IMAGING inONCOLOGY
Biomedical EngineeringP Verdonck
D De NaeyerS Staelens
Gastro-oncologyM Peeters
N Van DammeV Casneuf
RadiologyP Smeets
RadiotherapyT Boterberg
Nuclear MedicineC Van De Wiele
Surgical OncologyW CeelenI Debergh
Imaging of Angiogenesis
• Direct: In Vivo Microscopy; molecular probes• Indirect
– Blood volume– Vessel surface area– Vessel permeability– Vessel ‘normalization’
Neoplastic vessels are morphologically and functionally deficient
• Highly irregular and tortuous • Dependent on cell survival factors (VEGF) • Hyperpermeable
– deficient pericyte coverage– absence of a basement membrane– deficient intercellular junctions– presence of cellular lacunae– vascular mimicry
• Resulting in abnormal microenvironment: hypoxia, low pH, interstitial hypertension
Hyperpermeability of tumor vessels is important
• Results in increased interstitial fluid pressure
• Enhances macromolecular leakage
• Permeability change is a surrogate marker of angiogenesis
The concept of vessel normalisation by anti-angiogenic therapy
• Return to ‘normal’ phenotype by vascular pruning
• Results in more efficient drug delivery by lowering IFP and restoring microvessel function paradoxical synergism of anti-angiogenesis agents and cytostatic drugs
• Results in more efficient RT by enhanced oxygenation
Willett et al. NATURE MEDICINE VOLUME 10 | NUMBER 2 | FEBRUARY 2004
Bevacizumab normalises rectal cancer microvessels
Known Effects of Radiotherapy on tumor vessels
• Induces endothelial cell apoptosis• Induces EC ‘senescent’ phenotype• Stimulates production of endothelin• Effects on vascular permeability dependent
on dose, fractionation, tissue type• Direct or bystander effect?
Garcia-Barros et al. Tumor Response to Radiotherapy (15 Gy)Regulated by Endothelial Cell Apoptosis. Science 2003
Apoptosis resistant
TUNEL
How does anti-angiogenic therapy increase radiotherapy efficacy?
1. Inhibits protective VEGF signaling from tumor EC2. Enhances oxygenation 3. Reduces number of circulating EC and progenitor cells
Phase I trials combining neoadjuvant CRT with anti-angiogenic therapy in rectal cancer
• Czito IJROBP 2007– 11 patients, 50.4 Gy, capecitabine,oxaliplatin, and bevacizumab– Acceptable toxicity– 18% pCR; 27% microscopic disease
• Willett JCO 2005– 5 patients, 50.4 Gy, 5-FU, bevacizumab 10 mg/kg– 2 complete responses seen in patients with DLT
Functional imaging using Dynamic Contrast Enhanced MRI
• Inject contrast agent bolus• Acquire a series of MR images over time with
sufficient temporal resolution• Measure signal intensity changes as a
consequence of leakage of CA from the vascular compartment into the interstitial space
DCE-MRI Data Analysis
• Description of enhancement curve
• Semi-quantitative approach: AUC, TTP, maximal enhancement
• Pharmacokinetic compartmental models
• Statistical models
Farmacokinetic models in DCE-MRI
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Physiological significance of calculated endothelial transfer constant
• Small MW contrast agent: flow >> permeability
• Large MW contrast agent (preclinical): permeability >> flow
Oncology Imaging Research @ UZ Gent
• Preclinical– DCE-MRI
• Rat colorectal cancer model• Mouse pancreas cancer model
– Molecular MRI– Sequence optimisation; simulation; modelling– In vivo flurescence microscopy
• Hamster melanoma and pancreas cancer model• Human CRC model in athymic mouse
• Clinical– DCE-MRI in metastatic CRC treated with folfox-bevacizumab– USPIO in advanced solid tumors
In collaboration with researchdept. of Guerbet SA
Effects of RT on neovascular permeability measured with DCE-MRI using P792
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Before RT After RT
Ceelen et al. Int J Radiat Oncol Biol Phys 2006
rhEPO prevents radiotherapy-induced reduction in neovascular permeability
Ceelen et al. Br J Cancer 2007
Pre 20 min Post
Molecular imaging in HT29 tumors using a αvβ3 integrin targeted MR probe
Debergh I, Van Damme N, Smeets P, Peeters M, Pattyn P, Ceelen W. Molecular imaging of tumor associated angiogenesis using P1227, a novel MRI contrast agent targeting avb3 integrin. Br J Surg 2008;95 Suppl 6: 13.
Collaboration with the biomedical engineering department
• Modelling of the AIF in DCE-MRI (PhD student)– D De Naeyer et al. Modelling the arterial input function for P792 in dynamic contrast enhanced magnetic resonance imaging: concepts and
validation. Submitted, MRM
• Modelling interstitial fluid pressure and drug transport with computational fluid dynamics software (Fluent) based on DCE-MRI data (thesis student)
• Hyperpolarized gas MRI; 19F MRI (hypoxia imaging)• Small animal nuclear imaging
• Micro SPECT (spatial resolution 0.35 mm)• Micro CT (spatial resolution <15 µm), GE• Small animal PET• Dedicated radiopharmacy unit (Prof Devos)
Small animal nuclear imaging: installed hardware
Aims of the project• Study interaction of RT with anti-angiogenic
therapy• Verify phenomenon of ‘vascular normalization’
and its importance for therapy planning• Validate functional and molecular imaging as a
tool to monitor therapy response• Validate CFD modelling of vascular normalization
and drug transport
Methods• Athymic mouse model; human CRC cell line• AZD2171 (Cediranib, 6 mg/kg), RT, or both• Measurements and imaging
– Non invasive: DCE-MRI; P1227– Semi-invasive: IVM– Invasive: pO2, IFP
• Modelling of IFP and drug transport using Fluent• Possibility to study nuclear molecular probes in parallel