TUMOR HYPOXIA BENCH TO BEDSIDE

Transcription

1 TUMOR HYPOXIA BENCH TO BEDSIDE Marianne Nordsmark, Lise Saksø Mortensen, Morten Busk, Michael Horsman, Markus Alber, Niels Bassler, Jørgen Petersen and Jens Overgaard. Dept. Oncology, Aarhus University Hospital Denmark.

2 Hypoxia most cited topic in RT An overview of the ten most cited papers in each of the four top ranked international radiotherapy journals showed that three out of the four most cited papers in the journals are dealing with hypoxia, and among the 40 most cited papers 17 (43%) are related to hypoxia and radiation resistance.

3 Hypoxic markers prognostic for outcome of radiotherapy of HNSCC PET-hypoxia Hypoxic gene profile DCE-MRI Outcome after Radiotherapy po 2 - measurements Pimonidazole, EF5 CT-perfusion VEGF, Osteopontin

4 Hypoxic markers prognostic for outcome of radiotherapy of HNSCC PET-hypoxia Hypoxic gene profile DCE-MRI Outcome after Radiotherapy po 2 - measurements Pimonidazole, EF5 CT-perfusion VEGF, Osteopontin

5 Hypoxic cells are radioresistant Oxygen Enhancement Ratio (OER): Head and neck tumors are hypoxic Arterial end Venous end 18 FAZA PET Oxygenated cells Hypoxic cells Necrotic cells Gray et al Mortensen et al. 2010

6 Tumor Hypoxia Facts Tumors are hypoxic Increases radiation resistance Is heterogeneous within and between tumors A marker for poor prognosis A Target for therapy Induces malignant progression Response to targeted therapy has been predicted by hypoxia specific gene signatures

7 Hypoxia assessed by imaging PET/SPECT DCE MRI CT perfusion Horsman et al. Nat. Rev. Clin. Oncol. 2012

8 Hypoxia Imaging DCE MRI Horsman et al. Nat. Rev. Clin. Oncol. 2012

9 Hypoxia Imaging CT perfusion Horsman et al. Nat. Rev. Clin. Oncol. 2012

10 TUMOR HYPOXIA by PET/SPECT Horsman et al. Nat. Rev. Clin. Oncol. 2012

11 Hypoxia by PET advantages in imaging Measures hypoxia in unperturbed tissue The result can be readily available Is a biological target within a target amenable for adaptive radiation therapy

12 Hypoxia by PET Tracer retention of a labeled compound (typically a nitroimidazole) Reduced under po2 < 10 mmhg Horsman et al. Nat. Rev. Clin. Oncol. 2012

13 The PET hypoxia tracer race

14 Hypoxia Tracers by PET FMISO FAZA HX4 Horsman et al. Nat. Rev. Clin. Oncol. 2012

15 Hypoxia by PET Resolution Autoradiography 200 µm Micro PET mm Clinical PET > 4 mm

16 PET hypoxia - open questions Tumor target definition How, when and what based on PET? Dose Which dose to give and when? Do targeting PET hypoxia by RT improve tumor control and OS?

17 The voxel size by PET is so large that microscopic hypoxia may be missed

18 Hypoxia in mice heterogeneity in 3D Busk et al. Eur. J. Nucl. Mol. Imaging 2012

19 Hypoxia in mice heterogeneity in space Busk et al Radiother Oncol 2011

20 FAZA PET in radiotherapy: possibilities and challenges exemplified by hypoxia Hypoxia staining (bound pimonidazole) 4 mm T/M: 1.8 Clinical PET voxel T/M: 1.2 Autoradiogram showing bound (hypoxia) and unbound FAZA 4 mm Busk et al. Eur. J. Nucl. Mol. Imaging 2012

21 FAZA PET in radiotherapy: possibilities and challenges exemplified by hypoxia Hypoxia staining (bound pimonidazole) 4 mm Clinical PET voxel T/M: 1.8 The resolution of hypoxic -PET scans is probably too poor and heterogeneous T/M: 1.2 to allow dose-painting Autoradiogram showing bound (hypoxia) and unbound FAZA If so, we must treat the whole tumor. 4 mm Busk et al. Eur. J. Nucl. Mol. Imaging 2012

22 Bench to Bedside Mouse to Man

23 Cumulative frequency of patients (%) Hypoxia in man Heterogenity in head & neck tumors by electrodes range % Fraction of po 2 values < 2.5 mmhg (%) Loco-regional tumor control (%) n=63, p=0.01 Low Middle High Time after treatment start (months) 26/06/2004 mn

24 Hypoxia in mice Heterogeneity and thus a marker for prognosis Mortensen et al Radiother Oncol 2011

25 18 F FAZA, oxylite, EPR oximetry & 19 F MRI in an experimental model Tran et al Radiother Oncol 2012

26 18 F FAZA is an effective surrogate of hypoxic fraction in experimental models

27 PET hypoxia over time At baseline During Radiation therapy During chemotherapy During Chemo/radiotherapy During targeted therapy Busk et al. Eur. J. Nucl. Mol. Imaging 2012

28 PET hypoxia over time - baseline Busk et al. Eur. J. Nucl. Mol. Imaging 2012

29 PET hypoxia over time during RT Busk et al. Eur. J. Nucl. Mol. Imaging 2012

30 FMISO PET during chemo-rt

31 F MISO of HNSCC during treatment Zips et al. Radiother. Oncol. 2012

32 How to define hypoxia by PET? Trazer characteristics Scan protocol Data evaluation strategy

33 Additional information by dynamic imaging: tracer retention and perfusion. Perfusion P Hypoxia H FMISO, min pi From Alber and Thorwartz

34 18 F HX4 PET in lung cancer (NSCLC) Zegers et al. Radiother. Oncol. 2013

35 18 F HX4 PET in lung cancer (NSCLC) Zegers et al. Radiother. Oncol. 2013

36 18 F HX4 PET in lung cancer (NSCLC) Acquisition time Zegers et al. Radiother. Oncol. 2013

37 Using SUV to give a binary decision of hypoxic/nonhypoxic volume Mortensen et al. Radiother. Oncol. 2012

38 FAZA PET HNSCC hypoxia and heterogeneity Mortensen et al. Radiother. Oncol. 2012

39 Fig. 1 FAZA PET HNSCC hypoxia and failure Mortensen et al. Radiother. Oncol. 2012

40 FAZA PET hypoxia in HNSCC Mortensen et al. Radiother. Oncol. 2012

41 Hypoxic PET imaging vs outcome after radiotherapy in HNSCC Study Tumor Tracer Events / Total Odds ratio and 95% CI No Odds Lower Upper hypoxia Hypoxia ratio limit limit 2004 Lehtio HN FETNIM 4 / 9 4 / Rajendran HN FMISO 10 / / Rischin HN FMISO 1 / 10 8 / Thornwath HN FMISO 1 / 6 4 / Eschmann HN FMISO 2 / 4 4 / Dirix HN FMISO 2 / 6 5 / Lee HN FMISO 0 / 7 1 / Kikuchi HN FMISO 3 / 10 5 / Minagawa HN CuATSM 0 / 5 6 / Mortensen HN FAZA 1 / 17 5 / Zips HN FMISO 3 / 13 5 / / / Hypoxia worse Hypoxia better Mortensen et al. Radiother. Oncol. 2012

42 PET hypoxia more open questions How does PET hypoxia relate to known prognostic factors in multivariate analysis? Do changes in PET hypoxia during RT predict tumor response? Is PET hypoxia a predictive marker for hypoxia targeted therapy in general?

43 A B Dose -painting C D A: 18 FAZA PET B: CT with tumor outline C: fused PET and CT image D: irradiation Dose Painting-IMRT.

44 The challenge with dose painting: or Do we target every-thing? assuming all resistant cells visualized? is the resolution of PET too poor whereby some resistant cells are missed?

45 TUMOR HYPOXIA by PET Targeting the hypoxic volume hypoxic voxels based on signal intensity in the (molecular) PET image the entire GTV

46 Conclusions Hypoxi targeted Dose Painting (DP) is a promising, yet still eksperimental approach The cautious way ahead is first to target and dose escalate the entire GTV If this improves local control then the subsequent study would be to target only the hypoxic GTV

47 Thanks to Professor Overgaard & lab