Download - Hypoxia
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Hypoxia in Soft-Tissue Sarcomas on [18F]-Fluoroazomycin Arabinoside Positron Emission Tomography (FAZA-PET)
Powerfully Predicts Response to Radiotherapy and Early Relapse
Kenneth Khamly, Peter Choong, Samuel Ngan, Rodney Hicks, Guy Toner, Jayesh Desai, Dianne Saward and David Thomas
Peter MacCallum Cancer Centre,Melbourne, Australia
CTOS 14th Annual MeetingNovember 13 – 15, 2008
London
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Hypoxia
• Linked to various biologic changes– HIF-1α, GLUT, hexokinase, VEGF,
PI3K/AKT, p53 etc.
• Has been related to– Poor prognosis– Progression to a more malignant phenotype– Resistance to therapy
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CA-9 Glut-1 Ki-67
CD-31 VEGF-A VEGF-C
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Functional Imaging of Hypoxia
• Most studies to date utilize O2 electrode measurements– Sampling limitations
• Positron emission tomography– Non-invasive, allows evaluation of the whole tumour– [18F]-Fluoromisonidazole (F-MISO)– [18F]-Fluoroazomycin arabinoside (FAZA)
• Marginally lower uptake and sensitivity• pO2 ≤ 10 mmHg• Faster reduction of non-specific binding
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Study Rationale
• Hypoxia is associated with resistance to RT
• Angiogenesis inhibitors have the potential to modify tumour vasculature and hypoxia– Although single agent activity is generally limited– Combination with RT is potentially interesting.
• In preparation for an interventional study, this baseline study was performed to evaluate hypoxia and resistance to radiotherapy in resectable STS
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BaselineWeek
1Week
2Week
3Week
4Week
5Week 6
Pre-operative evaluation
SURGERY
Pathologic Response
Radiotherapy xxxxx xxxxx xxxxx xxxxx xxxxx xxx
Histology x1 x2
CT/MRI x x
FDG-PET x x
FAZA-PET x
IHC markers of hypoxia x x
Circulating markers of hypoxia
x * * * * * * x
Molecular profiling x
Radiotherapy to 50.4Gy in 1.8Gy fractions1Core Biopsy; 2Resected Tumor Specimen (including assessment of pathologic necrosis)*Circulating markers of hypoxia and angiogenesis will be evaluated during radiotherapy for any patterns of change that will be correlated with outcomes
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Objectives
• Primary objectives– Proportion of STS with hypoxia on functional
imaging
• Secondary objectives– Correlation with response– Correlation with molecular markers
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Eligibility Criteria
• Histologically confirmed STS
• Surgically resectable disease
• Suitable for neoadjuvant radiotherapy
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Results (1)
• 23 patients (17 with FAZA-PET)– 15 Female; 8 Male– Age 35 – 81 (median 61)– Histology
• MFH / High grade pleomorphic sarcoma – 43%
• Liposarcoma – 30%
• Other – 26%
– Mean tumour size – 88 ± 8.8 mm
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Results (2)
• Median follow-up just over 12 months
• Two patients have died
• Two patients developed metastases on completion of RT and prior to surgery
• Five further patients have relapsed
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Results (3)
• Response Rates
– RECIST – RR 14% (SD 57%; PD29%)
– FDG-PET – RR 32% (SD 47%; PD 21%)
– Histology – RR 31%
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FAZA-PET
• Hypoxia defined using tumour-to-background ratio (TBR)– TBR ≥ 1.2 classed as hypoxic (range 1.01 – 2.69)
• 8/17 (47%) patients had evidence of hypoxia– Strongly associated with outcomes– None had a good histological response at resection– Lower RR and greater incidence of disease progression
on RT– Predicts early relapse (< 6 months)
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Hypoxia on FAZA-PET
• Of patients with hypoxia on FAZA-PET
– 63% progressed on RT• (cf. 13% in patients without hypoxia; p=0.015)
– 86% progressed on RT and/or relapsed within 6 months
• (cf. 27% in patients without hypoxia; p=0.010)
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Plasma VEGF
• VEGF-A and -C levels strongly correlated with each other– Absolute levels of VEGF-C ~ x1 log. order
higher than VEGF-A
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VEGF-C
0100200300400500600700800
Hypoxic Intermediate Non-Hypoxic
PET-FAZA
pg/mL Baseline
Post-RT
VEGF-A
0
10
20
30
40
50
60
Hypoxic Intermediate Non-Hypoxic
PET-FAZA
pg/mL Baseline
Post-RT
p = 0.015
p = 0.017
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Vegf-A
0.000
20.000
40.000
60.000
80.000
100.000
120.000
Baseline week 1 week 2 week 3 week 4 week 5
pg/mL
RespondersNon-responders
Vegf-C
0.000
100.000
200.000
300.000
400.000
500.000
600.000
700.000
800.000
900.000
1000.000
Baseline week 1 week 2 week 3 week 4 week 5
pg/mL
RespondersNon-responders
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FAZA-PET Examples
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Case 1
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FAZA-PET
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Comparison of FDG and FAZA Scans
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Post Treatment FDG-PET
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Histological Response
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Case 2
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Baseline
Post-RT
FDG
FAZA
FDG
Comparison of PET Scans
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Summary & Conclusions (1)
• Hypoxia on FAZA-PET– is present in a significant proportion of STS– is strongly associated with clinical outcomes
• resistance to radiotherapy• early relapse
• Plasma VEGF-A may be a promising marker for response– Change in VEGF-A levels with radiotherapy is predictive of
response– Hypoxic tumours were associated with lower baseline levels of
VEGF-A (and possibly VEGF-C), and a subsequent rise in response to RT
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Summary & Conclusions (2)
• Hypoxia and vascular changes are promising therapeutic targets for improving outcomes in STS
• Study evaluating the impact of angiogenesis inhibitors in modifying hypoxia during RT for STS is currently underway
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Acknowledgements• David Thomas
• Guy Toner
• Peter Choong
• Samuel Ngan
• Jayesh Desai
• Gerard Powell
• Sarat Chander
• Julie Chu
• Lisa Orme
• Rodney Hicks
• David Binns
• Stuart Galloway
• John Slavin
• Richard Young
• Samantha Cauberg
• Dianne Saward• Marianne Griffin
• Haematology and Oncology Targeted Therapies (HOTT) Research Fellowship– Clinical Oncological Society of Australia (COSA)
– Medical Oncology Group of Australia (MOGA)
– Haematology Society of Australia and New Zealand (HSANZ)
– Roche Pty Ltd