Innovative radiotherapy in HNC:
IMRT and IGRT
Dr Chris Nutting MD FRCP FRCR
Consultant and Senior Lecturer in Clinical Oncology
Head and Neck Unit, Royal Marsden Hospital &
The Institute of Cancer Research, Fulham Road, London
ESMO Stockholm 2008

Goals of Head and Neck IMRT
1. Reduce local failure by improved target volume
localisation, and dose escalation
Site: larynx and hypopharynx organ preserving
chemoradiation protocols in Stage III and IV
2. Reduce toxicity by improved dose distributions to
OAR
Site: Oropharynx – Parotid gland sparing
3. Novel techniques
Site: Unknown primary SCCHN

Phase I/II IMRT Trial Protocol
Aim:To find a suitable dose
escalation level for Phase III trial
using IMRT
Method: Single phase 63 Gy to
to tumour and 51.8 Gy to lymph
nodes in 28# with induction CF
and concomitant cisplatin
•Escalate to by 10% 67.2 Gy to
larynx and 56 Gy to nodes in 28 #
if late toxicity acceptable
•To escalate further to 15-20% if
possible Guerrero Urbano et al 2008

Demographics Table 1. Patient characteristics, larynx/ hypopharynx dose escalation study
Cohort 63Gy Cohort 67.2 Gy
Median follow up in weeks (range) 87 (55-162) 40 (9- 64)
Median age (range) 57 (35-75) 66 (60-85)
Gender Male 11 10
Female 4 5
Primary tumour site Larynx 7 7
: e mi t t n e m t a e r t n a e M Hypopharynx 8 8
T stage T1 0 1
±
s y a d 3 9 3 :tr o h o c y G 0. 3 6 • T2 3 3
syad 1 83 :trohoc yG2.76• ± T3 8 8
T4 4 3
N stage N0 4 8
SKAERB TNE MTAERT ON N1 4 2
N2a 1 0
%001 RAEN N2b 3 2
HTI W E C N AIL P M O C N2c 2 3
TNATIMOCMOC
N3 1 0
YPAREHTO MEHC
Neoadjuvant chemotherapy 15 13
Concomitant chemotherapy 15 14
Guerrero Urbano et al 2008

ACUTE RADIATION
DERMATITIS
100.0%
75.0%
G3 63.0Gy
G3 67.2Gy
50.0%
G2 63.0Gy
G2 67.2Gy
25.0%
0.0%
1 2 3 4 5 6 7 8 9 10 14
•G3 peak prevalence:
-63Gy cohort: 16.7%, week 1 post-RT
-67.2Gy cohort: 21.4%, on the last week of RT.
•No real difference between dose levels
•Skin sparing effect of MV photons

ACUTE RADIATION-INDUCED
DYSPHAGIA
Prevalence of acute G3 dysphagia
100.0%
80.0%
G3 dysphagia, %
s’namraepS :trohoc yG0.36 60.0%
67.2Gy cohort
tneiciffeoc noitalerroc knar 40.0%
63.0Gy cohort
d n a si ti s o c u m n e e w t e b
20.0%
ai g a h p s y d
) 2 0. 0 = p ( 6. 0 0.0%
1 2 3 4 5 6 7 8 9 10 14
Follow-up (weeks)
•Peak prevalence of dysphagia in both cohorts occurred following completion
of chemo-IMRT.
-64.3% for the 63.0Gy cohort, on weeks 1 and 2 post-RT
-83.3% on week 3 post-RT for the dose escalated cohort
Guerrero Urbano et al 2008

ACUTE TOXICITY: NCI CTC v.2.0 scale
Incidence of acute G2 and G3 toxicity
63.0Gy cohort 67.2Gy cohort
G2 G3 G2 G3
Dermatitis 66.7% 20% 46.7% 20%
Mucositis 33.3% 66.7% 46.7% 40%
Dysphagia 20% 66.7% 13.3% 86.7%
Pain 46.7% 26.7% 53.3% 40%
Xerostomia 60% 0 73.3% 6.7%
Guerrero Urbano et al 2008

Late Normal Tissue Toxicity at 1 year
Dose Level I (63 Gy/28 #) Dose Level II (67.2 Gy/28 #)
Organ Grade I Grade II Grade III Grade I Grade II Grade III
Dysphagia 26% (4) 0% 0% 26% (4) 0% 6% (1)
Xerostomia 60% (9) 12% (2) 0% 53% (8) 0% 0%
Larynx 30% (5) 20% (3) 0% 46% (7) 6% (1) 0%
Subcutaneous 43% (6) 0% 0% 6% (1) 12% (2) 0%
Skin 20% (3) 20% (3) 0% 33% (5) 6% (1) 0%
Mucosa 33% (5) 0% 0% 43%(6) 0% 0%

Outcome: Survival
event_lr
100
Survival Function
90
1.0
80
Survival probability (%)
70
.8 60
group
50 0
1
40
.5 30
20
10
Cum Survival
.3 0
0 10 20 30 40 50 60 70
Survival Function Time
0.0 Censored Number at risk
0 12 24 36 48 Group: 0
29 25 16 10 7 5 2 1
Time to death- months Group: 1
31 24 13 10 7 0 0 0
%09 lavivrus eerf ymotcegnyraL llarevO
•Loco-regional 65% vs. 82% at 3 years
•To detect this difference in a Phase III trial would
require total of 320 patients (90% power 5% p)

Goals of Head and Neck IMRT
1. Reduce local failure by improved target volume
localisation, and dose escalation
Site: larynx and hypopharynx organ preserving
chemoradiation protocols in Stage III and IV
2. Reduce toxicity by improved dose distributions to
OAR
Site: Oropharynx – Parotid gland sparing
3. Novel techniques
Site: Unknown primary SCCHN

IMRT – Reducing the dose to the
parotid gland in tonsil cancer

Head and neck IMRT: Xerostomia
• Graff et al IJROBP 02/2007
• Matched case-control study of QoL after bilateral
CRT/IMRT
– IMRT improved dry mouth and sticky saliva (p= 0.0001)
– Prevalence Odds Ratios were: Dry mouth 3.2, Sticky
saliva 3.2, Oral pain 3.6, Trismus 2.6, Difficulty
swallowing 2.8.

Head and neck IMRT: Xerostomia
• Fang et al Cancer Jan 2007
• 237 Nasopharynx carcinoma patients
• Non-randomised allocation: Conv (152) vs
Conformal (CFRT – 33 IMRT 52)
• Conformal group showed improved QoL scores,
and multiple functional scores including
xerostomia, eating, speech, senses etc
• OR for xerostomia was 0.37 (CI 0.2-0.66)
• OR for global QoL was 2.0 (CI 1.2-3.7)

Head and neck IMRT: Xerostomia
• Pow et al IJROBP 2006
• Small randomised trial of 51 patients with T2
N0/1 M0 nasopharynx cancer
• CRT vs IMRT
• Recovery of parotid flow to at least 25% of pre-
treatment levels was 83% with IMRT, and 10%
with CRT
• IMRT patients had improved dry mouth and sticky
saliva

TROPSRAP Study Design
Head and neck cancer patients at high
risk of radiation induced xerostomia
Randomisation
Conventional Parotid-sparing
radiotherapy IMRT
1:1 randomisation

TROPSRAP Current status
PARSPORT closed to recruitment in Dec 2007
96 patients were randomised from 6 UK centers
Data collection rates ~80%
10% of trial participants died before reaching the
primary endpoint (usually of non-HNC)
Primary endpoint data collection should be
completed Dec 2008

IMRT – New tumour types
Expansion of indications into midline tumours: tongue
base, nasopharynx
PARSPORT II to investigate feasibility of bilateral parotid
gland sparing

vs
Mean doses to total
combined parotid salivary
tissue is the same with each
approach
This would predict that
saliva flow will be
equivalent in each approach
if gland is homogeneous

vs
Initial clinical results (n=60) suggest that the two approaches
are not equivalent, and that a higher rate of G0 xerostomia is
seen in patients treated with bilateral sparing of the superficial
lobes. This is an unexpected finding and may support the
findings from rat models that parotid tissue is not
homogeneous in its saliva production, or radiosensitivity.

Goals of Head and Neck IMRT
1. Reduce local failure by improved target volume
localisation, and dose escalation
Site: larynx and hypopharynx organ preserving
chemoradiation protocols in Stage III and IV
2. Reduce toxicity by improved dose distributions to
OAR
Site: Oropharynx – Parotid gland sparing
3. Novel techniques
Site: Unknown primary SCCHN

IMRT for unknown primary site
• Patients presenting with cervical lymph node
metastases and no mucosal tumour
• Post-operative options of hemi-neck RT or TMI
issues of local control vs survival
• Target volumes for post-op and potential
microscopic disease can be defined
• Hypothesis: Can TM-IMRT offer the advantages
of local control without the high levels of toxicity?

Basic principles of TM-IMRT
PTV1 (post-op) 60 Gy
in 30#
PTV2 elective
(microscopic disease)
50 Gy in 25#
Bhide et al 2008

Currently recruiting Phase
II protocol at RMH to
assess local control and
toxicity issues Bhide et al 2008

IGRT in Head and Neck Cancer
1. Optimise conventional anatomic imaging
Site specific protocols e.g. skull base/BOT
Image registration
2. Add functional/biological information
FDG PET/CT, dceMRI, dynamic CT
3. Image areas of potential radioresistance
Hypoxia tracers, proliferation markers

Adjuvant MRI for GTV definition
•CT-GTV (red), MR-GTV (blue) and combined-GTV (pink).
•Part of the GTV is identified only on CT, part on MRI only
onabrU orerreuG .T.M rD fo ysetruoC

onabrU orerreuG .T.M rD fo ysetruoC
Adjuvant MRI for OAR definition

RMH Experience With PET/CT For
RT Planning
• Two groups of patients: 9 with known
primary site and 9 unknown
• RT planning performed with or without
PET/CT data
• Unknown primary planned for ipsilateral
neck irradiation only
8002 la te dlobweN

Known primaries: Change in CTV
900
800
700
600
500
400
300
200
100
0
Co nventio nal P ET/CT
Median increase 11cm3 (1, 65.8)
p=0.012 8002 la te dlobweN

% change in target volumes in Unknown
primaries: CT to PET/CT
250
200
1 50
1 00
50
0
CT P E T / CT
M odal i ty
8002 la te dlobweN

Imaging of hypoxia in head and neck cancer
Probability of normal tissue damage
Probability of tumour control
Normoxia Hypoxia
Radiation dose (Gy)

DCE-MRI
Pimonidazole
Source image
ROIs
Enhancement vs time
CA9
Wash-in rate
Newbold in press IJROBP

Conclusions
• We have attempted to design clinical trials with
clear questions to test IMRT in HNC
• Phase I and II results support dose escalation
strategies in SCCHN
• Parotid sparing IMRT: Randomised trial data now
available
• Novel IMRT techniques can be formulated and
tested to expand indications
• IGRT potentially offers new RT targets
• More clinical research in this area is required