Brescia

May 200 9

Adaptive radiotherapy of HNSCC:

advantages, limits and clinical applications

in the treatment of oropharyngeal carcinoma.

Vincent GREGOIRE, M.D., Ph.D., Hon. FRCR

Head and Neck Oncology Program, Radiation

Oncology Dept. & Center for Molecular Imaging and

Experimental Radiotherapy, Université Catholique de

Louvain, St-Luc University Hospital, Brussels, Belgium

Brescia

May 200 9

Chemotherapy

Surgery

Surgery +radiotherapyRadiotherapy

not cure(local recurrence)

not cure(distal recurrence)

37%

18%

5%

22%

6%12%

Myths and facts in Oncology: the challenge

of local therapies

Brescia

May 200 9

Myths and facts in Oncology: the challenge

of local therapies in …HNSCC…

Chemotherapy

Surgery

Surgery + radiotherapy± chemo/biological

modifiers

Radiotherapy

± chemo/biological

modifiers

not cure(local recurrence)

not cure(distal recurrence)

˜ 10-15%

˜ 25-35%

0%

22%

>6%>>12%

Brescia

May 200 9

“My” vision of Radiation Oncology in 2009

and beyond …

• RO will be (even more) multidisciplinary…

• RO will be conformal (e.g. IMRT, proton, hadrons)…

• RO will be tailored (based on imaging and molecular

profiling) and adaptive …

• RO will be associated with targeted agents …

Brescia

May 200 9

“My” vision of Radiation Oncology in 2009

and beyond …

Brescia

May 200 9

Challenges in Head & Neck loco-regional

treatment

Brescia

May 200 9

“2D” Radiotherapy in oropharyngeal

cancers

Mendenhall et al., 2000

Brescia

May 200 9

Oropharyngeal SCC

T2-N0-M0

SIB-IMRT: 30x2.3 Gy

30x1.85 Gy

PRV Spinal cord

Left parotidRight parotid

Larynx

PTV 55.5 Gy

PTV 69 Gy

IMRT for Head and Neck Tumors

Brescia

May 200 9

IMRT for Head and Neck Tumors

Oropharyngeal carcinomas

Lee, N. et al Head & Neck 2007

Brescia

May 200 9

Salivary flow rate inunstimulated gland

Parotid gland sparing in IMRT

From Eisbruch, 1996

Salivary flow rate instimulated gland

Brescia

May 200 9

Parotid gland sparing in IMRT for NPC

Kam, et al. J Clin Oncol; 2007

Stage I-II; 2DRT (66 Gy) >< IMRT (66 Gy); brachytherapy boost; no chemotherapy

**

**

*

Brescia

May 200 9

Relationship between radiation dose to the pharyngeal

constrictors and aspirationR

isk o

f A

spir

ati

on

on V

ideofl

uoro

scopy

Mean Dose to the Total Pharyngeal Constrictor

1/52/13 2/15

3/12

14/19

7/8

Feng & Eisbruch, 2008

Brescia

May 200 9

Osteoradionecrosis with “modern”

radiotherapy techniques

Ben-David, 2007

• n= 176 (86% ORO/OC)

• IMRT ± CH

• Primary RT + post-op RT

• Median FU of 35 months

No case of ORN

• Pre-IMRT dental care

• Daily fluorination

• Dental protective stent

• Post-RT prophylactic dental

care

Mandible doseMean V50: 62 ± 18%

Brescia

May 200 9

Challenges in H&N IMRT

Harari et al., 2005

Brescia

May 200 9

18F-FDGPET

NMR (T1)

CAT Scan

Brescia

May 200 9 Daisne et al, 2004

How far are we from the truth ?

Brescia

May 200 9

Impact of imaging modality on dose distribution

Image-Guided Radiation Therapy in HNSCC

CT-based target volume FDG PET-based target volume

Geets et al, 2006

Brescia

May 200 9

Validation protocol in locally advanced HNSCC

Apport de l'imagerie fonctionnelle par Tomographie

par Emission de Positrons (TEP) dans le ciblage biologique

par radiothérapie de conformation (3D-CRT)

et par modulation d'intensité (IMRT) de tumeurs ORL

Use of functional imaging with PET for target volume

delineation in 3D-CRT/IMRT for head and neck tumors

Prof. V. Grégoire, UCL St-Luc, Brussels, Belgium

Prof. E. Lartigau, COL, Lille, France

Dr. JF Daisnes, Cliniques St-Elisabeth, Namur, Belgium

Brescia

May 200 9 C. Monet, 1894The Cathedral of Rouen

4D-IMRT

Brescia

May 200 9

MVCT

kVCT

Geometric 4D-IMRT

Vaandering, 2006

Brescia

May 200 9

First five MVCTs: CTV to PTV margins

0,00

2,00

4,00

6,00

8,00

10,00

12,00

14,00

16,00

18,00

1 6 11 16 21 26 31 36 41 46 51 56 61 66 71

In itial CTV-P TV m a rgin

Correcte d CTV-PTV m a rgin

4 m m m a rgin

0,00

2,00

4,00

6,00

8,00

10,00

12,00

14,00

1 5 9 13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73

Initial C TV-PTV margin

Corrected CTV-PTV margin

4mm margin

0 , 0 0

2 , 0 0

4 , 0 0

6 , 0 0

8 , 0 0

1 0 ,0 0

1 2 ,0 0

1 4 ,0 0

1 7 1 3 1 9 2 5 31 3 7 4 3 4 9 5 5 6 1 6 7 7 3

Initial

C T V-PT V m argin

C or rec t ed C T V-PT V m argin

4m m m argin

• 75 patients

• total of 1481 MVCT

• CTV-PTV: (2*Σ + 0.7s )

Vaandering, 2007

CT

V t

o P

TV

mar

gin

Cranio-caudal directionMedio-lateral direction

Antero-posterior direction

Geometric 4D-IMRT

Brescia

May 200 9

Alternate week MVCTs: CTV-PTV margins

0 ,0 0

2 ,0 0

4 ,0 0

6 ,0 0

8 ,0 0

10 ,0 0

12 ,0 0

14 ,0 0

16 ,0 0

18 ,0 0

1 6 1 1 1 6 2 1 2 6 3 1 36 4 1 4 6 5 1 56 6 1 66 7 1

I nit ial CTV-P TV m a rg in

Co rrect ed CTV-PTV m a rg in

4 m m m a rg in

0 ,0 0

2 ,0 0

4 ,0 0

6 ,0 0

8 ,0 0

10 ,0 0

12 ,0 0

14 ,0 0

1 6 11 16 2 1 26 3 1 3 6 4 1 4 6 51 5 6 6 1 6 6 7 1

In itial CTV-P TV m a rgin

Correcte d CTV-PTV m a rgin

4 m m m a rgin

0 ,0 0

2 ,0 0

4 ,0 0

6 ,0 0

8 ,0 0

10 ,0 0

12 ,0 0

14 ,0 0

1 6 1 1 1 6 2 1 2 6 3 1 36 4 1 4 6 5 1 56 6 1 66 7 1

I nit ial CTV-P TV m a rg in

Co rrect ed CTV-PTV m a rg in

4 m m m a rg in

• 75 patients

• total of 1481 MVCT

• CTV-PTV: (2*Σ + 0.7s )

Vaandering, 2007

CT

V t

o P

TV

mar

gin

Cranio-caudal directionMedio-lateral direction

Antero-posterior direction

Geometric 4D-IMRT

Brescia

May 200 9

Residual deviations analysis

-- First five days protocol (FFD)

-- Alternate week protocol (AW)

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

0,0 1,0 2,0 3,0 4,0 5,0 6,0 7,0 8,0

Cu

mu

lati

ve

dis

trib

tuti

on

Residual deviations (mm)

H&N cancer patients:

Residual deviations in m-l direction

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

0,0 1,0 2,0 3,0 4,0 5,0 6,0 7,0 8,0

Cu

mu

lati

ve

dis

trib

tuti

on

Residual deviations (mm)

H&N cancer patients:

Residual deviations in c-c direction

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

0,0 1,0 2,0 3,0 4,0 5,0 6,0 7,0 8,0

Cu

mu

lati

ve d

istr

ibtu

tio

n

Residual deviations (mm)

H&N cancer patients:

Residual deviations in a-p direction

FFD(avg±1S) : -0,03 ± 0,8mm

AW(avg±1S) : -0,07 ± 0,6mm

FFD(avg±1S) : -0,3 ± 0,8mm

AW(avg±1S) : -0,1 ± 0,6mm

FFD(avg±1S) : -0,4 ± 1,2mm

AW(avg±1S) : -0,1 ± 0,6mm

Residual deviationsGeometric 4D-IMRT

Vaandering, 2008

Brescia

May 200 9

CT MRI (T2) FDG-PET

PRE-R/

WEEK 3

WEEK 5

(Week 2)

(Week 4)

Brescia

May 200 9 Geets et al, 2003

0 Gy

50 Gy

FDG-PET

Image-Guided Radiation Therapy in HNSCC The 4th dimension …

Brescia

May 200 9

Raw

im

age

Image processing Image segmentation

SBR

W&C

UG 4mm

BG 6mm + deconvolution

PET image segmentation during RxTh

J. Lee & X. Geets, 2005

Brescia

May 200 9

Image registration…

Week 0

Week 3

Rigid Registration (mutual information)

Differential dysplay

Castadot & Lee, 2006

Brescia

May 200 9

Differential dysplay

Image registration…

Parraga, Castadot & Lee, 2006

Brescia

May 200 9

Mean slope: -1.46% / treat day (p<0.05)

Medial shift: 0.91mm after 25# (p<0.05)

Mean slope: -2.55% / treat day (p<0.05)

Lateral shift: 1.52mm after 25# (p<0.05)

Variation in therapeutic CTVs during RT-CH…

Castadot & Lee, 2008

Brescia

May 200 9

Mean slope: -0.47% / treat day (p<0.05)

No shift

Mean slope: -0.41% / treat day (p<0.05)

Medial shift: 1.76mm after 25# (p<0.05)

Variation in prophylactic CTVs during RT-CH…

Castadot & Lee, 2008

Brescia

May 200 9

Mean slope: -0.93% / treat day (p<0.05)

Medial shift: 3.21mm after 25# (p<0.05)

Mean slope: -1.03% / treat day (p<0.05)

No shift

Variation in parotid volumes during RT-CH…

Castadot & Lee, 2008

Brescia

May 200 9

Impact on Target Volume delineation

P<0.001

Geets, 2007

Brescia

May 200 9

0 ? 14Gy 14 ? 25Gy 25 ? 35Gy 35 ? 45Gy 45 ? 69Gy

Total Dose really received by each volume element of the

patient

+

w2? w0

+

w3? w0

+

w4? w0

+

w5? w0

Castadot & Lee, 2008

Brescia

May 200 9

Classic CT-based planning Adaptive PET-based planning

58%67%73%98%100%99%Adaptive PET-based

81%82%83%98%99%99%Classic PET-based

66%80%85%100%100%99%Adaptive CT-based

100%100%100%100%100%100%Classic CT-based

V100V95V90V80V50V10Planning

P<0.001

Geets, 2007

Impact on dose distribution

SIB-IMRT

30x2.3 Gy

30x1.85 Gy

Brescia

May 200 9

Dose distribution after adaptive RT-CH (n=5)

Castadot & Lee, 2008

Brescia

May 200 9

Survival is non-flat

(higher in resistant areas)

Non-flat doseFlat dose

More similar survival

across entire tumor

Far m

ore effic

ient use

of do

se

Mean Tumor Dose = 2 Gy

Courtesy of D. De Ruysscher

“Dose painting” by number…

Brescia

May 200 9

Metabolism: 18F-FDG

11C-Met

Proliferation: 76Br-BFU

Hypoxia: 18F-EF3

Which biological pathways? …

Brescia

May 200 9 C. Monet, 1874

The Bridge

at

Argenteuil

Challenges in Head & Neck loco-regional

treatment

• Target selection and delineation

• Adaptive IMRT: geometrical, biological &

dosimetrical

•which imaging modalities??

•which biological pathways??

•which volume/dose registration algorithms??

•how frequently??

• Concomitant association with drugs and/or

“small molecules”

Brescia

May 200 9

Acknowledgements

• Communication and Remote Sensing Lab. Adriana PARRAGA, Eng.

Benoit MACQ,Eng., Ph.D.

• ENT and Head & Neck surgery Marc HAMOIR, M.D.

• Imaging Emmanuel COCHE, M.D.

Thierry DUPREZ, M.D.

Max LONNEUX, M.D.

• Oral & Maxillo-Facial surgery Pierre MAHY, M.D.

Hervé REYCHLER, M.D., D.M.D.

• Pathology Birgit WEYNAND, M.D.

• PET laboratory Anne BOL, Ph.D.

Daniel LABARE, Ph.D.

• Radiation Oncology Nicholas CHRISTIAN, M.D.

Pierre CASTADOT, M.D.

Xavier GEETS, M.D., Ph.D.

John LEE, eng., Ph.D.

Pierre SCALLIET, M.D., Ph.D.