pet/ct imaging and cancer response to treatment dr. françois bénard
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PET/CT Imaging and Cancer Response to Treatment Dr. François Bénard. Potential Conflict of Interest. None. PET/CT imaging and cancer response to treatment. François Bénard, MD, FRCPC BC Cancer Agency. Cancer Resistance. Increased efflux of drug (P-glycoprotein and others) - PowerPoint PPT PresentationTRANSCRIPT
PET/CT Imaging and Cancer Response to TreatmentDr. François Bénard
Potential Conflict of Interest
• None
PET/CT imaging and cancer response to treatment
François Bénard, MD, FRCPC
BC Cancer Agency
Cancer Resistance
• Increased efflux of drug (P-glycoprotein and others)
• Decreased influx/transport
• Altered or absent binding sites
• Enzymatic inactivation
• Alternate growth pathways
Why use surrogate measures of tumour response?
• Ultimate goal (enhanced patient survival, quality of life, reduced costs) are appropriate endpoints for phase 3 trials
• Phase 2 trials need intermediate endpoints to speed up drug discovery and reduce trial costs
• Rapidly identify ineffective treatments• Speed up the identification of resistance and
target patients with sensitive or resistance phenotypes to identify causes (host-related, tumour related)
Treatment response biomarkers• Plasma or urine proteins (PSA, CA 15.3, CA 125, CEA)
• Circulating tumour cells
• Metabolomics profiles (urine, plasma)
• Histopathology/immunofluorescence (biopsies)
• Imaging methods– Conventional (morphological: CT, MRI, US)– Functional
• DCE/Diffusion MRI
• Perfusion CT
• Nuclear Medicine / PET
• Optical (surface imaging)
Conventional Tumor Response Assessment
• Usually performed using cross sectional imaging
• WHO criteria replaced with RECIST criteria• Modified RECIST criteria published 2009• Morphological measurements of solid
tumours• Assessment at least 8 weeks from treatment
initiation
RECIST 1.1
• Requires a measurable lesion– Size 10 mm (CT, caliper) to 20 mm (Chest X-
ray)– Enlarged lymph node > 15 mm in short axis– Non-measurable: < 10 mm (or nodes 10-15
mm short axis), leptomeningeal, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement skin/lung, most bone metastases, previously irradiated fields, cystic lesions
RECIST 1.1
• Up to 5 measurable lesions
• Maximum of 2 lesions per organ
• Selected by size (longest diameter)
• Lymph node size measured on shortest diameter
• Sum of the diameters of lesions (longest for non-nodal, shortest for nodes)
Treatment response prediction vs measurement
• Prediction– A test to predict response to treatment before it is
administered– Typically predicts sensitivity of a tumour to respond to
treatment– Classical examples: ER and HER2/neu in breast cancer
• Response measurement– Measurement of tumor sensitivity after onset of treatment– Biomarkers or imaging– Documents treatment resistance
Limitations of planar measurements
• Delay in identifying resistance• Not adapted to evaluate cytostatic rather than
cytotoxic treatments (progressive disease remains progressive disease even if tumor growth is slowed)
• May not identify the appearance of treatment resistant clones
• Not suitable for bone metastases or when no measurable lesion is available
• Residual fibrotic/necrotic masses
Functional Imaging in Cancer Response Assessment
• Conventional Nuclear Medicine– Bone scintigraphy and some receptor binding agents– Currently qualitative– Flare phenomena
• Contrast-enhanced CT– Perfusion CT– Density/enhancement signal changes
• Dynamic contrast-enhanced MRI / Diffusion imaging
• Positron emission tomography with CT
PET imaging 101
Treatment response to imatinib
• Before treatment
• 1 month after imatinib initiation
Van Den Abbeele AD, The Oncologist 2008; 13: 8-13
Large B-cell lymphoma: Baseline
Large B-cell lymphoma: After 1 cycle
Baseline
1 cycle
4 cycles
Rapid response assessment to therapy
Baseline
1 cycle
4 cycles
Rapid response assessment to therapy
False Positive Residual MassNon seminomatous GCT
Before chemotherapyGCT with bulky mets
After chemotherapyMild-moderate residual uptake
After surgeryPath: granulomatous inflammation
Recurrent Ovarian Cancer
12/9803/99
01/0009/00
Assessment of treatment response
Treatment Response Assessment in Breast Cancer
02/2002 06/2002
Lack of treatment response documented by PET after chemotherapy
Timing of the treatment response
Couturier O et al., Clin Canc Res 2006; 12:6437-6443
Predictive value of FDG-PET21 days after cycle 1 21 days after cycle 3
Couturier O et al., Clin Canc Res 2006; 12:6437-6443
From: Wester, HJ. Nuclear Imaging Probes: from Bench to Bedside. Clin Cancer Res 2007;13(12): 3470-3481
Radiotracers of interest in oncology
Avβ3 integrin imaging with 18F-RGD to predict/monitor anti-VEGF therapy
Beer AJ et al., J Nucl Med 2008; 49:22-29.
Estrogen Receptor Imaging in Metastatic Breast Cancer
FDG FES
Measuring response to hormone therapy
Baseline
After 2 months(aromatase inhibitor)
PRECLINICAL MICRO PET/CT IMAGES
Using 18F-FDG PET to monitor treatment response
Early response and flare reaction
Estrogen challenge to predict resistance to hormone therapy
• Baseline FDG-PET• Repeated after 3 x 10 mg
doses of estradiol q 8-10h• If increase in FDG uptake
< 12% after estradiol administration, this was predictive of hormone therapy failure
Dehdashti F et al., Breast Cancer Res Treat 2009; 113: 509-17
Role vs other predictors
• Tumor microarrays (DNA, RNA, microRNA) or IHC/FISH panels can provide information about expression of genes/proteins associated with resistance
• No « pattern » is entirely predictive• Combining genetic predictors with rapid imaging
assay of treatment failure could be a powerful way to identify resistance
• Rapidly select patients for phase II clinical trials or tissue banking
Increased Efflux
• P-glycoprotein substrates– [99mTc]-Sestamibi– [11C]-Verapamil– [11C]-carvedilol– [11C]N-Desmethyl-Loperamide– [11C]daunorubicin – 4-[18F]Fluoropaclitaxel
• Common problem: low tumour uptake / constrast
Chemotherapy influx
• Can chemotherapy response be predicted by tracers with similar uptake mechanisms?
• Cationic organic transporters
• Anionic transporters
• Other ions?
Folate receptor mediated transport
99mTc-EC20 Folate receptor scintigraphy. Fisher RE et al., J Nucl Med 2008; 49:899-906
Zr-89 CetuximabDisparity between WB receptor expression and antibody uptake
Aerts HJWL et al., J Nucl Med 2009; 50: 123-131
18F-Labeled HER2-Affibody
Kramer-Marek et al., Eur J Nucl Med Mol Imag 2008; 35:1008-1018; NIH, Bethesda, MD
Conclusion
• PET/CT imaging offers unique new opportunities to predict or rapidly identify treatment resistance
• In vivo targeted imaging• Radiopharmaceuticals to predict chemotherapy
influx / efflux ?• Possible role for combining predictive
biomarkers (DNA/RNA microarrays) and early response imaging to identify resistance