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