April 2008

An Introduction to Head & Neck Radiotherapy.

Vincent GREGOIRE, M.D., Ph.D.

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

April 2008

Myths and facts in Oncology: the challenge of local therapies

Chemotherapy

Surgery

Surgery + radiotherapy Radiotherapy

not cure (local recurrence)

not cure (distal recurrence)

37%

18%

5%

22%

6% 12%

April 2008

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%

April 2008 Bataini et al, 1982

, 4 5 5 5 6 5 7 5 8 5 9 5

T o t a l d o s e ( G y )

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

Tum

or c

ontro

l (%

)

Dose-response curve for neck nodes ≤ 3 cm

Tumor Control Probability (TCP)

April 2008

Human Monkey

Baumann et al., Strahlenther Onkol 170: 131-139, 1994

Normal Tissue Control Probability (NTCP)

April 2008

Unacceptable normal tissue damage

Tumour control

Uncomplicated tumour control

Effe

ct

Dose

Uncomplicated tumor control: Therapeutic Ratio

April 2008

Unacceptable normal tissue damage

Tumour control

Uncomplicated tumour control

Effe

ct

Dose

Uncomplicated tumor control: Therapeutic Ratio

April 2008

Unacceptable normal tissue damage

Tumour control

Effe

ct

Dose

Uncomplicated tumour control

Uncomplicated tumor control: Therapeutic Ratio

April 2008

n = 1 2 5 10 20

Total dose (Gy)

Less effect per gray at low doses/#

N = 1

April 2008

“Typical” dose per fraction • 1.8-2 Gy for standard

fractionation

• 1.1-1.3 Gy for hyper-fractionation

Fractionation sensitivity

Withers et al, 1983

Acute effects + tumor response

Late effects

April 2008

Hyperfractionation�Decreased dose per fraction

Conventional fractionation

Hyperfractionation (“pure”, SFD)

Hyperfractionation (“dose escalated”, MFD)

Hyperfractionation (“pure”, MFD)

2.0 Gy/ f, 1x/ d�6 weeks= 60 Gy

1.0 Gy/ f, 2x/ d�6 weeks= 60 Gy

1.2 Gy/ f, 2x/ d�6 weeks= 72 Gy

1.5 Gy/ f, 1x/ d�6 weeks= 60 Gy

April 2008

Oropharyngeal Ca T2-3, N0-1

Years

LOCAL CONTROL SURVIVAL

Years

EORTC Hyperfractionation trial in oropharynx cancer

Horiot 1992

80.5 Gy - 70 fx - 7 wks vs 70 Gy - 35-40 fx - 7-8 wks

p = 0.02 p = 0.08

April 2008

TCD

50 (G

y) Tclon= 9.8d [0;21] Tclon= 3.4d

[1.7;5]

Day 22 [13;30]

Radiobiological hypoxia

Tage nach 1. RT 10 20 30 0

0

60

120

RDI pAB

Petersen et al., IJRB 79: 469-477, 20030

EGF-Receptor

EGFR and repopulation during RT FaDu hSCC

April 2008

Influence of overall treatment time on HNSCC local control

Radiobiological and clinical issues in IMRT for HNSCC

Withers et al, 1988

April 2008

Accelerated fractionation (AF) Shortened overall treatment time, dose per week > 10 Gy

Expectations: • Increased tumor control • Increased early reactions • Unchanged or decreased�

late damage �(AF/HF and/or reduced�total dose) AF/HF

54Gy/ 3x1.5Gy/ ti=6h/ 12d

70Gy/ 2.0 Gy/ 7w CF

70Gy/ 2.0 Gy/ 5w CB

April 2008

DAHANCA 6&7 - H&N SCC - stage II-IV (n=1476)

Overgaard et al. Lancet, 2003

IIIIII IIIIII IIIIII IIIIII IIIIII IIIIII 64-68 Gy/ 2.0 Gy/ 5.5w

IIIII IIIII IIIII IIIII IIIII IIIII IIII 64-68 Gy/ 2.0 Gy/ 6.5w

April 2008

H&N SCC: MACH-NC

Pignon, Lancet, 2000 April 2008

c 1x

3x SD18Gy

18Gy + 1x

18Gy + 3x

Milas et al. Clin Cancer Res 6: 701-708, 2000

RT SD/1xC225 SD/3xC225

Nasu et al., IJROBP 51: 474-477, 2001

C225 anti EGFR Ab; A 431 tumours:

April 2008

Stratify by  Karnofsky score: 90-100 vs. 60-80  Regional Nodes: Negative vs. Positive  Tumor stage: AJCC T1-3 vs. T4  RT fractionation: Concomitant boost vs. Once daily vs. Twice daily

Arm 2 (RT+E) Radiation therapy + Cetuximab, weekly

EGF-R inhibitor and RxTh in HNSCC�Phase III Study Design

R A N D O M I Z E

Arm 1 (RT) Radiation therapy

Bonner, 2004 April 2008

Efficacy

Locoregional Control

Overall Survival

Erbitux + RT

Erbitux + RT

RT

RT

Log-rank p

Bonner, 2004

April 2008

Image-Guided Radiation Therapy in HNSCC

1900

1937 1963

1976 April 2008

Image-Guided Radiation Therapy in HNSCC

2000 Intensity Modulated Radiation Therapy

(IMRT)

April 2008

April 2008

(1) Eisbruch 1999, Dawson 2000: University of Michigan (U-M) (2) Lee 2002: University of California at San Francisco (UCSF) (3) Claus 2002, Duthoy 2003: Ghent University Hospital (GUH) (4) Chao 2003: Washington University, St. Louis (WU)

U-M (1) Oral cavity Oro- hypopharynx Larynx

UCSF (2) Nasopharynx

GUH (3) Nasal cavity

Paranasal sinus

WU (4) All sites

CUP

Clinical outcome of IMRT in head and neck cancer

April 2008

April 2008

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

0 1 2 3 4 5 6 7 8 9 10 Deviation from the isocenter (mm)

Cum

ulat

ive

inci

denc

e

Head (3-5 FP)

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

0 1 2 3 4 5 6 7 8 9 10 Deviation from the isocenter (mm)

Cum

ulat

ive

inci

denc

e

Neck (3-5 FP)

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9

1

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Deviation of the isocenter (mm)

Cum

ulat

ive

inci

denc

e Shoulder (4 & 5 FP)

April 2008

Image acquisition •  Dual detector spiral CT

•  2.7 mm collimation, pitch 0.7, reconstruction of 2 - 2.5 mm

•  Display matrix of 512 x 512 pixels

•  Contrast enhancement (interstitial and blood vessel contrast)

April 2008

Conformal radiotherapy: 3D reconstruction

April 2008

Conformal radiotherapy: image display

April 2008 ICRU report 62, 1999

•  Gross Tumor Volume: GTV

•  Clinical Target Volume: CTV

•  Planning Target Volume: PTV

Target volumes in Radiation Oncology: ICRU definition

•  Organs at Risk: OAR

•  Planning Organ at Risk Volume: PRV

April 2008

Conformal radiotherapy and IMRT in Head and Neck Tumors

April 2008

State of the art • Predictive pattern of lymph node involvement in

HNSCC

• Selective neck treatment (irradiation or dissection) for selected N stage

Definition of the extend of the CTV in the neck

April 2008

Incidence of pathologic lymph node metastasis in oropharyngeal tumors

2%

2% 25%

19%

8%

Clinically N0 neck (n=48)

From Candela, 1990

Clinically N+ neck (n=165)

9%

15% 71%

42%

27%

April 2008

Oropharyngeal Carcinoma Stage Ipsilateral neck Controlateral neck

N0-N1 (Ib1)-II-III-IV + RP for post. II-III-IV + RP for post. pharyngeal wall tumor pharyngeal wall tumor

N2a-N2b Ib-II-III-IV-V +RP II-III-IV + RP for post. pharyngeal wall tumor

N2c According to N stage on According to N stage on each side of the neck each side of the neck

N3 I-II-III-IV-V +RP ± adjacent II-III-IV + RP for post. structures according to clinical pharyngeal wall tumor and radiological data 1Ib only if extension to oral cavity

Grégoire et al., 2000 April 2008

DAHANCA: http://www.dshho.suite.dk/dahanca/guidelines.html EORTC: http://www.eortc.be/home/ Radio/EDUCATION.htm RTOG: http://www.rtog.org/hnatlas/main.htm

Conformal radiotherapy and IMRT in Head and Neck Tumors

April 2008

Ant. symphysis menti / platysma Post. hyoid bone / submandibular

gland Lat. ant. belly of digastric m. (Ia) mandible / platysma (Ib) Med. ant. belly of digastric m. (Ib) Cra. geniohyoid m./mandible (Ia) mylohyoid m,

submandibular gland (Ib) Cau. hyoid bone

Level Ia and Ib

RP

LII

LIb

LIa

CT-based delineation of lymph node levels in the neck: Brussels- Rotterdam consensus guidelines

April 2008

Ant. sternohyoid m./ sternocleidomastoid m.

Post. sternocleidomastoid m. Lat. sternocleidomastoid m. Med. paraspinal m. int. carotid artery Cra. hyoid bone Cau. cricoid cartilage

Level III

LV

LIII

CT-based delineation of lymph node levels in the neck: Brussels- Rotterdam consensus guidelines

April 2008

Mr H. D. (77 years): T3-N0-M0 base of tongue (ICD0-10: C01)

April 2008

Rx 6 MV 40 Gy

Rx 6 MV 30 Gy

Rx 6 MV 50 Gy

Elect 8 MeV 10 Gy

“Antique” (7 fields)

April 2008

Rx 6 MV 50 Gy

“Art nouveau” (10 fields, 12 segments )

Ant. RPO LPO

SRAO SLAO

…

Post. Seg. 1 Post. Seg. 2

April 2008

Rx 6 MV 20 Gy

“Art nouveau” (11 fields, 12 segments )

Ant. RAO LPO

LAO1 LAO2

April 2008 April 2008

April 2008

Forward planning IMRT

•  « human optimization »

Inverse planning IMRT

•  Dose-volume constraints & weights for PTV and OARs

•  optimization algorithms

•  Penalty function

April 2008

  Spare cord   Spare left parotid   15 segments   10 levels

1 6. Cummulative % of MUs Segment #

Courtesy of C. Field

April 2008

PTVs

Spinal cord

Left parotid

Right parotid

Hypopharyngeal SCC T4-N0-M0 Dose: 25 x 1.8 Gy bid

April 2008

Left parotid ADC Dose: 30 x 2.0 Gy

PTV

Right parotid

Spinal cord

Inner ear

April 2008

Objective assessment

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70

Bilateral irradiation Unilateral irradiation

R= 0,77

Max

imum

secr

etio

n (%

)

Mean parotid dose (Gy) April 2008

Subjective assessment

0

2

4

6

8

10

12

0 10 20 30 40 50 60 70

Bilateral irradiation Unilateral irradiation

R= 0,63

SOM

A sc

ale

(arb

itrar

y un

its)

Mean parotid dose (Gy)

April 2008

•  88 patients irradiated with parotid sparing •  saliva flow rates for 152 parotid glands •  dose / volume / function relationships

•  parotid mean dose < 26 Gy is planning goal •  Lyman NTCP: n = 1, m = 0.18, TD50=28.4 Gy

Oral cavity, oro- hypopharynx, larynx parotid-sparing 3D-CRT

12/58 patients developed recurrences: 10 in GTV region 2 in elective region (1st echelon)

Limits: local control in GTV area

April 2008 Lee et al. IJROBP 53: 12-22, 2002

Nasopharynx

•  67 patients treated April 1995-October 2000

•  Stages I (n=8); II (n=12); III (n=22); IV (n=25)

•  Non-keratinizing (n=34); undifferentiated (n=33)

•  IMRT by compensators, MLC or MIMiC

•  Conventional fields to treat the neck

4-year actuarial distant metastasis-free rate: 66%

Limits: distant metastasis rate

April 2008

-Number of patients 44 -R0 surgery 44 - Male/female ratio 9/1 - Median age at diagnosis 60 years [30-76] - Subsite

Ethmoid sinus 33 (75%) Maxillary sinus 6 (14%) Nasal cavity 5 (11%)

W. Duthoy, 2003

Paranasal sinus

Limits: local control in T4(b)

Complications of postoperative radiation therapy for ethmoid sinus tumors

period 1985 - 1994 1995 - 1998 1999 - 2002

RT 2D 3D

IMRT

PTS 19 11 33

Optic neuropathy

0 2 0

Dry eye syndrome

5 2 0

April 2008

April 2008

Duration of treatment planning procedure 2D planning Forward planning Inverse planning (St-Luc) (Edmonton Cancer center)

Volume delineation 0 - 0.25h 2 - 3h 1 - 1.5h

Planning 0.25h 2 - 8h 1 - 2h

Individualized QC 0h 0.25h 1h

Treatment (per session) 10 - 15 min 20 - 25 min 15 min

April 2008 From Azoury, 2000

Activity-Based Costing (ABC) in radiotherapy

Type of treatment Cost (EURO)

Palliative irradiation (10 fractions) 1,686

Breast irradiation (25 fractions) 2,701

H&N irradiation (35 fractions) 4,724

April 2008

CT MRI (T2) FDG-PET

PRE-R/

WEEK 3

WEEK 5

(Week 2)

(Week 4)