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