Transcript PowerPoint - Q-CROC

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)
• 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
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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 Xray)
– 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
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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
Rapid response assessment to
therapy
Baseline
1 cycle
4 cycles
Rapid response assessment to
therapy
Baseline
1 cycle
4 cycles
False Positive Residual Mass
Non seminomatous GCT
Before
chemotherapy
GCT with bulky
mets
After
chemotherapy
Mild-moderate
residual uptake
After surgery
Path:
granulomatous
inflammation
Recurrent Ovarian Cancer
12/98
03/99
01/00
09/00
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-PET
21 days after cycle 1
21 days after cycle 3
Couturier O et al., Clin Canc Res 2006; 12:6437-6443
Radiotracers of interest in oncology
From: Wester, HJ. Nuclear Imaging Probes: from Bench to
Bedside. Clin Cancer Res 2007;13(12): 3470-3481
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
18F-FDG
Using
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 Cetuximab
Disparity 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; 35:10081018; 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