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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Thank You for all…….

roberto.orecchia@ieo.it 17th ESO-E

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