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

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

CA-9 Glut-1 Ki-67

CD-31 VEGF-A VEGF-C

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

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

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

Objectives

• Primary objectives– Proportion of STS with hypoxia on functional

imaging

• Secondary objectives– Correlation with response– Correlation with molecular markers

Eligibility Criteria

• Histologically confirmed STS

• Surgically resectable disease

• Suitable for neoadjuvant radiotherapy

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

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

Results (3)

• Response Rates

– RECIST – RR 14% (SD 57%; PD29%)

– FDG-PET – RR 32% (SD 47%; PD 21%)

– Histology – RR 31%

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)

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)

Plasma VEGF

• VEGF-A and -C levels strongly correlated with each other– Absolute levels of VEGF-C ~ x1 log. order

higher than VEGF-A

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

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

FAZA-PET Examples

Case 1

FAZA-PET

Comparison of FDG and FAZA Scans

Post Treatment FDG-PET

Histological Response

Case 2

Baseline

Post-RT

FDG

FAZA

FDG

Comparison of PET Scans

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

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

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