image-guided imrt forguided imrt for head and neck cancer · post-op nonop non-imrt 142 3.9 yr...

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

T2N1M0 SCC of Base of the TongueT2N1M0 SCC of Base of the Tongue

Conventional RTConventional RT IMRTIMRT

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

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

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

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.

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

Step One: Identify GTVp/nStep One: Identify GTVp/n

GTVp GTVn

Step 2: Add CTV1Step 2: Add CTV1

Defined as GTVp/n plus 10 mm of marginp g

M Truncating around normal structures

M


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


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

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

CTV 2 CTV 3CTV 1GTVnGTVp

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

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

PTV6654 Gy

GTV60 Gy Underdose

66 Gy PTV54

Outcome: Local recurrence

Treatment plan of a patient with a major PTV66 underdose

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

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

CNodal CTV Delineation – Margin?

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

TC

T CT

2 mm2 mm

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


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

Nodal CTV Delineation

0.5-1 cm CTV marginsg


Advanced KnowledgeAdvanced Knowledge--based Intelligent Toolbased Intelligent Tool

IJROBP 68:1512-1521, 2007

Knowledge-based Computer-assisted Target DelineationKnowledge based Computer assisted Target Delineation

Contouring from scratch Computer-assisted Contouring

Advanced KnowledgeAdvanced Knowledge--based Intelligent Toolbased Intelligent Tool

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

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

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

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

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%

But we need something more than FDG…But we need something more than FDG…gg

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

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

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

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

Target Hypoxic Tumor Guided by 60Cu-ATSM PETg yp yChao et al. IJROBP 49: 1171-1182, 2001

Coronal view

Axial view

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

Persistence of Cu-ATSM-vivid Regions after 20 Gy

Red GTVRed - GTVYellow – hGTV 0Gy

Green – hGTV 20Gy

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

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

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

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.

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?

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)

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


0


0


0

Days After IrradiationDays After IrradiationDays After IrradiationDays After IrradiationApisarnthanarax et al. Clinical Cancer Research 12:4590, 2006

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)

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

image-guided imrt forguided imrt for head and neck cancer · post-op nonop non-imrt 142 3.9 yr...

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