase in tumor size ≥10% and does not comply with criteria for PR for tumor attenuation No symptomatic deterioration due to PD Does not comply with criteria of CR, PR or PD No symptomatic deterioration due to PD Does not comply with criteria of PR or PD Onset of new lesions Increase in tumor size ≥10% and does not comply with criteria of PR for tumor attenuation Appearance of new lesions UNFAVOURABLE RESPONSE Increase in tumor size ≥20% New metastases, increase in necrosis Central fill-in NON-RESPONDERS - No decrease in size ≥10% EVALUATING RENAL CANCER Beyond RECIST – The mess of response criteria Which are the best imaging criteria for evaluating tumor response? PRE-ART PRE-PORT 50 UH 78 UH PRE-ART PRE-PORT POST-ART 30 UH POST-ART POST-PORT 37 UH POST-PORT RECIST 1.1 -- PD / EPTIC – Non responder / CHOI – PR / CHOI modified – SD / SACT – Indeterminate response /MASS – Favorable response BRAND NEW RESPONSE CRITERIA?? 1 2 3 4 The assessment of response with Non-RECIST criteria may improve the evaluation. Every criteria include several conditions that must be known (phase of contrast-enhanced of the evaluation, type of lesions to evaluate, etc.) We must consider the kind of evaluation that we are performing (response?, prognosis?) with these criteria Non-RECIST criteria are based on series with a small number of patients. TEXTURE CT ANALYSIS • CT texture analysis reflecting tumor heterogeneity is an independent factor associated with time to progression and has potential as a predictive imaging biomarker of response of metastatic renal cancer to targeted therapy. Tumor entropy decreased by 3%–45% and uniformity increased by 5%–21% for the different scale values after administration of a TKI. Vicky Goh Radiology 2011 Conventional CT image of a right upper lobe lung metastasis (upper left) and corresponding CT images selectively displaying fine (upper middle), medium (lower left), and coarse (lower middle) texture obtained with filter values of 1.0 (width, 4 pixels), 1.5 (width, 6 pixels), and 2.5 (width, 12 pixels). Genetic / Cancer / Imaging / Therapy Genetic / Cancer / Imaging / Therapy Tumor Poor prognosis renal carcinoma. Baseline BV BV BF BF Tumor Early evaluation post-treatment with Tensirolimus = NO CHANGES TUMOR IMAGING FEATURES Usual findings in renal cancer Angiogenic phenotype depends on tumor type and shows a wide individual variability BF Prostate Colon Tumor Lung Renal 50 BV Clear cell renal carcinoma. Perfusion CT 50 100 100 Breast ml/100g/min Blood flow (BF) NEW IMAGING TECHNIQUES RECIST SIZE / DENSITY -Choi -Nathan 1.1 -SACT -MASS FUNCTIONAL MOLECULAR IMAGING EVALUATING RENAL CANCER BEYOND RECIST PRE Pharmacokinetic End-points are POST focused on“what the body does to the drug,” in terms of absorption, distribution, metabolism and excretion Pharmacodinamic Biomarkers try to evaluate “what the drug does to the body” NEW IMAGING TECHNIQUES Can functional and molecular imaging represent tumor biology? BF 115 ml/min/100 g PRE BV 16.3 ml/100 g PS 35 ml/min/100 g VEGF BF 23 ml/min/100 g POST PS 7.5 ml/min/100 g BV 2.4 ml/100 g VEGF Parameters Dynamic Contrast-Enhanced Computed Tomography as a Potential Biomarker in Patients With Metastatic Renal Cell Carcinoma Invest Radiol 2014 High baseline BF and reductions in BF and BV during early treatment are associated with improved outcome PERFUSION-CT Imaging as a biomarker of Early Response Aorta PRE POST Aorta Tumor enhancement curve Tumor enhancement curve BV BF Metastatic renal Carcinoma (arrows). Baseline BV BF 14 days post-treatment with Sunitinib = Partial RESPONSE As enhancement parameters of dynamic CT correlate with microvessel density (MVD) in RCC, DCECT may have additional value for early assessment of tumor response to antiangiogenic therapy. NEW IMAGING TECHNIQUES Can functional and molecular imaging represent tumor biology? The importance of an evaluation based on multiple parameters PRE-PS PRE-BF 70 ml/min/100 g 7.2 ml/min/100 g POST- BF POST-PS 50% 36 ml/min/100 g VEGF 50% 10.3 ml/min/100 g NEW IMAGING TECHNIQUES Technique CT ADVANTAGES Availability Easy quantification DISADVANTAGES Radiation dose Limited in patients with renal insufficiency Not predictive for early response DCE-CT DCE-US MRI PET Availability Straightforward quantification Predictive of early response High radiation dose Limited in patients with renal insufficiency Predictive value for OS not yet established Cost No radiation Simple standardised quantification using bolus injection Largest clinical data with strong evidence No renal failure contraindication Acquisition window restricted to 10-15 cm Not a whole-body technique (bone, lung, and brain not evaluable) No radiation Can be done without contrast agent injection (ASL) Multiparametric evaluation (DCE, DWI) Predictive of early response Potentially predictive of OS No standardised acquisition Imaging of metabolic activity Availability Cost Radiation dose Very limited experience with data not validated Allow for studying different metabolic pathways Quantification more complex Cost Availability Predictive value for OS not yet validated in larger studies Limited experience DCE-US AUC >40% RELATED TO TTP Y OS Lassau, N., Vilgrain, V., Taieb, S., Lacroix, J., Aziza, R., Cuinet, M. et al. (2012) Evaluation with DCE-US of antiangiogenic treatments in 539 patients allowing the selection of one surrogate marker correlated to overall survival. J Clin Oncol 30(Suppl.): abstract 4618. Williams, R., Hudson, J., Lloyd, B., Sureshkumar, A., Lueck, G., Milot, L. et al. (2011) Dynamic microbubble contrast-enhanced US to measure tumor response to targeted therapy: a proposed clinical protocol with results from renal cell carcinoma patients receiving antiangiogenic therapy. Radiology 260: 581–590. METASTATIC RENAL CANCER to the liver: pre and post Sunitinib LIMITED EVALUATION DCE-MRI - Elevated baseline Ktrans was a statistically significant predictive marker for favorable response to treatment - Change in Ktrans or IAUGC90 with treatment were not significantly related to PFS Flaherty, K., Rosen, M., Heitjan, D., Gallagher, M., Schwartz, B., Schnall, M. et al. (2008) Pilot study of DCE-MRI to predict progression-free survival with sorafenib therapy in renal cell carcinoma. Cancer Biol Ther 7: 496–501. Hahn, O., Yang, C., Medved, M., Karczmar, G., Kistner, E., Karrison, T. et al. (2008) Dynamic contrast-enhanced magnetic resonance imaging pharmacodynamic biomarker study of sorafenib in metastatic renal carcinoma. J Clin Oncol 26: 4572– 4578. COMPLEX QUANTIFICATION NON-CE MRI - Changes in blood flow detected by ASL-MRI at 1 month correlated with the change in tumor size measured at 4 months or at disease progression (p < 0.01) ASL De Bazelaire, C., Rofsky, N., Duhamel, G., Michaelson, M., George, D. and Alsop, D. (2005) Arterial spin labeling blood flow magnetic resonance imaging for the characterization of metastatic renal cell carcinoma1. Acad Radiol 12: 347– 357. DWI - IVIM Desar, I., ter Voert, E., Hambrock, T., van Asten, J., van Spronsen, D., Mulders, P. et al. (2011) Functional MRI techniques demonstrate early vascular changes in renal cell cancer patients treated with sunitinib: a pilot study. Cancer Imaging 11: 259–265. ASL IVIM RENAL CANCER: Arterial Spin Labelling and IVIM-DWI WHOLE BODY-DWI 67 F. Metastatic renal cancer (lung, liver and lymph nodes) treated with Sunitinib. Courtesy AR Padhani (UK) 10 July/12 18 Sept/12 Renal tumor: volume 1249.7 ml, ADC 1617 ± 530 µm2/s Metastases: volume 212.5 ml, ADC 942 ± 300 µm2/s Renal tumor: volume 1636.7 ml, ADC 1651 ± 650 µm2/s Metastases: volume 85.4 ml, ADC 1090 ± 300 µm2/s MRI - MULTIPARAMETRIC Is there any added value in using multiparametric imaging? T2 DCE T1 out T1 in DWI – b 800 ADC Multiparametric MR imaging – DCE + DWI + T1 + T2 MR Imaging can perform a multiparametric approach, including anatomy, T1 and T2 contrast, in/out of phase sequences, fat saturation, DCE imaging and diffsuion weighted imaging MOLECULAR IMAGING Tumor cells Ramona GLUCOSE metabolism – Aerobic Glycolysis FDG-PET Tumor cells Integrins αvβ3 expressed on TUMOR cells potentiate metastasis by facilitating invasion and movement across blood vessels. Tumor cells produces VEGF “Non-tumoral” cells in tumor matrix Inflammatory cells (such as macrophages) or platelets also express integrins Tumor Vessels ANGIOGENIC pathways – Integrins αvβ3 expressed on ENDOTHELIAL cells modulate cell migration and survival during tumor angiogenesis. They are upregulated on tumor vasculature but not on quiescent endothelium Endothelial cells also express VEGF receptors MOLECULAR IMAGING is mainly based on FDG-PET. However, new PETradiotracers which target integrins or VEGF pathway and may opens new opportunities specifically on imaging of the angiogenesis PET - IMAGING One prospective study involving 67 mRCC patients further supports that survival is predicted by SUVmax Several studies have shown that early assessment by FDG-PET/CT of response to TKIs using a combination of FDG uptake and tumor size predicted both PFS and OS in mRCC patients Specific radiotracers of angiogenesis may improve these data Liver metastasis pancreatic cancer: [68Ga]TRAP-RGD(3) PET/MR: fusion PET + Anatomic T2 Courtesy Ambors Beer, Tulm, Germany NEW IMAGING TECHNIQUES CHALLENGES Renal Cancer 16 days post Sunitinib 70% change in BV Which threshold must be consider response? Which one is linked to patient improvement? SIGNIFICANCE represents the variability of a parameter that may be consider a true change, NEW IMAGING TECHNIQUES Tumor enhancement CHALLENGES 100 tBF change ≤ -50% Overall Survival (%) 90 tBF change > -50% 80 70 60 50 40 30 20 10 0.0 HR,1.25, 95%CI, 0.46 to 3.57; p=0.64 0 12 24 36 48 Time since the beginning of the treatment (months) Which one is the right threshold? Progression-free survival curves in patients given antiangiogenic drugs according to their change (>50% or ≤ 50%) in tumor blood flow (TBF) after a single cycle of treatment. There was no significant difference in survival between the two groups of patients. 1. Fournier LS, et al. Radiology. 2010; 256(2):511-8 “IN GOD WE TRUST. ALL THE OTHERS BRING DATA” W. Edwards Deming James P.B. O'Connor and Gordon C. Jayson Do Imaging Biomarkers Relate to Outcome in Patients Treated with VEGF Inhibitors? Clin Cancer Res; 18(24) December 15, 2012 No phase I (mixed population) study has shown significant association between imaging biomarkers and TTP or OS. Non-progression has an association with some imaging biomarkers but is a weak clinical endpoint. Pretreatment (Ktrans) and acute change biomarkers [size, Hounsfield units (HU), Ktrans] show promise as predictive and/or prognostic indicators. “Why Most Published Research Findings Are False?” -The smaller the studies conducted in a scientific field, the less likely the research findings are to be true. -The smaller the effect sizes in a scientific field, the less likely the research findings are to be true. -The greater the financial and other interests and prejudices in a scientific field, the less likely the research findings are to be true. -The hotter a scientific field (with more scientific teams involved), the less likely the research findings are to be true. John P. A. Ioannidis, PLoS Medicine August 2005 Volume 2 lssue 8 e124 CONCLUSIONS - Non-RECIST criteria improve the evaluation of mRCC patients. - Several criteria seem to be able to identified patients with a poor prognosis. - These criteria have been only evaluated in a reduced number of patients -There are several promising novel techniques for the assessment of response to treatment in patients with mRCC treated with targeted therapies. - Functional and molecular imaging techniques provide quantitative evaluation parameters. - High values of perfusion related parameters are usually associated to a good response to antiangiogenic therapies - However, these techniques need to be standardized