Innovative radiotherapy in HNC: IMRT and IGRT

Dr Chris Nutting MD FRCP FRCRConsultant 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 techniquesSite: 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

Mean treatment time:•63.0Gy cohort: 39±3 days•67.2Gy cohort: 38±1 days NO TREATMENT BREAKSNEAR 100% COMPLIANCE WITH COMCOMITANT CHEMOTHERAPY

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)

Male 11 10 Gender

Female 4 5

Larynx 7 7 Primary tumour site

Hypopharynx 8 8

T1 0 1

T2 3 3

T3 8 8

T stage

T4 4 3

N0 4 8

N1 4 2

N2a 1 0

N2b 3 2

N2c 2 3

N stage

N3 1 0

Neoadjuvant chemotherapy 15 13

Concomitant chemotherapy 15 14

Guerrero Urbano et al 2008

ACUTE RADIATIONDERMATITIS

•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

0.0%

25.0%

50.0%

75.0%

100.0%

1 2 3 4 5 6 7 8 9 10 14

G3 63.0Gy

G3 67.2Gy

G2 63.0Gy

G2 67.2Gy

ACUTE RADIATION-INDUCED DYSPHAGIA

•Peak prevalence of dysphagia in both cohorts occurred following completionof 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

63.0Gy cohort: Spearman’s rank correlation coefficient between mucositis and dysphagia 0.6 (p=0.02)Prevalence of acute G3 dysphagia

0.0%

20.0%

40.0%

60.0%

80.0%

100.0%

1 2 3 4 5 6 7 8 9 10 14

Follow-up (weeks)G

3 dy

spha

gia,

%

67.2Gy cohort

63.0Gy 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

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%

Late Normal Tissue Toxicity at 1 year

Outcome: SurvivalSurvival Function

Time to death- months

483624120

Cum

Sur

viva

l

1.0

.8

.5

.3

0.0

Survival Function

CensoredOverall Laryngectomy free survival 90% •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)

group01

event_lr

0 10 20 30 40 50 60 70

100

90

80

70

60

50

40

30

20

10

0

Time

Sur

viva

l pro

babi

lity

(%)

Number at riskGroup: 0

29 25 16 10 7 5 2 1Group: 1

31 24 13 10 7 0 0 0

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 sparing3. Novel techniquesSite: 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

Study Design

Head and neck cancer patients at high risk of radiation induced xerostomia

Randomisation

Conventional radiotherapy

Parotid-sparingIMRT

1:1 randomisation

PARSPORT

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

PARSPORT

IMRT – New tumour typesExpansion of indications into midline tumours: tongue base, nasopharynx

PARSPORT II to investigate feasibility of bilateral parotid gland sparing

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.

vs

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 sparing3. Novel techniquesSite: 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?

PTV1 (post-op) 60 Gy in 30#

PTV2 elective (microscopic disease) 50 Gy in 25#

Basic principles of TM-IMRT

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 imagingSite specific protocols e.g. skull base/BOTImage registration

2. Add functional/biological informationFDG PET/CT, dceMRI, dynamic CT

3. Image areas of potential radioresistanceHypoxia tracers, proliferation markers

•CT-GTV (red), MR-GTV (blue) and combined-GTV (pink).

•Part of the GTV is identified only on CT, part on MRI only

Adjuvant MRI for GTV definition

Courtesy of Dr M.T. Guerrero Urbano

Adjuvant MRI for OAR definition

Courtesy of Dr M.T. Guerrero Urbano

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 Newbold et al 2008

Known primaries: Change in CTV

0

100

200

300

400

500

600

700

800

900

Conventional PET/CT

Median increase 11cm3 (1, 65.8)p=0.012 Newbold et al 2008

% change in target volumes in Unknown primaries: CT to PET/CT

0

50

1 00

1 50

200

250

CT PET / CT

M o d a l i t y Newbold et al 2008

Imaging of hypoxia in head and neck cancer

Normoxia Hypoxia

Probability of tum

our control

Probability of norm

al tissue damage

Radiation dose (Gy)

DCE-MRI

Pimonidazole

CA9

ROIs

Source image

Wash-in rate

Enhancement vs time

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