Innovative Radiotherapy In Hnc
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Transcript of Innovative Radiotherapy In Hnc
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