Clinical Imaging Hypoxia


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Lecture by Prof. Lambin in the course: "Tumour Hypoxia: From Biology to Therapy III". For the complete e-Course see

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  • Primary tumor right lower lobe (August 2011: 4.7 x 4.0 cm)
  • Clinical Imaging Hypoxia

    1. 1. Imaging of hypoxia Philippe Lambin Octobre 12th 2012 This course is funded with the support of the METOXIA project under the FP7 Programme.
    2. 2. Learning objectives1. Know the advantages and disadvantages of hypoxia imaging2. Be able to name the various hypoxia imaging modalities with some basic features
    3. 3. Advantage of imaging: 3D & non invasiveAdvantageous compared to IHC, gene-miRNA signatures because tumours are heterogeneous in space Courtesy of B. van der Kogel
    4. 4. Disadvantage: The oxygen distribution inside a voxel Measured voxel pO2 is average pO2 of the cells inside it. Each voxel contains a mixture of cells at different oxygen concentrations. Ignoring this will affect the correct choice of dose.4
    5. 5. Why should we do it?For prognosis (Give prognosis of disease outcome regardless of therapy)For prediction (Predict outcome with a specific therapy & allow to adapt treatment (drugs, boost BTV…)As endpoint (secondary or primary: e.g. reduction of hypoxia with nitroglycerine patch, pattern of relapse…)For research purposes (no immediate clinical benefit)
    6. 6. How to measure tumor oxygenation ? Non Imaging methods Imaging methods• Polarographic measurements • Hypoxia markers • Eppendorf® • Nitroimidazoles PET/SPECT • CA9 ligands PET/SPECT• Optical measurements • MR • Phosphorescence • 19F relaxation • Fluorescence (OxyLite ®) • BOLD • DCE-MRI• Hypoxia markers • 1H relaxation • Nitroimidazoles • Immunohistochemistry • EPR-related methods• Gene signatures• Blood biomarkers B. Gallez, NMR Biomed. 2004, 17, 240
    7. 7. How to measure tumor oxygenation ? Oxygen-sensitive Real oxygen measurements measurements • NMR• Polarographic measurements • DCE-MRI • Eppendorf® • BOLD• Optical measurements • 1H relaxation • Fluorescence (OxyLite ®)• EPR-related methods • Hypoxia markers • Nitroimidazoles• MRI • Immunohistochemistry 19F relaxation • • PET/SPECT • CA9 ligands PET/SPECT • Gene signatures • Blood biomarkers
    8. 8. How to measure tumor oxygenation ? Invasive Imaging Or not immediately Clinically applicable clinically applicable • NMR• Polarographic measurements • DCE-MRI • Eppendorf® • BOLD • 1H relaxation• Optical measurements • Fluorescence (OxyLite ®) • Hypoxia markers • Nitroimidazoles PET/SPECT• EPR-related methods • CA9 ligands PET/SPECT• MRI • 19F relaxation
    9. 9. Ideal clinical oxygen imaging modality• Able to distinguish normoxia/hypoxia/anoxia/necrosis• Able to distinguish between perfusion-related and diffusion-related hypoxia (sensitive to changes of hypoxia)• Able to reflect cellular oxygenation in preference to vascular oxygenation• Be applicable to any tumor site• Simple to perform, non toxic and allowing repeated measurements• Sensitive at pO2 relevant to tumor therapies A. Padhani, Eur. Radiol. 2007, 17, 861.• Results independant of the timing of imaging
    10. 10. EPR (Electron Paramagnetic Resonance) Oximetry B. Gallez, NMR Biomed. 2004,17, 240O2 dependent broadening of the EPRlinewidth (LW) of a paramagnetic O2 nitrogensensor implanted in the tumor airA particular material can be calibratedin terms of the effect of oxygen on theLW 3168 3318 3468 Magnetic Field (G)When introduced in vivo, the 40measurement of LW can be 30interpreted in terms of oxygenation in LW (G) 20the vicinity of the probe 10 0 0 7 14 21 % O2
    11. 11. Non-invasive imaging of chronic andcycling tumour hypoxia in xenografts with EPR Yasui et al., 2010, Can Res, 70:6427-6436.
    12. 12. EPR (Electron Paramagnetic Resonance) Oximetry  • Absolute measurement of pO2 • 1GHz: penetration depth of 1 cm• High sensitivity at low pO2: variations lower than 1 mm Hg can be • Not applicable immediately into the measured clinic: pionneer clinical studies• Minimally invasive: few ongoing in Dartmouth Medical microparticles should be introduced School on superficial tumors in the tissue (invasive only the first time)• Measurements can be repeated from the same site over long periods of time (hours, days, months) N. Khan, Antiox. Redox. Signal. 2007, 9, 1169
    13. 13. 19F-relaxometry• Intratumoral injection of PFC (i.e. hexafluorobenzene, single 19F line)• Measurement of the R1 relaxation of 19F relaxation that is strongly dependent on pO2• Maps of pO2 Mason RP et al, IJROBP 1998, 42, 747; and following works of Mason’s group
    14. 14. 19F-relaxometryRapid estimation of R1 using SNAP-IR sequenceSimultaneous monitoring using 19F-MRI and fiber optic probes B. Jordan MRM 2009, 61, 634-638
    15. 15. 19F-relaxometry   Rather sensitive method  Problem to inject the PFC in the Quantitative method: pO2 entire tumor values  The technique is likely to slightly No 19F NMR background overestimate pO2 signal in tissues  Not applicable for chronic Good temporal & spatial purposes (only acute studies) resolutions for O2 mapping  Toxicity concerns with some PFCs  Lack of translation into the clinic (invasiveness, 19F coils)
    16. 16. DCE-MRI Attempt to correlate DCE-MRI parameters with tumor hypoxia Ktrans significantly higher for radiation sensitive tumors without hypoxia than for radiation resistant tumors with hypoxic regions (Gribbestad., Dynamic Contrast-EnhancedMagnetic Resonance Imaging in Oncology, 2006) K Gullisksrud, Radiother. Oncol. 2011, 98, 360
    17. 17. Dynamic MRI of cervix carcinoma A. T2-weighted spin echo image a B. [Gd] max image C. [Gd] time-to-peak image 2 4 3A B 1 [Gd] 1 2 3 a 4 tC C D D Modified from:J. Barentsz
    18. 18. Tumor OxygenationPerfusion Oxygen consumption
    19. 19. High O2 consumption rate by tumor cells  Cancer cells consume oxygen at high rate, even if they generally present a highly glycolytic metabolism  This high consumption rate significantly contributes to the tumor hypoxia resulting from the imbalance between oxygen delivery and oxygen consumption
    20. 20. Strategies to decrease the oxygen consumption by tumor cells and potentiate radiotherapy Theoretical simulations: To alleviate tumor hypoxia, decreasing the O2 consumption rate of tumor is more effective than increasing oxygen delivery Secomb, Acta Oncol. 1995 34, 313 Pre-clinical studies• Meta-iodobenzylguanidine JE Biaglow, IJROBP 1998, 42, 871• Nitric oxide donors B. Jordan, Int. J. Cancer 2004, 109, 768• Insulin B. Jordan, Cancer Res. 2002, 62, 3555• NSAIDs N. Crokart, Cancer Res. 2005, 65, 7911• Glucocorticoids N. Crokart, Clin. Cancer Res. 2007, 13, 630• SU5416, ZD6474 R. Ansiaux, Cancer Res. 2006, 66, 9698; Radiat. Res. 2009, 172, 584• Propylthiouracil B. Jordan, Radiat. Res. 2007, 168, 428• Arsenic trioxide C. Diepart, submitted
    21. 21. DCE-MRI   Trend of perfusion  No absolute values of pO2 parameters to differentiate  It is unlikely that a treshold value between hypoxic vs normoxic of a DCE-MRI parameter will tumors predict the radiosensitivity Clinically usable  Tumor perfusion is not the main or sole factor that is responsible for the tumor oxygenation (oxygen consumption)
    22. 22. BOLD-MRI – R2* From fMRI …… to tumor oxygenation Carbogen breathing Level of blood oxygenation  Oxy-Hemoglobin: diamagnetic DeoxyHb  /OxyHb  blood content Deoxy-Hemoglobin: Paramagnetic  SI S. Ogawa et al, PNAS 1990, 87, 9868 GS Karczmar, NMR Biomed 1994, 12, 881 SP Robinson, IJROBP 1995, 33, 855 F Howe, MRI 1999, 17, 1307
    23. 23. BOLD-MRIT2* is sensitive to the relative Hb/HbO2 ratio in vessels: Blood oxygen saturation Hematocrit Blood volume
    24. 24. Basal R2* and tumor oxygenationCorrelation between pimonidazole uptake Inverse correlation between pimoninazole and high R2* in prostate cancer uptake and R2* values in mammary tumors PJ Hoskin, IJROBP 2007, 68, 1065 McPhail, Radiology 2010, 254, 110 R2*: phenotype specific ? Requires simultaneous measurements of vasculature function ? AR Padhani, Radiology 2010, 254, 1
    25. 25. Change in R2* and change in tumor oxygenation Comparison with OxyLite: simultaneous measurement of R2* and pO2 BOLD signal response correctly reflected the evolution of tumor oxygenation in carbogen challenge pO2 C. Baudelet and B. Gallez Magn.Reson. Med. 2002;48:980. LocalBOLD signal Whole tumor T2*w SI T2*
    26. 26. Tumor OxygenationPerfusion Oxygen consumption
    27. 27. Change in R2* and change in tumor oxygenation Increase in pO2 through changes in O2 consumption Insulin infusion Control NS-398 Changes in BOLD signal and R2* in tumors do not depend uniquely on changes in oxygenation status B. Jordan, MRM 2006, 56, 637
    28. 28. BOLD-MRI and R2*   Variations in tumor oxygenation  No absolute values of pO2 can be qualitatively measured  The value of basal R2* is during carbogen breathing debatable Rapid dynamic measurement  Variation in R2* cannot predict Clinically usable changes in oxygenation induced by treatments modulating the oxygen consumption
    29. 29. T1-based measurements O2 H20 H20 H20 H20 H20 O2 O2 O2 O2 O2 H20 H20 Carbogen H20 H20 H20 H20 breathing O2 H20 O2 Dissolved oxygen acts as a T1-shortening paramagnetic contrast agentOxygen produces changes in relaxation rate R1 of water KI Matsumoto, MRM 2006, 56, 240
    30. 30. T1-based measurements MOBILEMapping of Oxygen By Imaging Lipids Relaxation Enhancement R1 (Lipids @ ~ 3.5 ppm) R1 (H2O) 50 0.2 40 pO2 (mmHg) relative change (%) 30 0.0 20 air carbogen postmortem post 10 mortem -0.2 0 air carbogen 0 50 100 time (min) -0.4 20 R1 (Lipids @ ~ 3.5 ppm) relative change (%) 15 R1 (H2O) 10Pooled results 5 N=5 0 en r ai og -5 rb ca
    31. 31. Nitroimidazole-based PET: How does it work? Nitro-imidazoles mechanism of uptake vascular space cellular compartment e- reduction e- reduction RNO2 RNO2 RNO2- RNH2 necrosis hypoxia normoxia retention metabolites• Initial distribution is flow dependent• Local oxygen tension = main determinant for long-term retention • NO2 reduction in radical anion; • if O2 is present, back to the original structure • in absence of O2, second reduction with product binding to macromolecules • depends on the nitroreductase activity • generally assumed to have retention under 10 mm Hg
    32. 32. Rat rhabdomyosarcoma: optimizing imaging conditions with HX4 NS NS ** 8 max Tissue to Blood ratio * 6 * 4 2 0 0 1 2 3 4 5 6 4h p.i. Time (hours) after injection Dubois et al. PNAS 2011
    33. 33. Is there a significant correlation between pimonidazole staining (“the gold standard”) and HX4 uptake?
    34. 34. Validation of 18F-HX4 uptake using IHC (setup) HEAD b a d c a b c d DORSAL VENTRAL TAIL region selection %HX4 per region based on CT Dubois et al. PNAS 2011
    35. 35. Validation with pimonidazole IHC: first results Courtesy of B. van der Kogel Dubois et al. PNAS 2011
    36. 36. Validation of 18F-HX4 uptake using IHC (results) %PIMO vs %HX4 summary Spearman R p-value total 0.6000 0.2848 regions 0.7222 < 0.0001 III-1 0.7334 0.0028 III-2 0.6588 0.0055 I-2 0.9046 < 0.0001 II-3 0.8202 0.0002 III-3 0.6627 0.0733 n = 76 Dubois et al. PNAS 2011
    37. 37. Is there a causal relationship between hypoxia and HX4 uptake?
    38. 38. [18F]HX4 accumulation is oxygen dependent Basal scan Carbogen/Nicotinamide Basal scan 7% oxygen breathing Dubois et al. PNAS 2011
    39. 39. Which hypoxic biomarker is the best?
    40. 40. Hypoxia PET tracersNitro-imidazoles: 18F-FMISO Hypoxia 18F-FAZA 18F-HX4 sensitive Rest part group Positron- emitting radionuclide• Clearance: Liver –intestine – Kidney – intestine – Kidney – bladder kidney liver• Hydrophilicity:
    41. 41. Tumor to bloodS. Peeters et al. In preparation
    42. 42. Imaging Hypoxia Prognostic value of outcome F-MISO PET in 73 patients with H&N cancer FMISO Tumor/Blood is a prognostic measure of the outcome JG Rajendran, Clin. Cancer Res. 2006, 12, 5435Correlation also found in:FMISO PET in 40 patients with H&N cancerSM Eschmann, J. Nucl. Med. 2005, 46, 253No correlation found in:FMISO PET in 20 patients with H&N cancerNL Lee, IJROBP 2009, 75, 201
    43. 43. (A) Baseline [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) of patient with T2N2b squamous cell carcinoma of the pyriform fossa with left nodal mass (A) Baseline [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) of patient with T2N2b squamous cell carcinoma of the pyriform fossa with left nodal mass. (B) (B) [18F]-fluoromisonidazole (FMISO) -PET at baseline, nonhypoxic primary tumor, and hypoxic node. (C) C) FDG-PET 12 weeks after chemoboost, complete response in nonhypoxic primary tumor, and poor response in hypoxic node. Residual tumor in nodal mass was confirmed pathologically after neck dissection. Rischin, D. et al. J Clin Oncol; 24:2098-2104 2006 Copyright © American Society of Clinical Oncology
    44. 44. Phase 1 HX4 imaging: clinically feasible? Van Loon et al, EJNM 2010 1,6 1,2 T/MCT delineated tumor 0,8 [18F]HX4 accumulation 0,4 0 30 60 120 Tim e (m in) after injection Van Loon J. et al. EJNM 2010
    45. 45. NSCLC Stage IIIB 18HX4-PETCT Van Loon et al. Eur J Nucl Med Mol Imaging. 2010
    46. 46. Time to local failure (Kaplan-Meier method) by treatment arm and hypoxia in the primary tumor (censored times are indicated as tick marks on the curves) Rischin, D. et al. J Clin Oncol; 24:2098-2104 2006Copyright © American Society of Clinical Oncology
    47. 47. Zips et al. Radiother Oncol 2012
    48. 48. Zips et al. Radiother Oncol 2012
    49. 49. Biomarker: Hypoxia (F-MISO PET) 0 Gy 10 Gy 20 Gy 40 Gy [18F]Misonidazol Zips et al [18F]Misnidazole [18F]FDG Zips , Kotzerke, Baumann et al.Department of Radiation Oncology M. Baumann |Regaud Lecture 2012
    50. 50. Radiolabelled nitroimidazoles   Hypoxia-sensitive method  No absolute values of pO2 Relevant to estimate  Poor correlation with pO2 values radioresistant relevant for some tracers hypoxia (< 10 mm Hg)  Accumulation dependent on the Clinically usable level of nitroreductases Prognostic value (especially if repeated)
    51. 51. Imaging of tumor acute hypoxia Spontaneous fluctuations in tumor oxygenation/perfusion Technique Spatial Temporal Characteristics Reference resolution resolutionNITRO-PET 4.2 mm Day 1,2,5 Hypoxia Wang, Med. Phys. (More or less 2009, 36, 4400 than 10 mm Hg) DCE-MRI 0.5x0.2 mm3 15 min Flow variation Brurberg, MRM 2007, 58, 473T2*w-GE MRI 470x470 µm2 12.8s Oxygen/flow Baudelet, Phys. Med. Biol. variation 2004, 49, 3389 19F-MRI 1.88 mm 1.5 min Quantitative Magat, Med. Phys. pO2 2010, 37, 5434 EPRI 1.8 mm 3 min Quantitative Yasui, Cancer Res. pO2 2010, 70, 6427
    52. 52. In vivo CAIX specific sulfonamide accumulation is reversible upon reoxygenation Dubois et al, Radiother & Oncol 2009 Dubois et al, Radiother & Oncol 2009 *P < 0.05; **P < 0.01
    53. 53. Imaging of CAIX with antibody MAb-N-succinyldesferal-89Zr (MAb-N-sucDf-89Zr) (*) PET images of mice with tumor located subcutaneously onright hind leg at 4 (A) and 24 h (B) after injection. p.i. = after injection; SUV = standardized uptake value. This course is funded with the support of Hoeben, Kaanders et al. 2010 Jul;51(7):1076-83. the METOXIA project under the FP7 Programme.
    54. 54. How to include hypoxia imaging in the clinic?
    55. 55. Exploiting intra patient heterogeneity for dose painting of radiation
    56. 56. Intensity modulated radiation therapy (IMRT) Galvin, J. Clin. Oncol. 2007, 25, 924 Possibility to sculpt the doses as a function of possible needs
    57. 57. Hypoxia Guided IMRT: dose escalation in hypoxic areasDose Painting by Contours Proof-of-concept using Cu-ASTM KSC Chao, IJROBP 2001, 49, 1171Dose Painting by Numbers Theoretical feasibility 0.4 using 18F-FMISO 0.6 1.9 Dose prescription 1.1 based on tumor hypoxia 2.7 D. Thorwarth, IJROBP 2007, 68, 291 2.9 Z. Lin, IJROBP 2008, 70, 1219 NY Lee, IJROBP 2008, 70, 2 I. Toma-Dasu, Acta Oncol. 2009, 48, 1181 W. Choi, Radiother. Oncol. 2010, 97, 176
    58. 58. Hypoxia Guided IMRT: dose escalation in hypoxic areasDose Painting by Contours Proof-of-concept using Cu-ASTM KSC Chao, IJROBP 2001, 49, 1171Dose Painting by Numbers Theoretical feasibility 0.4 using 18F-FMISO 0.6 1.9 Dose prescription 1.1 based on tumor hypoxia 2.7 D. Thorwarth, IJROBP 2007, 68, 291 2.9 Z. Lin, IJROBP 2008, 70, 1219 NY Lee, IJROBP 2008, 70, 2 I. Toma-Dasu, Acta Oncol. 2009, 48, 1181 W. Choi, Radiother. Oncol. 2010, 97, 176
    59. 59. Conclusions• To bridge the gap between hypoxia-induced radioresistance and optimized radiotherapeutic treatment with drugs – Oxygenation imaging is mandatory – Qualification of oxygenation biomarkers is still mandatory at the pre-clinical and the clinical level – There is a crucial need to validate the value of hypoxia- gimaging inprospective trials with interventions ISMRM 2011: Clinical Needs and Research Promises
    60. 60. AcknowledgementsUniversity of Maastricht – Ludwig Dubois * University of Nijmegen (The Netherlands) – Judith van Loon – Albert van der Kogel – Jan Bussink – Sarah Peeters – Hans Kaanders – Karen Zeghers University of Amsterdam (VUmc) – Guus van Dongen – Bert Windhorts – Jonas Eriksson University of Florence (Italy) – Andrea Scozzafava – Claudiu Supuran Euroxy-Metoxia 6th & 7th Framework University of Brussels (UCL) – Bernard Gallez* – Vincent Grégoire Our patients (No immediate benefit for them) NIH (USA) Siemens MI