Head & Neck
cancer
Radiotherapy
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The Goal
1. Higher LR control and survival rates in limited stage disease
2. Increased survival in locally advanced disease (improved LR control, reduced probability of DM and second malignancies)
3. Increased organ and function preservation
4. Increased therapeutic ratio (cure/toxicity)
The best treatment in H&N cancer patients
should be made to obtain:
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Stage I / II Single modality (Surgery or RT) Stage III / IV Combined modality
- Surgery + RT - Surgery + RT + CT - RT + CT
Management for H&N Cancers
When different modalities have same results, one offering better QoL, with organ preservation and
good cosmetic results should be used
When different modalities are available, one with maximum chance of cure should be used
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Need for RT. ESTRO-HERO estimation
Borras JM et al, Radiother Oncol 2016
Tumor
site
RT
courses
2012
Increase
in number
2025
Increase
in rate
(%)
Breast 396,891 40,524 10.2
Lung 315,197 56,558 17.9
Prostate 243,669 59,493 24.4
Head&Neck 108,194 13,337 12.3
Rectum 99,493 18,314 18.4
Lymphoma 74,852 9871 13.3
Others …………… …………. …………
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5
Improvement in
Clinical Results
Improvement in
Technology 17th E
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• IMRT/IGRT (organ sparing)
• Radiosurgery (brain & body)
• IG-Brachytherapy
• Hadrontherapy (particles)
High Precision Radiotherapy
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Early Stages
(T1, T2 N0)
Nasopharynx
Oropharynx
Larynx
Hypopharynx
Oral cavity
Lip
External Beam RT Linac Brachytherapy Intestitial
Contact
Endocavitary
RT as single modality
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EBRT as single modality
T1 glottic
LC rate: 82-94%
Ultimate LC: 90-96%
Larynx preservation:
83-95%
T2 glottic
LC rate: 61-89%
Ultimate LC: 80-91%
Larynx preservation:
60-82%
Vocal cord
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Brachytherapy as single modality
T1 N0, mobile tongue
LC rate: 85-90%
Ultimate LC: 95%
Low dose rate
High/Pulsed Dose Rate
Oral cavity
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SBRT BRT
SBRT or BRT as boost modality
Nasopharynx 17th ESO-E
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Study
N. patients Follow-up
(months)
Dose (Gy)/
Fractions (n.) Response Toxicity
Vargo, 2015
50 18 40-44 / 5 1-y OS: 40% G3: 6%
Lartigau, 2013
60 11.4 36 / 6 RR: 58.4%
1-y OS: 47.5%
G3: 9%
Unger, 2010
65 26 30 / 5 2-y OS: 33% G4: 4.9%
Roh, 2009 36 17.3 18-40 / 3-5 RR: 80%
2-y OS: 30.9%
G3: 50%
Necrosis: 8%
Voynov, 2006 22 19 10-36 / NA 2-y LC: 26%
2-y OS: 22%
No G4
Orecchia, 1992
16 36 12-46 /2-6 CR: 43.7%
2-y OS: 28%
3-y OS 10%
G3: 32%
G4: 6%
SBRT for recurrent NPC
From: Baliga S et al, SBRT for recurrent head and neck cancer: a critical review, Head & Neck 2017 (modified) 17th E
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Forastiere , JCO 2015 Denaro, Radiother Oncol 2014
Larynx and hypopharynx sites T2N+ T3 and selective T4 (without massive cartilage invasion
and or extension in the surrounding soft tissues) Baseline normal laryngeal function Good performance status Fit for treatment
- No tracheotomy - No vocal cord fixation
Organ and Function Preservation
Who?
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Organ and Function Preservation
Induction CT-RT
1. The addition of induction CT for larynx preservation did not compromise the survival when compared with upfront surgery (up to 68%)
2. Induction CT did not compromise subsequent treatment (either salvage surgery of definitive RT) in terms of tolerance or efficacy. Larynx preservation rate was up to 70%
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Organ and Function Preservation
Concurrent CT-RT
1. Concurrent CT-RT provides the highest larynx preservation rate defined as the larynx in place (up to 83%)
2. Concurrent CT-RT generates a substantial acute toxicity
3. Late toxicity after concurrent CT-RT may compromise the laryngeal function. For QoL only the preservation of a functioning larynx is meaningful 17th E
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Ann Oncol 2017
GSTTC Italian Study Group
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No difference in toxicities, except neutropenia
(8% IC-CCRT versus 1% CCRT; P=0.038)
Compliance to concomitant treatments was not affected by
induction TPF
IC arms better for:
OS (P=0.031) CRs (P=0.0028) PFS (P=0.013) LRC (P=0.036)
Ghi MG et al, Ann Oncol 2017 17th E
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Postoperative management
Risk-adapted strategies
Involved margins N3 disease 2+ invaded nodes Node 3+ cm Extra-capsular extension T4 disease Tumor volume Perineural invasion Perivascular extension Oral cavity primary
RT only (54-60 Gy) Duration (shorter ) Interval (6 weeks) RT-CT (higher risk)
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Interval Surgery - RT
Graboyes EM et al, Cancer 2017
National Cancer Data Base 2006-2014
47,273 H&N patients
55.7% failed to commence PORT within 6 weeks
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Postoperative RT. Larynx
Graboyes EM et al, Cancer 2017
PORT is not associated with improved OS in pT3N0 laryngeal SCC
with negative margins
National Cancer Data Base 2006-2013
1460 pT3-pT4a N0 patients
PORT is associated with improved OS in pT4N0 laryngeal SCC, but despite OS benefit nearly 50% of
patients do not receive standard-of-care PORT 17th E
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Recommendations for CTV selection and delineation in the neck
Node-negative neck: DAHANCA, EORTC, GORTEC, NCIC, RTOG Radiother Oncol 2003 Node-positive neck and PORT: Radiother Oncol 2006 Neck node levels: DAHANCA, EORTC, HKN-PCSG, NCIC CTG, NCRI, RTOG; TROG Radiother Oncol 2014
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T2 SCC of the internal wall of the right piriform sinus
T4a SCC of the glottic larynx
Gregoire V et al, Radiother Oncol 2018
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IMRT is the standard ! 17th E
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Patient set-up
MLC/ MMLC
Export
Dose evaluation
Treatment technique
Targeting
Dose prescription
Contouring Localization
ImageFusion
MRI / PET-CT
Image acquisition
Treatment
Immobilization Device
Imaging Treatment Planning Hardware
CT
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Planning CT 3 weeks into RT
Planning CT Mid course RT
Adapted IMRT. Re-planning
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BTV = Biological Target Volume
IMRT and
Dose
Painting
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Biologically Adapted RT
Gregoire V et al, Lancet Oncol 2012
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Biologically Adapted RT
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IMRT 1. To reduce xerostomia in all naso-, oro-, and
hypo-pharyngeal, laryngeal, oral cavity and unknown primary cancers
2. To reduce ocular toxicities in nasal and paranasal sinus cancer or other sites where the disease is juxtaposed to the optic apparatus
3. To reduce osteoradionecrosis in oral cavity, naso- and oro-pharynx, paranasal sinuses and where significant dose of radiation are required
4. Related to clinical outcomes (LC and OS) there are no study data to support or refuse IMRT over 2D- or 3D-RT in any H&N sites 17th E
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Parotid sparing
(<26 Gy)
3D-CRT
IMRT
To reduce xerostomia
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Constrictor muscles sparing
Swallowing muscles dose-volume parameters are strongly related with
chronic RAD (Radiation Associated Dysphagia)
Alterio D, … R.Orecchia. Contouring of the Pharyngeal Superior Constrictor Muscle (PSMC). A cooperative study of the Italian Association of Radiation Oncology (AIRO) Head and Neck Group. Radiother Oncol 2014
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85% Isodose
2 Gy/die
95% Isodose
2,2 Gy/die
30 fractions
66 Gy Tumor
60 Gy Lymph nodes
Simultaneous Integrated Boost SIB
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Improved survival using IMRT in H&N cancers. A SEER-Medicare analysis
Beadle BM et al, Cancer 2014
IMRT patients
No IMRT patients
Overall Survival
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Radiotherapy de-intensifications
HPV16+ versus HPV16-
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Lassen P et al, Radiother Oncol 2018
815 patients from 4 randomized trials: RTOG 9003, Dahanca 6&9,
RTOG 0129, ARTSCAN
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Lassen P et al, Radiother Oncol 2018
Clear advantage in OS for p16-positive patients, and never
smokers (+22.2% at 10-y)
Small advantage for
never smokers patients also in p16 negative group, but without statistical
significance (+8.4% at 10-y)
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Trial
Phase N. pts Inclusion criteria Schedule
NRG HN-002
II 296 T1-2, N1-2b, or T3, N0-2b
HPV+, OPC
<10 Py
Reduced IMRT dose
(60 Gy)
with/w-out weekly cisplatin
NCT01530997
II 40 T1-3, N0-2c
HPV+, OPSCC
<10 Py or >5y abstinence
IMRT (54-60 Gy)
with weekly cisplatin
ECOG 1308
II 80 Resectable IIIA&B, IVA&B
HPV+, OPSCC
(p-16 high or HPV-16 ISH+)
IC, then response adapted
RT (54 Gy or 66-70 Gy)
with cetuximab
Quarterback III 365 III/IV (M0)
HPV associated
OPSCC/Unknown/NPC
<20 Py / no active smokers
IC with TPF: CR/PR
randomly assigned 2:1
to CBDCA with RT
(56 versus 70 Gy).
Non responders: standard RT
RT de-intensification trials
From: Kelly JR et al, EJC 2016 (modified) 17th E
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Particle Therapy (Hadrons)
X-rays
electron
negative
ions proton
neutron
Helium
Carbon
Argon
Boron
Neon
General Radiation From Lighter to Heavier Particles
Oxygen
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Hadrons versus Photons (X-rays)
Photon beam decreases exponentially with depth in the
irradiated tissues
Hadrons have a finite
range (no exit dose)
Hadrons deposit most
of their radiation energy
in the Braggs peak
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Carotid artery
Optic nerve
Mandibular bone Brain Stem
Main Goal: OARs Sparing
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Comparison of dose distribution between IMRT and IMPT in T4N0 OPSCC
Gregoire V et al, JC0 2015 17th E
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10 – 20 keV/mm = 100 – 200 MeV/cm =
20 – 40 eV/(2 nm)
Radiobiological Effectiveness (C12)
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Up-regulated
oncogenes
Which tumors might benefit of
high LET particles?
Radioresistant
for genetic alteration
Mutated tumor
suppresor genes
Dis-regulated
apoptosis
Radioresistant
for intratumoral
micromilieau
Deprivation
of oxigen
Up-regulated
defense system
High angiogenetic
potential
Radioresistant
for proliferation status
High content
of quiescent
cell clones
Slow
proliferation
activity
Cancer Stem
Cells (CSCs)
Immuno
Modulation
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Bone and Soft Tissue Sarcomas
Carbon ion at Chiba
Local Control over 80% at 5 y
Overall Survival over 60% at 5y
(Kamada, Orecchia …Lancet Oncol, 2015)
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Take Home Message (I)
1. About 75% of patients with H&N SCC benefits from RT as part of their primary treatment or as adjuvant modality
2. Loco-regional control has improved in the last 10-15 years, and these improvements have translated into gains in survival rates
3. As a consequence, a progressive shift has been observed from primary surgery to function-preservation RT
4. Significant progress has been made in improving the QoL of the patients by decreasing the long-term adverse effects of RT, such as xerostomia and swallowing difficulties 17th E
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Take Home Message (II)
5. IMRT is today the standard technique for H&N cancers, with BRT and SBRT available to treat selected cases
6. Increasing interest in particle therapy is justified by
the possibility to spare OARs and to overcame radio-resistance in specific tumor types
7. Molecular signatures on individuals could help in
the next future to properly select patients to be treated by intensifing or de-intensifing therapies
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Molecular signature for H&N RT
There is a tremendous
potential in this era of precision medicine
to apply molecular signature to predict response to various
tumors to RT
Many pathways are known to regulate
radiation sensitivity, and novel markers
are emerging to regulate such
pathways
Pardo-Reoyo S et al, Ann Transl Med 2016 17th E
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