Image-guided IMRT forguided IMRT for Head and Neck Cancer · Post-op Nonop Non-IMRT 142 3.9 yr...
Transcript of Image-guided IMRT forguided IMRT for Head and Neck Cancer · Post-op Nonop Non-IMRT 142 3.9 yr...
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Image-guided IMRT forImage-guided IMRT for Head and Neck Cancer
Reggio Emilia, Italy October 21, 2011
K.S. Clifford Chao, MDChairman, Combined Radiation Oncology, New York Presbyterian Hospital
Ch i R di ti O l C l bi U i it C ll f P & SChairman, Radiation Oncology, Columbia University College of P & SChief, Radiation Oncology, Weill Cornell Medical College
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T2N1M0 SCC of Base of the TongueT2N1M0 SCC of Base of the Tongue
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Conventional RTConventional RT IMRTIMRT
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Therapeutic Outcome of Oropharyngeal Carcinoma
Def. CRT Def. IMRT Post-op CRT Post-op IMRTDef. CRT (n=153)
Def. IMRT (n=12)
Post op CRT (n=142)
Post op IMRT (n=14)
Acute Grade 3-4 mucositis
25% 42% 20% 21%NS
Late Grade 2-3 t i
84% 30% 77% 17%
P=0.134 NS
xerostomia(12m post-RT) P
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Tumor Control by IMRT vs nonTumor Control by IMRT vs non--IMRTIMRTin Patients with Oropharyngeal Carcinomain Patients with Oropharyngeal Carcinoma
Patient No. Median F/U 2yr LRC 2yr DFSPatient No. Median F/U 2yr LRC 2yr DFS
Def. NonDef. Non--IMRT 153 3.5 yr (1.6IMRT 153 3.5 yr (1.6--17.7) 68.3%17.7) 68.3% 58.4%58.4%
Def. IMRT 31 3 yr (12Def. IMRT 31 3 yr (12--58) 87.5%58) 87.5% 73.5%73.5%
PostPost--op Nonop Non--IMRT 142 3.9 yr (1.3IMRT 142 3.9 yr (1.3--19.8) 75.7%19.8) 75.7% 73.5%73.5%PostPost op Nonop Non IMRT 142 3.9 yr (1.3IMRT 142 3.9 yr (1.3 19.8) 75.7%19.8) 75.7% 73.5%73.5%
PostPost--op IMRT 43 2.8 yr (9op IMRT 43 2.8 yr (9--60) 95.0%60) 95.0% 94.3%94.3%
D il d f Ch l R di h & O l 61 2 2001Data compiled from Chao et al. Radiotherapy & Oncology, 61:275, 2001 and Chao et al. IJROBP 59:43-50, 2004
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LocoLoco regional Control ofregional Control ofLocoLoco--regional Control of regional Control of Oropharyngeal CarcinomaOropharyngeal Carcinoma
Conventional IMRT
7070--90%90% 92%92%T1-2
3030 70%70% 8787 94%94%3030--70%70% 8787--94%94%T3-4
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T2N1M0 SCC of Base of the TongueT2N1M0 SCC of Base of the Tongue
CTV1
CTV2 CTV3CTV2 C V3
Chao et al. Int J Radiat Oncol Biol Phys. 2004 May 1;59(1):43-50.
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Target Delineation and Dose Spec in 2011
DefinitiveDefinitive CTV1CTV1 CTV2CTV2 CTV3CTV3
IMRTIMRT35 fx35 fx
70/2.070/2.0 63/1.863/1.8 56/1.656/1.6CTV1
35 fx35 fxIMRTIMRT33 fx33 fx
70/2.170/2.1 60/1.860/1.8 54/1.654/1.6
2D2D 70/2 070/2 0 60/2 060/2 0 50/2 050/2 0
GTV
2D2D35 fx35 fx
70/2.070/2.0 60/2.060/2.0 50/2.050/2.0
PostPost--opop CTV1CTV1 CTV2CTV2 CTV3CTV3
IMRTIMRT 63/2 163/2 1 60/2 060/2 0 54/1 854/1 8CTV2 CTV3
IMRTIMRT30 fx30 fx
63/2.163/2.1 60/2.060/2.0 54/1.854/1.8
2D2D 66/2.066/2.0 60/2.060/2.0 50/2.050/2.0
T2N1M0 SCC of Base of the Tongue
30 fx30 fx
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Step One: Identify GTVp/nStep One: Identify GTVp/n
GTVp GTVn
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Step 2: Add CTV1Step 2: Add CTV1
Defined as GTVp/n plus 10 mm of marginp g
M Truncating around normal structures
M
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Step 3: Add CTV2Step 3: Add CTV2
X V
V
X
W W CTV2-Coverage
V CTV margin ~ 5mm
Y
W gremaining tongue base
XY
Level IB
Level IIA/B
Z Z Level V
GTVp GTVn CTV 1 CTV 2
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Step 4: Add CTV3Step 4: Add CTV3
SS Submandibular
glandS gland
T Level II (a/b) t l t l
T
contralateral neck CTV3
T
GTVp GTVn CTV 1 CTV 2 CTV 3
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A Involved sideA Involved side coverage to jugular foramen
A B Contralateral coverage (NED) neck begins atneck begins at top C1
BJugular foramen
CTV 2 CTV 3CTV 1GTVnGTVp
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CTV 2 CTV 3CTV 1GTVnGTVp
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CTV 2 CTV 3CTV 1GTVnGTVp
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Variations in CTV Target Delineation Variations in CTV Target Delineation for Head and Neck IMRTfor Head and Neck IMRTfor Head and Neck IMRTfor Head and Neck IMRT
An International SurveyAn International Surveyyy
Theodore S. Hong,Theodore S. Hong,Wolfgang A. Tomé, Wolfgang A. Tomé, Richard J. Chappell, Richard J. Chappell,
Paul M. HarariPaul M. Harari
University of WisconsinUniversity of WisconsinDepartment of Human OncologyDepartment of Human Oncology
2020 institutions
H&N IMRTH&N IMRTPractice HeterogeneityPractice Heterogeneity
Courtesy of Dr. Harari
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Local failure in RTOGLocal failure in RTOG--0022 protocol variations0022 protocol variations
•• 4 of 53 patients with evaluable plans had 4 of 53 patients with evaluable plans had p pp pmajor protocol variations due to underdose major protocol variations due to underdose of PTV66.of PTV66.
•• Local recurrence:Local recurrence:Local recurrence:Local recurrence:–– 2/4 2/4 (50%)(50%) patients with major PTV66 variation patients with major PTV66 variation
(underdose)(underdose)( )( )–– 3/49 (6%) patients without major PTV66 variations3/49 (6%) patients without major PTV66 variations–– P=0.04P=0.040 00 0
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PTV6654 Gy
GTV60 Gy Underdose
66 Gy PTV54
Outcome: Local recurrence
Treatment plan of a patient with a major PTV66 underdose
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Ph III R i t ti T i lPh III R i t ti T i lPhase III Registration TrialPhase III Registration TrialTROG 02.02 (HeadSTART)TROG 02.02 (HeadSTART)
Patients with Stage III or IV SCCHNPatients with Stage III or IV SCCHN
( )( )
(stratified by stage, site, hemoglobin)(stratified by stage, site, hemoglobin)
R d i tiR d i tiRandomizationRandomization
•• Cisplatin, RTCisplatin, RT •• Tirapazamine, Tirapazamine, p ,p , ppcisplatin, RTcisplatin, RT
Courtesy of Dr. Lester Peters
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RT Volume Variation Adversely Impacts RT Volume Variation Adversely Impacts Tumor ControlTumor ControlTumor Control Tumor Control
Patients who had received at least 60Gy of RT to PTV2Patients who had received at least 60Gy of RT to PTV2100
80
100
ure-
free
60
80
egio
nal f
ailu
40
60
tage
loco
re
20
40
ted
perc
ent
compliant plan by TMC
no adv impact
adv impact20
Estim
at adv impact
2P < 0.0001
00 1 2 3 4
Years following end of radiotherapy
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CNodal CTV Delineation – Margin?
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Microscopic Tumor Extension outside Microscopic Tumor Extension outside Nodal CapsuleNodal Capsule
•• 97 ECE+ LNs from 49 patients97 ECE+ LNs from 49 patients
•• Tumor extension through the LN capsule by:Tumor extension through the LN capsule by:ØØ Actual presence of tumor cellsActual presence of tumor cellsØØ Desmoplasia (associated stromal reaction)Desmoplasia (associated stromal reaction)
Gi t ll ti t k tiGi t ll ti t k tiØØ Giant cell reaction to keratinGiant cell reaction to keratin
•• Greatest linear distance perpendicular from external Greatest linear distance perpendicular from external capsule border to furthest extent of tumorcapsule border to furthest extent of tumorcapsule border to furthest extent of tumorcapsule border to furthest extent of tumor
ØØ Nearest tenth of millimeter with micrometerNearest tenth of millimeter with micrometerØØ Extrapolation when appropriateExtrapolation when appropriateØØ p pp pp pp p
•• Largest axial diameter of LNLargest axial diameter of LN
Apisarnthanarax et al. Int J Radiat Oncol Biol Phys. 64:678, 2006
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TC
T CT
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2 mm2 mm
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ResultsResultsResultsResults
•• 96%96% ECE within ECE within 5 mm5 mmof capsuleof capsule
35
40
•• None beyond 10 mmNone beyond 10 mm•• Inverse correlation Inverse correlation
b t ECEb t ECE25
30
ence
(%)
between ECE between ECE incidence and incidence and distance from capsuledistance from capsule 10
15
20
ECE
inci
de
r = 0.87
pp
0
5
0-1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9
n 4 outliersØ 5.7 mm ECE – 1.9 cm LN
Distance from LN capsule (mm)Ø 6.0 mm ECE – 1.1 cm LN Ø 8.0 mm ECE – 0.7 cm LN Ø 9 0 mm ECE – 0 8 cm LNØ 9.0 mm ECE 0.8 cm LN
Apisarnthanarax et al. Int J Radiat Oncol Biol Phys. 64:678, 2006
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ResultsResults100
Hypothesis
80
100
e (%
)
60
80
cide
nce
(%)
40
60
80
e EC
E In
cide
nce
< 1 cm LNs1-2 cm LNs> 2 cm LNs
40
60
ativ
e EC
E in
c
< 1 cm LNs> 1 cm LNs
0
20
Cum
ulat
ive
20
Cum
ula
0-1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9
Distance from capsule (mm)0
0-1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9
Distance from LN capsule (mm)
•• No correlation between LN and extent of ECENo correlation between LN and extent of ECE•• Mean ECEMean ECE
LN 1 2 1LN 1 2 1ØØ LN < 1 cm: 2.1 mmLN < 1 cm: 2.1 mmØØ LN > 1 cm: 2.2 mm LN > 1 cm: 2.2 mm
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Nodal CTV Delineation
0.5-1 cm CTV marginsg
Apisarnthanarax et al. Int J Radiat Oncol Biol Phys. 64:678, 2006
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Advanced KnowledgeAdvanced Knowledge--based Intelligent Toolbased Intelligent Tool
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IJROBP 68:1512-1521, 2007
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Knowledge-based Computer-assisted Target DelineationKnowledge based Computer assisted Target Delineation
Contouring from scratch Computer-assisted Contouring
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Advanced KnowledgeAdvanced Knowledge--based Intelligent Toolbased Intelligent Tool
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Accurate Delineation of GTVAccurate Delineation of GTV
I F iI F i
Accurate Delineation of GTVAccurate Delineation of GTV
Image FusionImage FusionDiagnostic MRI ↔ Planning CT
A LeeA Lee
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GTV: Fusion of MRI & PETGTV: Fusion of MRI & PET CT CT GTV: Fusion of MRI & PETGTV: Fusion of MRI & PET--CT CT
MRI PET-CTPlanning CT
A LeeA Lee
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Current Recommendation on NPC WorkCurrent Recommendation on NPC Work--UpUpCurrent Recommendation on NPC WorkCurrent Recommendation on NPC Work UpUp
Imaging for distant metastases (chest liver bone)Imaging for distant metastases (chest liver bone)Imaging for distant metastases (chest, liver, bone)Imaging for distant metastases (chest, liver, bone)particularly for stage IIIparticularly for stage III--IV disease IV disease
FDGFDG PET/CTPET/CTFDGFDG--PET/CTPET/CTfor systemic workfor systemic work--up +up +
supplement locoregional assessmentsupplement locoregional assessmentsupplement locoregional assessmentsupplement locoregional assessment
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Improved Staging Accuracy by PETImproved Staging Accuracy by PET
Stage Distribution (%) in 95 patientsW k b MRI (h d & k) CXR b bd i l U/S FDG PETWork-up by MRI (head & neck), CXR, bone scan, abdominal U/S, FDG-PET
With PET
Without PET I II III IVA IVB IVCWithout PET I II III IVA IVB IVC
I 3
II 12
III 1 38 4
IVA 26 1
IVB 5 5
IVC 4
Chang, IJROBP 2005
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How FDG PET Changes RT Plan andHow FDG PET Changes RT Plan andTarget Volume DelineationTarget Volume Delineationgg
• Influence RT plan for lung cancer ~30%
• Influence RT plan for H&N cancer ~40%
M dif t t l f l 4 65%• Modify target volume for lung cancer 4 – 65%
• Modify target volume for H&N cancer 5 – 55%Modify target volume for H&N cancer 5 55%
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But we need something more than FDG…But we need something more than FDG…gg
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Imaging Targets of Biological Interest
Metabolic Proliferative Hypoxic Angiogenesisyp g g
Anatomical Tumor VolumeBiological Tumor Volume(GTV) (BTV)
Apisarnthanarax and Chao, Radiation Research, 2005, 163:1-25
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PET Tracers DEPICT BiologyPET Tracers DEPICT BiologyPET Tracers DEPICT BiologyPET Tracers DEPICT Biology
[18F]-FDG glucose metabolism[18F] FLT t lif ti[18F]-FLT tumor proliferation[18F]-FMISO hypoxia[64Cu]-ATSM hypoxia[18F]-F-RGD peptides angiogenesis[15O]-Water blood flow[18F] F i t i
[ F] F RGD peptides angiogenesis
[18F]-F-annexin apoptosis
Clinical investigational
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NIH Oncology Biomarker Qualification Initiative (OBQI)NIH Oncology Biomarker Qualification Initiative (OBQI)
•Assess after one or two treatments if a tumor is responding to treatment
•Determine more definitively if a tumor is dying, even if it is not shrinking
•Identify which cancer patients are at high risk of tumor return after therapy
•Determine if a patient's tumor is likely to respond to a specific treatment
•Efficiently evaluate whether an investigational therapy is effective•Efficiently evaluate whether an investigational therapy is effective
•Evaluate new, promising technologies that will shorten clinical trials , p g g
•Reduce the time and resources spent during the treatment development process
•Improve the linkage between drug approval and drug coverage
•Increase the safety and appropriateness of treatment choices for cancer patients
Swift, Safe, Save3S
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PETPET--CT ImageCT Image--guided Approaches in guided Approaches in Radiation OncologyRadiation OncologyRadiation Oncology Radiation Oncology
• To guide precision therapy to tumor
• To select patients for the suitableTo select patients for the suitable therapy and depict treatment response at an early phaseresponse at an early phase
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Target Hypoxic Tumor Guided by 60Cu-ATSM PETg yp yChao et al. IJROBP 49: 1171-1182, 2001
Coronal view
Axial view
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Reduction & Shifting of Cu-ATSM-vivid Regions after 20 Gy
Cu-ATSM PET at 0Gy
Red GTVCu-ATSM PET at 20Gy
Red - GTVYellow – hGTV 0Gy
Green – hGTV 20Gy
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Persistence of Cu-ATSM-vivid Regions after 20 Gy
Red GTVRed - GTVYellow – hGTV 0Gy
Green – hGTV 20Gy
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Drug Response: Imaging OptionsDrug Response: Imaging Options
•• AnatomicAnatomic•• CT CT –– multimulti--detector spiraldetector spiral
MRIMRI•• MRIMRI•• Functional and MolecularFunctional and Molecular
•• PETPET FDGFDG•• PET PET –– FDGFDG•• Dynamic Contrast Enhanced MRIDynamic Contrast Enhanced MRI
•• ExperimentalExperimentalExperimentalExperimental•• Other NMOther NM•• MRSMRS•• Exotic MR sequencesExotic MR sequences•• OpticalOptical
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Chemotherapy Response by MRI & MRSChemotherapy Response by MRI & MRS1 k D 1 D 42 D 70 D 112 D 1781 wkpre-Tx76 cc
Day 1 AC x179 cc
Day 42AC x326 cc
Day 70AC x425 cc
Day 112taxol x211 cc
Day 178taxol x46 cc
593 486 267 79 481 595
Univ. of Minnesota
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FDGFDG PET M it i R t STI571 i GISTPET M it i R t STI571 i GISTFDGFDG--PET Monitoring Response to STI571 in GIST PET Monitoring Response to STI571 in GIST
Baseline 24 hrs 7 days 2 mos 5.5 mos
Dana-Farber Cancer Institute
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Prediction of Overall Survival After Chemo in Patients with Prediction of Overall Survival After Chemo in Patients with NSCLC by FDGNSCLC by FDG--PETPETyy
Weber WA et al. J Clin Oncol 2003.
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Predict Treatment Response Predict Treatment Response –– a timing issuea timing issue
•• Whole tumor imaging characteristics vs tissue biopsyWhole tumor imaging characteristics vs tissue biopsy•• Depict tumor heterogeneityDepict tumor heterogeneity•• Serial nonSerial non--invasive images vs serial biopsiesinvasive images vs serial biopsies
3 months too late?3m post-CRT
3 months too late?
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Proliferation (Ki-67) and Apoptosis in Seg-1 Tumor Treated with Chemoradiotherapy (Taxotere + xRT)Treated with Chemoradiotherapy (Taxotere + xRT)
80
90
100
8
9
10
m)
50
60
70
x (%
)
5
6
7
Size
(mm
Ki-67TUNELTumor Size
20
30
40
50
Inde
x
2
3
4
5
Tum
or S
0
10
20
0 4 8 12 16 24 48 72 960
1
2 T
0 4 8 12 16 24 48 72 96
Time (hrs)
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FLT and FDG TimeFLT and FDG Time--course Biodistributioncourse BiodistributionFLT and FDG TimeFLT and FDG Time--course Biodistribution course Biodistribution
d 100
120
Tumor Sized 100
120
Tumor Sized 100
120
Tumor Sized 100
120
Tumor Sizere
ated
80
reat
ed
80
reat
ed
80
reat
ed
80 FDG Uptake
of U
nt
40
60
of U
nt
40
60 Ki-67 Expression
of U
nt
40
60 Ki-67 Expression
of U
nt
40
60 Ki-67 Expression
% o
20
% o
20
% o
20 FLT Uptake
% o
20 FLT Uptake
D Aft I di ti0 1 2 3 4
0
D Aft I di ti0 1 2 3 4
0
D Aft I di ti0 1 2 3 4
0
D Aft I di ti0 1 2 3 4
0
Days After IrradiationDays After IrradiationDays After IrradiationDays After IrradiationApisarnthanarax et al. Clinical Cancer Research 12:4590, 2006
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Optimal Timing and Image-pathological Validation
MolecularSignat re
Tailor CRT
CRT SurgerySignature
When? How? How much?Tailor CRT When? How? How much?
Functionalimaging
ResponderFunctionalimaging
Non-responder (alternative treatment)
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IMRT Beyond CT & FDG…..
Accumulation viamAb, Fragments
HormonesDrugs and ligands
Reporter Probe
Accumulation viaPhosphorylation
[18F]FDG PeptidesAccumulation viaaa Transport orProtein Synthesis
H ki
Glut 4
Hexokinase
InternalizationHypoxia
Enzyme Activity:Inhibition, Synthesis
Reporter Gene
TranscriptionOligonucleotidesmRNA BindingAccumulation via
DNA-Synthesis[18F]FLT