HYPOXIA IMAGING DR. PUNIT SHARMA DR. PUNIT SHARMA MODERATOR: PROF. A. MALHOTRA MODERATOR: PROF. A. MALHOTRA DEPARTMENT OF NUCLEAR MEDICINE, AIIMS.
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HYPOXIA IMAGINGHYPOXIA IMAGING
DR. PUNIT SHARMADR. PUNIT SHARMA
MODERATOR: PROF. A. MALHOTRAMODERATOR: PROF. A. MALHOTRADEPARTMENT OF NUCLEAR MEDICINE, AIIMSDEPARTMENT OF NUCLEAR MEDICINE, AIIMS
HYPOXIAHYPOXIA
Hypoxia Hypoxia is the absolute or relative is the absolute or relative deficiency of oxygendeficiency of oxygen
Ischemia Ischemia is deficit in blood supplyis deficit in blood supply
Pathological correlatePathological correlate
CancerCancerIschemic heart disease/myocardial Ischemic heart disease/myocardial
infarctioninfarctionStroke/ cerebrovascular accidentsStroke/ cerebrovascular accidentsVascular insufficiencyVascular insufficiencyChronic inflammatory disease (IBD,RA)Chronic inflammatory disease (IBD,RA)
Hypoxia in cancerHypoxia in cancer
Most extensively studiedMost extensively studied
Seen in solid tumorsSeen in solid tumors
Responsible for resistance to therapyResponsible for resistance to therapy
However, can be exploited therapeuticallyHowever, can be exploited therapeutically
Oxygen tension in solid tumors and Oxygen tension in solid tumors and
normal tissuesnormal tissues
Factors that determine the pOFactors that determine the pO22 distribution distribution
in tumor tissuein tumor tissue
Etiology of tumor hypoxiaEtiology of tumor hypoxia
Uncontrolled cellular proliferationUncontrolled cellular proliferation
Relative oxygen deficitRelative oxygen deficit
AcidosisAcidosisDeranged vasculatureDeranged vasculature
AngiogenesisAngiogenesis
Altered rheologyAltered rheologyChronic vs Acute hypoxiaChronic vs Acute hypoxia
Pattern of Pattern of viable, viable, hypoxic hypoxic
and and necrotic necrotic cells in a cells in a
solid solid tumor tumor
HIF-1ß
HIF-1α
HIF-1ß
HIF-1α
HIF-1α HIF-1α
Pro-OH
Pro-OH
Low O2 tension Normal O2 tension
Proline hydroxilase
Gene expression
degradation
Consequences of tumor Consequences of tumor hypoxiahypoxia
Promotes metastasisPromotes metastasis
Selection of more malignant phenotypeSelection of more malignant phenotype
Promotes angiogenesisPromotes angiogenesis
Resistance to radiotherapyResistance to radiotherapy
Resistance to chemotherapyResistance to chemotherapy
Correlation between hypoxia and anticancer Correlation between hypoxia and anticancer therapiestherapies
Critical OCritical O22 tension Effect observed tension Effect observed
30-35 Immunotherapy30-35 Immunotherapy
15-35 Photodynamic therapy15-35 Photodynamic therapy
25-30 Radiotherapy25-30 Radiotherapy
10-20 Binding of hypoxia markers10-20 Binding of hypoxia markers
1-15 Proteome changes1-15 Proteome changes
0.2-1 Genome changes0.2-1 Genome changes
Hockel V, Vaupel Hockel V, Vaupel P. J Natl Cancer InstP. J Natl Cancer Inst 2001; 93; 266-276 2001; 93; 266-276
(mm of Hg)
Radiotherapy resistanceRadiotherapy resistance
OO2 2 is a radiosensitizeris a radiosensitizer
Decreases with pODecreases with pO22, greatly reduced below , greatly reduced below
5mm of Hg5mm of Hg
Metabolic changesMetabolic changes
Chemotherapy resistanceChemotherapy resistance
Limited penetrationLimited penetration
Low proliferation fractionLow proliferation fraction
Biochemical properties of the drugsBiochemical properties of the drugs
AcidosisAcidosis
Heterogenous drug deliveryHeterogenous drug delivery
Implications of Hypoxia assessmentImplications of Hypoxia assessment
CancerCancer Prediction of responsePrediction of response Patient selectionPatient selection Therapy selection/modificationTherapy selection/modification Follow upFollow upCardiacCardiac StratificationStratification Stunned myocardiumStunned myocardium Salvage therapySalvage therapy
Implications of Hypoxia assessmentImplications of Hypoxia assessment
CerebralCerebral
Salvage therapySalvage therapy
StratificationStratificationVascular insufficiencyVascular insufficiency
ProphylaxisProphylaxis
StratificationStratificationInflammatory diseasesInflammatory diseases
Hypoxia assessmentHypoxia assessment InvasiveInvasive
OO22 electrode electrode
Non-invasiveNon-invasive
PETPET
SPECTSPECT
19-F NMR 19-F NMR
BOLD-MRIBOLD-MRI
Lactate spectroscopyLactate spectroscopy
Optical imagingOptical imaging
Positron emission tomographyPositron emission tomography
Most widely evaluatedMost widely evaluatedMost reliable among the non-invasive Most reliable among the non-invasive
techniques availabletechniques availableBest spatial resolutionBest spatial resolutionCan be used for planning radiotherapy Can be used for planning radiotherapy Help in selecting hypoxia specific therapyHelp in selecting hypoxia specific therapy
PET radiotracers PET radiotracers
FF1818-FMISO (Fluromisonidazole)-FMISO (Fluromisonidazole)FF1818-FAZA (Fluoroazomycin arabinoside)-FAZA (Fluoroazomycin arabinoside)FF1818- EF- 5 [2-(2-nitro-1H-imidazol-1-yl)-N-- EF- 5 [2-(2-nitro-1H-imidazol-1-yl)-N-
(2,2,3,3,3-pentafluoropropyl) acetamide](2,2,3,3,3-pentafluoropropyl) acetamide]FF1818-FETNIM-FETNIMII124124–IAZG (Iodoazomycin galactopyranoside)–IAZG (Iodoazomycin galactopyranoside)CuCu6464- ATSM (diacetyl-bis-N4-- ATSM (diacetyl-bis-N4-
methylthiosemicarbazone)methylthiosemicarbazone)CuCu6464- PTSM (pyruvaldehyde-bis-N4-- PTSM (pyruvaldehyde-bis-N4-
methylthiosemicarbazone)methylthiosemicarbazone)
FF1818-Fluromisonidazole-Fluromisonidazole NitroimidazoleNitroimidazole
Uptake is passive and flow Uptake is passive and flow independentindependent
Undergoes intracellular Undergoes intracellular bioreductive metabolism bioreductive metabolism
Retained preferentially in Retained preferentially in hypoxic cells (pO2<10mm hypoxic cells (pO2<10mm of Hg)of Hg)
FMISO: uptake and metabolismFMISO: uptake and metabolism
nitroreductasenitroreductase
NO2NO2
NO2NO2NO2NO2
.-.-
DNA
O2O2O2O2.-.- HypoxiaHypoxia
ImagingImaging
Synthesised by nucleophilic substitution by Synthesised by nucleophilic substitution by [18F]fluoride on the tetrahydropyranyl-protected [18F]fluoride on the tetrahydropyranyl-protected precursorprecursor
No fasting requiredNo fasting required
Dose: 0.1mCi/kg (max: 10mCi)Dose: 0.1mCi/kg (max: 10mCi)
Image is acquired 1.5-2 hr after injectionImage is acquired 1.5-2 hr after injection
Quantification is with tumor/blood Quantification is with tumor/blood maxmax ratio (1.2-1.5) ratio (1.2-1.5)
FMISO/PET in GlioblastomaFMISO/PET in Glioblastoma
MRIMRI MRI/FMISO-PETMRI/FMISO-PET
Lawrence M. Cher, Carmel Murone; Lawrence M. Cher, Carmel Murone; Journal of Nuclear Medicine Vol. 47, 2006 Journal of Nuclear Medicine Vol. 47, 2006
FMISO in head & neck CAFMISO in head & neck CA
FDG/PETFDG/PET
FMISO/PETFMISO/PET
Bernd GagelBernd Gagel, , Marc Piroth Marc Piroth et alet al. . BMC CancerBMC Cancer 2007,7 2007,7::113113
FMISO FMISO in head in head & neck & neck
CACA
Jim Koropatnick, Ting LeeJim Koropatnick, Ting Lee et alet al Department of Otolaryngology, Department of Otolaryngology,
University of Western OntarioUniversity of Western Ontario
FDG/PET FDG/PET and and
FMISO/ FMISO/ PET in CA PET in CA
lunglung
Bernd GagelBernd Gagel, , Patrick ReinartzPatrick Reinartz
BMC Cancer 2006, 6:51
FMISO/PET FMISO/PET in stroke: in stroke:
Serial PET Serial PET and CT and CT
changes of changes of ischemic ischemic
penumbrapenumbra
S.H. Yeh, R.S. LiuS.H. Yeh, R.S. Liu
FMISO/PET in Diabetic footFMISO/PET in Diabetic foot
R.S. Liu, L.S. ChuR.S. Liu, L.S. Chu
IMRT with FMISO/PETIMRT with FMISO/PET
Daniela ThorwarthDaniela Thorwarth
FMISO/PET & prognosis in head FMISO/PET & prognosis in head and neck cancerand neck cancer
FDG/PETFDG/PETFMISO/PETFMISO/PET TNM STAGETNM STAGEJoseph G. Rajendran, David L. Schwartz . Joseph G. Rajendran, David L. Schwartz . JNM,2007JNM,2007
DisadvantagesDisadvantages
Discordant half life (110 min FDiscordant half life (110 min F1818 vs 380 min vs 380 min FMISO) - increased backgroundFMISO) - increased background
Low in vivo stabilityLow in vivo stability
Non – oxygen dependent adduct changesNon – oxygen dependent adduct changes
Difficult to image liver and urinary systemDifficult to image liver and urinary system
FF1818- FAZA- FAZA
Fluorinated azomycin nucleosideFluorinated azomycin nucleoside
Low lipophilicityLow lipophilicity
More stable in vivoMore stable in vivo
FF1818- FAZA- FAZA
Eliminated via bile and urineEliminated via bile and urine
Less background compared to FMISOLess background compared to FMISO
Dose :10 mCiDose :10 mCi
Imaging : 2-3 hrs after injectionImaging : 2-3 hrs after injection
FAZA FAZA PET in PET in head head and and neck neck
cancercancer
Souvatzoglou Souvatzoglou et alet al; Eur J Nucl Med Mol Imaging. 2007; Eur J Nucl Med Mol Imaging. 2007
Eur J Nucl Med Mol Imaging. 2007 Apr 20; Eur J Nucl Med Mol Imaging. 2007 Apr 20;
IMRT with FAZA/PETIMRT with FAZA/PET
A.L Grosu, M Piert, M Molls.A.L Grosu, M Piert, M Molls. British Journal of Radiology Supplement_28British Journal of Radiology Supplement_28 (2005),18-32 (2005),18-32
FF1818-EF5-EF5
Previously used as immunohistological markerPreviously used as immunohistological marker Better in vivo stabilityBetter in vivo stability Low backgroundLow background Undergoes very little non-oxygen dependent adduct Undergoes very little non-oxygen dependent adduct
formation formation
EF-5 PET imageEF-5 PET image
II124124––IAZGIAZG
Iodinated azomycin nucleosideIodinated azomycin nucleoside
Less lipophilicLess lipophilic
Rapid renal excretionRapid renal excretion
Less backgroundLess background
II124124––IAZGIAZG
Synthesized by exchange labeling between the non Synthesized by exchange labeling between the non radioactive iodoazomycin nucleoside andradioactive iodoazomycin nucleoside and
124124I-NaI I-NaI
Poor image quality due to IPoor image quality due to I124 124 physicsphysics
Optimal time for imaging 24-48 hrsOptimal time for imaging 24-48 hrs
FMISO/PET IAZG/PETFMISO/PET IAZG/PET
Riedl, C.C., P. BraderRiedl, C.C., P. Brader. . Eur J Nucl Med Mol ImagingEur J Nucl Med Mol Imaging, , 2007.2007.
CuCu6464 -ATSM -ATSM
Copper labeled chelate complexCopper labeled chelate complexUndergoes bioreduction in cytosol/ Undergoes bioreduction in cytosol/
microsomesmicrosomesRetained in hypoxic cells, rapidly washed out Retained in hypoxic cells, rapidly washed out
from normoxic cellsfrom normoxic cells
CuCu6464 ATSM: Uptake & Metabolism ATSM: Uptake & Metabolism
Nucleus
Cytochrome P450 reductaseCytochrome P450 reductase
NADNAD++NADHNADHHYPOXIAHYPOXIA
NORMOXIANORMOXIA
Cu(I)64
Cu(I)64
Cu(II)64
BindingBinding
CuCu6464 -ATSM -ATSM Synthesized by reacting CuSynthesized by reacting Cu6464ClCl22 with H with H22ATSM in presence ATSM in presence
of a bufferof a buffer
Low backgroundLow background
Dose: 12-14 mCiDose: 12-14 mCi
Can be used for targeted radiotherapy (39% ß-decay)Can be used for targeted radiotherapy (39% ß-decay)
ATSM also labeled with CuATSM also labeled with Cu6060 and Cu and Cu6262
CuCu6464-ATSM in lung cancer-ATSM in lung cancer
Terence Z. Wong, Jeffrey L. Lacy et al, EJNM, 2007Terence Z. Wong, Jeffrey L. Lacy et al, EJNM, 2007
ResponderResponder Non-responderNon-responder
Terence Z. Wong, Jeffrey L. Lacy et al, EJNM, 2007Terence Z. Wong, Jeffrey L. Lacy et al, EJNM, 2007
CuCu6464-ATSM/PET in cervical cancer-ATSM/PET in cervical cancer
CuCu6464-ATSM/PET-ATSM/PETFDG/PETFDG/PET
Dehdashti .F, Grigsby P.WDehdashti .F, Grigsby P.W. . Int J Radiat Oncol Biol PhysInt J Radiat Oncol Biol Phys. 2003; 55(5):1233-8. 2003; 55(5):1233-8
SPECT hypoxia tracersSPECT hypoxia tracers
II123123-IAZA (Iodoazomycin arabinoside)-IAZA (Iodoazomycin arabinoside)
TcTc99m99m-BNAO (Butylene amineoxime)-BNAO (Butylene amineoxime)
Radioiodinated 2-nitroimidazole derivativeRadioiodinated 2-nitroimidazole derivative
More lipophilicMore lipophilic
Imaging: 4-8 hrsImaging: 4-8 hrs
II123123-IAZA-IAZA
II123123 IAZA SPECT IAZA SPECT
Rheumatoid arthritisRheumatoid arthritisDiabetic footDiabetic foot
BOLD- MRIBOLD- MRI
Blood oxygen level dependent MRIBlood oxygen level dependent MRIBased on magnetic properties of hemoglobinBased on magnetic properties of hemoglobinDeoxygenated Hb is less diamagnetic than Deoxygenated Hb is less diamagnetic than
oxygenated Hboxygenated HbNon- quantitative methodNon- quantitative method
BOLDBOLDMRI of MRI of brain brain tumortumor
Christine Baudelet and Bernard GallezChristine Baudelet and Bernard Gallez ;Current in Medical Imaging Reviews, 2005 ;Current in Medical Imaging Reviews, 2005
Conclusion Conclusion
Hypoxia play an important role in initiation Hypoxia play an important role in initiation and/or progression of many diseases, and/or progression of many diseases, ranging from cancer to arthopathiesranging from cancer to arthopathies
Hypoxia have serious repercussions on Hypoxia have serious repercussions on cancer therapeuticscancer therapeutics
ConclusionConclusion
Among the non-invasive modalities Among the non-invasive modalities available for imaging hypoxia, PET appears available for imaging hypoxia, PET appears to be most practical and informativeto be most practical and informative
FMISO is the tracer most widely used. FMISO is the tracer most widely used. However, because of its pharmacokinetic However, because of its pharmacokinetic limitations newer tracers are under limitations newer tracers are under evaluationevaluation
ConclusionConclusion
Hypoxia imaging with PET can be Hypoxia imaging with PET can be employed for radiotherapy planningemployed for radiotherapy planning
It can also guide regarding bioreductive It can also guide regarding bioreductive
drug therapydrug therapy
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