Radiotherapy

in Head & Neck

cancer

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The Goal

1. Higher LR control and survival rates inlimited stage disease

2. Increased survival in locally advanceddisease (improved LR control, reducedprobability of DM and 2nd malignancies)

3. Increased organ preservation in resectableand unresectable tumors

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 (in most patients)- CT+ RT/CT (in selected patients)

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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An example …..

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An example …..

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6

Improvement in

Clinical Results

Improvement in

TechnologyDo not d

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• IMRT/IGRT (organ sparing)

• Radiosurgery (brain & body)

• IG-Brachytherapy

• Particle Therapy (Hadrons)

High Precision Radiotherapy

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Early Stages

(T1, T2 N0)

Nasopharynx

Oropharynx

Larynx

Hypopharynx

Oral cavity

Lip

External Beam RT (EBRT)→

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

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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)

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▪ Larynx and hypopharynx sites

▪ T2N+, and T3

▪ Selective T4 (without massive cartilage invasion and or

extension in the surrounding soft tissues)

▪ Baseline normal laryngeal function

▪ Good performance status

▪ Fit for treatment

▪ Patients’ desires

▪ Experience of the treating physicians

▪ Possibility of adequate follow-up

- No tracheotomy

- No vocal cord fixation

Organ and Function Preservation

Who?

Denaro, Radiother Oncol 2014

Forastiere , JCO 2015

Bonomi, Oral Oncol 2018

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Organ and Function Preservation

Induction CT-RT

1. Induction CT-RT is the preferred treatment approach in Europe

2. Induction CT did not compromise subsequent treatment(salvage surgery or RT) in terms of tolerance or efficacy

3. None of the different induction CT regimens (PF or TPF) hasbeen able to improve survival in larynx preservation programs.Better rate of larynx preservation with TPF (+ 13% in GORTECgroup)

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Organ and Function Preservation

Concurrent CT-RT1. Concurrent CT-RT is the preferred treatment approach in US

2. Concurrent CT-RT provides the highest larynx preservation ratedefined as the larynx in place

3. Concurrent CT-RT generates a substantial acute toxicity (twicehigher than other regimens)

4. Late toxicity after concurrent CT-RT may compromise thelaryngeal function (up to more than 40% of severe toxicity)

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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)Do n

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Interval Surgery - RT

Graboyes EM et al, Cancer 2017

National Cancer Data Base2006-2014

47,273 H&N patients

55.7% failed to commence PORT within 6 weeks

of surgery

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Patient set-up

MLC/ MMLC

Export

Dose evaluation

Treatment technique

Targeting

Dose prescription

ContouringLocalization

ImageFusion

MRI / PET-CT

Image acquisition

Treatment

Immobilization Device

Imaging Treatment Planning Hardware

CT

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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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Recommendations for Neck CTV

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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IMRT is the standard !

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Non-modulated vs modulated RT

CTV

OR

CTV

OR

Conformal with

non-modulated beams-3DCRTConformal with modulated

beams-IMRT

Prescription Dose

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Lesion

Radiation Critical Organs

Multileaf Collimator

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Planning CT 3 weeks into RT

Planning CT Mid course RT

Physically Adapted IMRT

Re-planning

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Biologically Adapted RT

Dose Painting

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IMRT

1. To reduce xerostomia in all naso-, oro-, and hypo-pharyngeal, laryngeal, oral cavity and unknownprimary cancers

2. To reduce ocular toxicities in nasal and paranasalsinus cancer or other sites where the disease isjuxtaposed to the optic apparatus

3. To reduce osteoradionecrosis in oral cavity, naso-and oro-pharynx, paranasal sinuses and wheresignificant dose of radiation are required

4. Related to clinical outcomes (LC and OS) there areno study data to support or refuse IMRT over 2D- or3D-RT in any H&N sites

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Parotid sparing

(<26 Gy)

3D-CRT

IMRT

Prevention of 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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Radiosensitivity in H&N cancer

1. The radiosensitivity index values for patients withH&N cancer is heterogeneous – the differencebetween the most sensitive and most resistantsamples is more than 3 time (less in OP cancer)

2. This variability implies that a uniform strategy isnot always recommended in clinical practice, andthe use of integrating approaches based onindividual difference could improve results

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Molecular signature for H&N RT

There is a tremendous

potential to apply molecular

signature to predict response

to RT

Many pathways are known to

regulate radiation

sensitivity, and novel markers are emerging

Pardo-Reoyo S et al, Ann Transl Med 2016

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Radiotherapy de-intensifications

HPV16+ versus HPV16-

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Trial Phase N.

patients

Inclusion criteria Response

NRG HN-002 II 296 T1-2, N1-2b, or T3, N0-2b

HPV+, OPC

<10 PY

Reduced IMRT dose (60

Gy)

with/without 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/IIIB, IVA/IVB

HPV+, OPSCC

(p-16 high or HPV-16 ISH+)

IC, then response

adapted RT (54 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

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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+

patients, and never

smokers

(+24.2% at 10-y)

• Small advantage

for never smokers

patients also in p16-

patients

(+8.4% at 10-y)

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Particle Therapy (Hadrons)

X-rays

electron

negative

ions

proton

neutronHelium Carbon

ArgonBoronNeon

General RadiationFrom Lighter to Heavier Particles

Oxygen

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Particles versus Photons (X-rays)

▪ Irradiate smaller volume of normal tissues

▪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 what is known as

Braggs peak

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Particles. A new dimension …….

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Carotid artery

Optic nerve

Mandibular boneBrain Stem

Main Goal: OARs Sparing

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10 – 20 keV/mm = 100 – 200 MeV/cm =

20 – 40 eV/(2 nm)

Radiobiological Effectiveness (C12)

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Carbon ion

in Chiba (J)

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Take Home Message (I)

1. About 75% of patients with H&N SCC benefits fromRT as part of their primary treatment or as adjuvantmodality

2. Loco-regional control has improved in the last 10-15years, and these improvements have translated intogains in survival rates

3. As a consequence, a progressive shift has beenobserved from primary surgery to function-preservation RT

4. Significant progress has been made in improving theQoL of the patients by decreasing the long-termadverse effects of RT, such as xerostomia andswallowing difficulties

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Take Home Message (II)

5. IMRT is today the standard technique for H&Ncancers, with BRT and SBRT available to treatspecial cases

6. Increasing interest in particle therapy is justified bythe possibility to spare OARs and to overcameradio-resistance in specific tumor types

7. Molecular signatures on individuals could help inthe next future for properlyselecting patients to betreated by intensifing combinedtherapies and/or de-intensifingapproaches

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Thank You for Your attention !!!!...

roberto.orecchia@ieo.it

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