HEAD & NECK CANCERS - ESMO POCKET GUIDELINE - 2021

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HEAD & NECK CANCERS 2021

ESMO POCKET GUIDELINES
HEAD & NECK

CANCERS
2021
GUIDELINES COMMITTEE
Chair: Giuseppe Curigliano; Deputy Chair: Cristiana Sessa; Steering Committee Members: Christian Buske,
Paolo G. Casali, Nathan Cherny, Nicoletta Colombo, Silke Gillessen, Karin Jordan, Sibylle Loibl, Jean-Pascal
Machiels, Matthias Preusser, Rolf A. Stahel, Arndt Vogel; Subject Editors: Paolo Ascierto, Eric Baudin, Alfredo
Berruti, Andrew Davies, Michel Ducreux, Caroline Even, Karim Fizazi, Francesca Gay, Nicolas Girard, Nadia
Harbeck, Mats Jerkeman, Karin Jordan, James Larkin, Jonathan Ledermann, Natasha Leighl, Erika Martinelli,
Olivier Michielin, Ana Oaknin, Shani Paluch-Shimon, Thomas Powles, Martin Reck, Carla Ripamonti, Daniele
Santini, Florian Scotté, Elizabeth Smyth, Silvia Stacchiotti, Michael Weller; International Coordinator of
Guidelines Adaptation in Asia Pacific: Takayuki Yoshino; Staff: Claire Bramley, Sarah Escuin, Catherine Evans,
Louise Green, Lone Kristoffersen, Svetlana Jezdic, Jennifer Lamarre, Richard Lutz, Keith McGregor, Teodora
Pavlova, George Pentheroudakis, Francesco Rho.
ESMO CLINICAL PRACTICE GUIDELINES

Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx:
EHNS–ESMO–ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Machiels J-P, René Leemans C, Golusinski W, Grau C, Licitra L and Gregoire V, on behalf of the EHNS Executive
Board, ESMO Guidelines Committee and ESTRO Executive Board
Ann Oncol 2020:31(11):1462-75
https://www.annalsofoncology.org/article/S0923-7534(20)39949-X/fulltext
Nasopharyngeal carcinoma: ESMO–EURACAN Clinical Practice Guidelines for diagnosis,
treatment and follow-up
Bossi P, Chan AT, Licitra L, Trama A, Orlandi E, Hui EP, Halámková J, Mattheis S, Baujat B, Hardillo J, Smeele L,
van Herpen C, Castro A and Machiels J-P, on behalf of the ESMO Guidelines Committee and EURACAN
Ann Oncol 2021:32(4):452-65
https://www.annalsofoncology.org/article/S0923-7534(20)43210-7/fulltext
Distributed with support from F. Hoffmann-La Roche Ltd.

F. Hoffmann-La Roche Ltd has not influenced the content of this publication.
2
ESMO POCKET GUIDELINES PROVIDE YOU WITH A CONCISE SUMMARY OF THE
FUNDAMENTAL RECOMMENDATIONS MADE IN THE PARENT GUIDELINES IN AN
EASILY ACCESSIBLE FORMAT.
This quick reference booklet provides you with the most important content of the
ESMO Clinical Practice Guidelines (CPGs) on the management of nasopharyngeal
cancer and squamous cell carcinoma of the oral cavity, larynx, oropharynx
and hypopharynx. Key content includes diagnostic criteria, staging of disease,
treatment plans and follow-up for nasopharyngeal cancer and squamous cell
carcinoma of the oral cavity, larynx, oropharynx and hypopharynx. The ESMO
CPGs on nasopharyngeal cancer and squamous cell carcinoma of the oral cavity,
larynx, oropharynx and hypopharynx are intended to provide you with a set of
recommendations for the best standards of care for nasopharyngeal cancer and
squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx,
using evidence-based medicine. Implementation of ESMO CPGs facilitates
knowledge uptake and helps you to deliver an appropriate quality of focussed care
to your patients.
The approval and licensed indication of drugs mentioned in this pocket guideline
may vary in different countries. Please consult your local prescribing information.
This booklet can be used as a quick reference guide to access key content
on evidence-based management of patients with nasopharyngeal cancer and
squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx.
Please visit http://www.esmo.org or http://oncologypro.esmo.org to view the

full guidelines.
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5-32
SQUAMOUS CELL CARCINOMA OF THE ORAL CAVITY, LARYNX,

OROPHARYNX AND HYPOPHARYNX
DIAGNOSIS AND PATHOLOGY/MOLECULAR BIOLOGY............................................5
Diagnosis..................................................................................................................5
Pathology assessment..............................................................................................6
Molecular biology.....................................................................................................7
STAGING AND RISK ASSESSMENT..........................................................................7
Staging......................................................................................................................7
Pre-treatment risk assessment...............................................................................11
TREATMENT...........................................................................................................12
Management of local/locoregional disease.............................................................12
Management of recurrent and/or metastatic disease..............................................22
PERSONALISED MEDICINE....................................................................................25
FOLLOW-UP............................................................................................................25
SUMMARY RECOMMENDATIONS FOR SQUAMOUS CELL CARCINOMA OF
THE ORAL CAVITY, LARYNX, OROPHARYNX AND HYPOPHARYNX................. 27
33-52
NASOPHARYNGEAL CARCINOMA
DIAGNOSIS AND PATHOLOGY/MOLECULAR BIOLOGY..........................................33
Diagnosis................................................................................................................33
Pathology/molecular biology...................................................................................33
Screening................................................................................................................34
STAGING AND RISK ASSESSMENT........................................................................34
TREATMENT...........................................................................................................37
Management of local/locoregional disease.............................................................37
Management of advanced/metastatic disease.........................................................42
PERSONALISED MEDICINE....................................................................................45
FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP..........................45
SUMMARY RECOMMENDATIONS FOR NASOPHARYNGEAL CARCINOMA......... 48
53-54
GLOSSARY
4
SQUAMOUS CELL CARCINOMA OF THE
ORAL CAVITY, LARYNX, OROPHARYNX AND
HYPOPHARYNX
DIAGNOSIS AND PATHOLOGY/MOLECULAR BIOLOGY
Diagnosis
• The following symptoms should prompt examination for squamous cell
carcinoma of the head and neck (SCCHN): Chronic pain in the throat, persistent
hoarseness, chronic sore tongue or non-healing ulcers or red/white patches in
the mouth, painful or difficulty swallowing and neck masses
• Clinical evaluation should include a history of symptoms, complete physical
examination, including neck palpation and flexible head and neck fibreoptic
endoscopy, performance status (PS), nutritional status with weight assessment,
dental examination, speech and swallowing function and psychosocial evaluation,
as shown in the table below
WORK-UP FOR STAGING AND DIAGNOSIS
STRONGLY
ALTERNATIVE IF INDICATED
RECOMMENDED
• Tumour biopsy
• Medical history • Speech and swallowing
• Physical examination function
including head and • Nutritional status with
General -
neck examination weight assessment
• PS • Social and psychological
• Dental examination evaluation
• Blood test*
• Head and neck CE-CT
and/or MRI
Local and regional
SECTION
• Rigid head and neck - • Teeth extraction†
assessment
endoscopy under
general anaesthesia
Assessment of distant
• FDG–PET • Chest CT -
UPDATE
metastases
•Head and neck •Oesophagoscopy

Second primaries -
endoscopy •Bronchoscopy
*CBC, assessment of liver enzymes, serum creatinine, albumin, coagulation parameters and TSH if RT is foreseen
Ideally to be carried out during the head and neck endoscopy under general anaesthesia if indicated
†
CBC, complete blood count; CE, contrast-enhanced; CT, computed tomography; FDG, [18F]2-fluoro-2-deoxy-D-glucose;
MRI, magnetic resonance imaging; PET, positron emission tomography; PS, performance status; RT, radiotherapy;
TSH, thyroid-stimulating hormone
5
• A complete blood count (CBC), assessment of liver enzymes, serum creatinine,
albumin, coagulation parameters and thyroid-stimulating hormone (TSH) should
be carried out routinely
• Pathological confirmation is mandatory
• Stomatological evaluation with tooth extraction when required is also usually
carried out
• Systematic bronchoscopy and oesophagoscopy are not advised but should be
driven by symptoms and/or other diagnostic findings
• Contrast-enhanced (CE) computed tomography (CT) scan and/or magnetic
resonance imaging (MRI) are mandatory to assess the primary tumour
and regional lymph nodes as well as cartilage invasion for laryngeal or
hypopharyngeal cancer
• Chest imaging is important to assess the presence of distant metastases in
high-risk tumours or a second lung primary in heavy smokers
As a minimum, a chest CT should be carried out
• [18F]2-fluoro-2-deoxy-D-glucose (FDG)–positron emission tomography (PET)
plus CE-CT has a higher sensitivity than the separate modalities
• FDG–PET is also recommended for the work-up of a carcinoma of unknown
primary to direct specific mucosal biopsy and to evaluate the neck response
to radiotherapy (RT) or chemoradiotherapy (CRT) or in cases of suspected
recurrence
Pathology assessment
• SCCHN should be classified according to the World Health Organization (WHO)
4th edition classification
• Human papillomavirus (HPV) evaluation using p16 immunohistochemistry (IHC)
should be carried out on all patients with newly diagnosed oropharyngeal
squamous cell carcinoma (SCC)
• For neck metastases of unknown origin, p16 status should also be assessed,
and in case of positivity, another specific HPV test [e.g. DNA, RNA or in situ
hybridisation (ISH)] is required for confirmation
• In case of neoplastic lymph node(s) with an unknown primary, ISH-determined
Epstein-Barr-encoded RNA for Epstein-Barr virus status is required to exclude
nasopharyngeal carcinoma
• Determination of p16 status is not mandatory for non-oropharyngeal cancers of
the head and neck
6
• Pathological assessment of surgical specimens should include the size of
tumour, growth pattern, depth of invasion (DOI) for oral cavity cancer, total
number of lymph nodes removed, number of invaded lymph nodes and their
location, presence of extracapsular nodal extension, perineural and lymphatic
infiltration and the surgical margins [i.e. resection with no residual tumour at the
margin (R0) and resection with microscopic residual tumour at the margin (R1)]
• For recurrent and/or metastatic SCCHN, tumour programmed death-ligand 1
(PD-L1) expression should be evaluated by an approved PD-L1 test, either as the
tumour proportion score (TPS) or the combined positive score (CPS)
CPS is needed to define first-line treatment strategies of recurrent and/or
metastatic disease
Molecular biology
• Tobacco- and/or alcohol-induced SCCHN and HPV-positive oropharyngeal cancer
differ significantly at both a clinical and a molecular level
• For HPV-negative SCCHN, the two most frequent genomic alterations are TP53
and CDKN2A
• 56% of HPV-positive oropharyngeal cancers harbour PI3KCA amplifications/
mutations, but other genetic alterations are rare
• Mesenchymal, basal, classical and atypical subgroups have been defined based
on gene expression profiles
• HPV-positive SCCHN can be subclassified into different gene profile groups,
some of which are prognostic
• However, the current management of these patients is not based on genomic
alterations or gene expression profiles
STAGING AND RISK ASSESSMENT
Staging
• SCCHN should be staged according to the Union for International Cancer Control
(UICC) tumour-node-metastasis (TNM) Cancer Staging Manual 8th edition, as
shown in the table on the next page
7
STAGING AND STAGE GROUPING ACCORDING TO THE UICC TNM 8TH EDITION
FOR SCCHN
PRIMARY TUMOUR (T)

TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ
Lip and oral cavity

T1 Tumour ≤ 2 cm in greatest dimension and ≤ 5 mm DOI*
Tumour ≤ 2 cm in greatest dimension and > 5 mm but not > 10 mm DOI or tumour > 2 cm
T2
but ≤ 4 cm in greatest dimension and DOI ≤ 10mm
T3 Tumour > 4 cm in greatest dimension or > 10 mm DOI
Tumour invades through cortical bone, inferior alveolar nerve, floor of mouth or skin (of the
T4a (lip)
chin or the nose)
Tumour invades through the cortical bone of the mandible or maxillary sinus, or invades
T4a (oral cavity)
the skin of the face
T4b Tumour invades masticator space, pterygoid plates or skull base, or encases internal carotid
(lip and oral cavity) artery
Larynx cancer: Supraglottis

T1 Tumour limited to one subsite of supraglottis with normal vocal cord mobility
Tumour invades mucosa of more than one adjacent subsite of supraglottis or glottis or
T2 region outside the supraglottis (e.g. mucosa of base of tongue, vallecular, medial wall of
piriform sinus) without fixation of the larynx
Tumour limited to larynx with vocal cord fixation and/or invades of the following: Postcricoid
T3
area, pre-epiglottic space, paraglottic space and/or inner cortex of thyroid cartilage
Tumour invades through the thyroid cartilage and/or invades tissues beyond the larynx,
e.g. trachea, soft tissues of the neck including deep/extrinsic muscle of the tongue
T4a
(genioglossus, hyoglossus, palatoglossus and styloglossus), strap muscles, thyroid or
oesophagus
T4b Tumour invades prevertebral space, encases carotid artery or mediastinal structures
Larynx cancer: Glottis

Tumour limited to vocal cord(s) (may involve anterior or posterior commissure) with normal
mobility
T1
• T1a – Tumour limited to one vocal cord
• T1b – Tumour involves both vocal cords
T2 Tumour extends to supraglottis and/or subglottis and/or with impaired vocal cord mobility
8
Tumour limited to larynx with vocal cord fixation and/or invades paraglottic space and/or
T3
inner cortex of the thyroid cartilage
Tumour invades through the outer cortex of the thyroid cartilage and/or invades tissues
beyond the larynx, e.g. trachea, soft tissues of the neck including deep/extrinsic muscle of
T4a
the tongue (genioglossus, hyoglossus, palatoglossus and styloglossus), strap muscles,
thyroid or oesophagus
Larynx cancer: Subglottis

T1 Tumour limited to subglottis
T2 Tumour extends to vocal cord(s) with normal or impaired mobility
T3 Tumour limited to larynx with vocal cord fixation
Tumour invades cricoid or thyroid cartilage and/or invades tissues beyond the larynx,
e.g. trachea, soft tissues of the neck including deep/extrinsic muscle of the tongue
T4a
(genioglossus, hyoglossus, palatoglossus and styloglossus), strap muscles, thyroid or
oesophagus
Hypopharynx
T1 Tumour limited to one subsite of hypopharynx or ≤ 2 cm in greatest dimension
Tumour invades more than one subsite of hypopharynx or an adjacent site, or measures
T2
> 2 cm but ≤ 4 cm in greatest dimension, without fixation of hemilarynx
Tumour > 4 cm in greatest dimension, or with fixation of hemilarynx or extension to
T3
oesophagus
Tumour invades any of the following: Thyroid/cricoid cartilage, hyoid bone, thyroid gland,
T4a
oesophagus, central compartment soft issue†
T4b Tumour invades prevertebral fascia, encases carotid artery or invades mediastinal structures
p16-negative oropharyngeal cancer

T1 Tumour ≤ 2 cm in greatest dimension
T2 Tumour > 2 cm but ≤ 4 cm in greatest dimension
T3 Tumour > 4 cm in greatest dimension or extension to lingual surface of epiglottis
Tumour invades any of the following: Larynx‡, deep/extrinsic muscle of tongue

T4a (genioglossus, hyoglossus, palatoglossus, and styloglossus), medial pterygoid, hard palate
or mandible
Tumour invades any of the following: Lateral pterygoid muscle, pterygoid plates, lateral
T4b
nasopharynx, skull base; or encases carotid artery
9
p16-positive oropharyngeal cancer
T1 Tumour ≤ 2 cm in greatest dimension
T2 Tumour > 2 cm but ≤ 4 cm in greatest dimension
T3 Tumour > 4 cm in greatest dimension or extension to lingual surface of epiglottis
Tumour invades any of the following: Larynx‡, deep/extrinsic muscle of tongue

(genioglossus, hyoglossus, palatoglossus and styloglossus), medial pterygoid, hard palate,
T4
mandible, lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, skull base; or
encases carotid artery
REGIONAL LYMPH NODES (N)
Larynx, lip and oral cavity, hypopharynx and p16-negative oropharyngeal cancer
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
Metastasis in a single ipsilateral lymph node ≤ 3 cm in greatest dimension without

N1
extranodal extension
Metastasis described as:
• N2a – Metastasis in a single ipsilateral lymph node > 3 cm but ≤ 6 cm in greatest
dimension without extranodal extension
N2 • N2b – Metastasis in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension
without extranodal extension
• N2c – Metastasis in bilateral or controlateral lymph nodes, none > 6 cm in greatest
dimension without extranodal extension
N3a Metastasis in a lymph node > 6 cm in greatest dimension without extranodal extension
N3b Metastasis in a single or multiple lymph nodes with clinical extranodal extension§

NX Regional lymph nodes cannot be assessed
N1 Unilateral metastasis in lymph node(s), all ≤ 6 cm in greatest dimension
N2 Controlateral or bilateral metastasis in lymph node(s), all ≤ 6 cm in greatest dimension
N3 Metastasis in lymph node(s) > 6 cm in dimension
DISTANT METASTASIS (M)

M0 No distant metastasis
M1 Distant metastasis
10
DISEASE STAGE
Oral cavity, lip, larynx, hypopharynx and p16-negative oropharyngeal cancer

0 Tis N0 M0
I T1 N0 M0
II T2 N0 M0
T3 N0 M0
III
T1, T2, T3 N1 M0
T1, T2, T3, N2 M0
IVA
T4a N0, N1, N2
T4b Any N M0
IVB
Any T N3 M0
IVC Any T Any N M1

0 Tis N0 M0
I T1, T2 N0, N1 M0
T1, T2 N2 M0
II
T3 N0, N1, N2 M0
T1, T2, T3 N3 M0
III
T4 Any M0
IV Any T Any N M1
*Superficial erosion alone of bone/tooth socket by gingival primary is not sufficient to classify a tumour as T4a
†
Central compartment soft tissue includes prelaryngeal strap muscles and subcutaneous fat
‡
Mucosal extension to lingual surface of epiglottis from primary tumours of the base of the tongue and vallecula does not
constitute invasion of the larynx
§
The presence of skin involvement or soft tissue invasion with deep fixation/tethering to underlying muscle or adjacent
structures or clinical signs of nerve involvement is classified as clinical extranodal extension
DOI, depth of invasion; SCCHN, squamous cell carcinoma of the head and neck; TNM, tumour-node-metastasis; UICC, Union for
International Cancer Control
Brierley JD et al, eds. TNM Classification of Malignant Tumours, 8th edition. Oxford: John Wiley & Sons, Inc. 2016, Reprinted with
permission from John Wiley & Sons, Ltd
Pre-treatment risk assessment

• Treatment proposals should integrate objective tumour parameters and patient
parameters
• In addition to locoregional staging, patients should undergo evaluation of their
nutritional status, comorbidities, cardiopulmonary and renal function, frailty index
(geriatric patients), and psychological, social and dental status, with rehabilitation
in case of foreseen RT
11
• In case of significant malnutrition (more than 10% weight loss during the 6
months prior to diagnosis), enterally administered nutritional improvement is
highly recommended prior to treatment initiation
• The optimal treatment strategy must be discussed in a multidisciplinary team
(MDT), including personnel involved in diagnosis, treatment and treatment
support
• Patients should be treated at high-volume facilities, as this has been reported as
a strong and significant prognostic factor
TREATMENT
Management of local/locoregional disease
• Proposed management strategies for oral cavity, laryngeal, oropharyngeal and
hypopharyngeal cancers are shown in the figures on the next pages
12
MANAGEMENT OF ORAL CAVITY CANCER (STAGE I-IVB), EXCLUDING LIP CARCINOMA
Oral cavity cancer (excluding lip carcinoma)
cT3-4a cN0-3 cM0

cT1-2 cN0 cM0 cT4b and/or unresectable lymph nodes cM0
cT1-4a cN1-3 cM0
Standard: Standard: Options:

• Surger y (T and N*) followed by postoperative • Surgery (T and N) followed by postoperative RT • Concomitant CRT (T and N)
RT or CRT if indicated or CRT if indicated • Induction ChT followed by RT or CRT for
responders (T and N)
Options: Option: • Palliative treatment: Systemic
• Radical RT (T and N) • Definitive CRT (T and N) (contraindications to ChT/immunotherapy and/or palliative RT
• Brachytherapy for primary (selected T1) surgery, including functional unresectability) and/or BSC
*If DOI < 10 mm, sentinel lymph node biopsy is a valid option; if DOI < 5 mm and cT1N0, active surveillance of the neck is a valid option
BSC, best supportive care; ChT, chemotherapy; CRT, chemoradiotherapy; DOI, depth of invasion; M, metastasis; N, node; RT, radiotherapy; T, tumour
13
14
MANAGEMENT OF LARYNGEAL CANCER (STAGE I-IVB)
Larynx cancer
cT1-3 cN0-3 cM0* cT1-2 cN2-3 cM0, cT3b cN0-3 cM0 cT4a cN0-3 cM0 cT4b cN0-3 cM0
Standard: Standard: Standard: Options:

• Conservative (laser) surgery • Concomitant CRT (T and N) • Surgery (T and N) followed by RT or • Induction ChT followed by RT
(T and N**) followed by RT • If total laryngectomy is necessary, CRT (T and N)
or CRT if indicated concomitant CRT (T and N) or • Concomitant CRT (T and N)
• RT (T1-2, N0) (T and N***) or CRT induction ChT followed by (i) RT Option: • Palliative treatment: Systemic
(T3 or N1-3****) (T and N) (T and N) in case of complete or • Concomitant CRT (T and N) ChT/immunotherapy and/or
partial response after induction palliative RT and/or BSC
or (ii) surgery in case of stable or
progressive disease after induction
Option:
• Surgery (T and N) and lymph node
dissection followed by RT or CRT if
indicated
*Not requiring total laryngectomy

**Requiring total laryngectomy
***cT1-2N0 glottic cancer does not require neck dissection or neck RT
****Altered fractionation (accelerated or hyperfractionated) RT is a valid option for selected T3 or T3N1
BSC, best supportive care; ChT, chemotherapy; CRT, chemoradiotherapy; M, metastasis; N, node; RT, radiotherapy; T, tumour
MANAGEMENT OF OROPHARYNGEAL CANCER (P16-NEGATIVE STAGE I-IVB;
P16-POSITIVE STAGE I-III)
Oropharyngeal cancer p16-negative or p16-positive
cT1-2 cN0-N1 cM0 cT3-4 cN0 cM0, cT1-4 cN1-3 cM0
Standard: Standard:
• RT* (T and N) • Concomitant CRT (T and N)**
• Transoral surgery (T and N)
followed by RT or CRT if indicated Option:
• Surgery (T and N) followed by RT or
CRT if indicated
*Altered fractionation (accelerated or hyperfractionated) RT is a valid option for T1-N1, T2-N0 or T2-N1
**Altered fractionation (accelerated or hyperfractionated) RT is a valid option for T1-N1 or T2-N1
CRT, chemoradiotherapy; M, metastasis; N, node; RT, radiotherapy; T, tumour
15
16
MANAGEMENT OF HYPOPHARYNGEAL CANCER (STAGE I-IVB)
Hypopharyngeal cancer
cT1-2 cN0 cM0 cT1-2 cN1-3 cM0, cT3 cN0-3 cM0 cT4a cN0-3 cM0 cT4b cN0-3 cM0
Larynx-preserving surgery feasible
Standard: Standard: Standard: Options:

• RT (T and N) • Concomitant CRT (T and N) • Surgery (T and N) followed by RT or • Induction ChT followed by RT for
• Conservation larynx surgey (T and N) • If laryngectomy necessary, CRT if indicated responders (T and N)
followed by RT or CRT if indicated concomitant CRT (T and N) or • Concomitant CRT (T and N)
induction ChT followed by (i) RT Options: • Palliative treatment: Systemic
(T and N) in case of complete or • CRT (T and N) ChT/immunotherapy and/or
partial response after induction • Induction ChT followed by (i) RT palliative RT and/or BSC
or (ii) surgery (T and N) in case of (T and N) in case of complete or
stable or progressive disease after partial response after induction or (ii)
induction surgery (T and N) in case of stable or
progressive disease after induction
Option:
• Surgery (T and N) followed by RT or
CRT if indicated
BSC, best supportive care; ChT, chemotherapy; CRT, chemoradiotherapy; M, metastasis; N, node; RT, radiotherapy; T, tumour
• In the case of RT, all patients should be treated with intensity-modulated
RT (IMRT) or volumetric modulated arc therapy (VMAT)
• Treatment delays should be avoided or compensated
• Consensus guidelines have been published for the optimal selection of node
levels and for the delineation of tumour target volumes
• There are no randomised clinical trial data available to recommend the routine
use of intensity-modulated proton therapy
Early-stage disease
• In early-stage disease (T1-2N0 oral cavity, laryngeal, hypopharyngeal and
p16-negative oropharyngeal cancer or T1-2N0 p16-positive oropharyngeal
cancer), conservative surgery or RT (external beam or brachytherapy for selected
stage I oropharyngeal or oral cavity subsites) give similar locoregional control
The choice should be based on assessment of functional outcome and
treatment morbidity, along with institute and patient preference
Single-modality treatment should be used as much as possible
Surgery
• Minimally invasive surgical treatments, including transoral laser microsurgery
(TLM) and transoral robotic surgery (TORS), offer the potential for organ
preservation with less functional morbidity than open surgery and often less
long-term toxicity than RT, providing the extent of resection does not jeopardise
functional outcome
This is especially relevant given the increasing incidence of HPV-positive
SCCHN as these patients tend to be younger and have a better prognosis
• The ability of functional organ preservation to improve functional outcomes and
quality of life (QoL) remains to be confirmed
• Transoral surgery is usually recommended as a single modality for oral cavity,
oropharyngeal and laryngeal lesions, the technique depending on tumour location
and patient-related factors
• For oropharyngeal cancer, oncological outcomes with TORS are comparable to
those with open surgery and (C)RT
The use of TORS does not obviate the need for postoperative RT in some cases
• TLM is a current standard of care for early glottic cancers, but TORS has been
used to treat early-stage disease
• With the exception of T1-2 glottic cancer, ipsilateral selective neck dissection or
sentinel node biopsy is recommended for cT1-2 SCCHN tumours treated with
primary surgery
17
RT
• Early-stage disease can be treated by RT alone without the use of concomitant or
induction ChT
• For stage I disease, a standard fractionation regimen with a primary tumour dose
ranging from 66 to 70 Gy, depending on the tumour volume and location, is
recommended
• For stage II disease, either hyperfractionation with a slightly higher total dose
(e.g. 80.5 Gy delivered in 70 fractions of 1.15 Gy twice daily over 7 weeks) or
moderately accelerated RT with a similar RT dose (e.g. 66-70 Gy delivered in
33-35 fractions of 2 Gy over 5.5-6 weeks) are recommended
Such regimens could also be offered to patients with T1 or T2 tumours and
neck disease with a single positive lymph node of < 3 cm
• Except for T1 glottic laryngeal tumours, prophylactic nodal RT is required up
to an equivalent dose of 50 Gy delivered in fractions of 2 Gy; in case of a single
positive lymph node of < 3 cm, the RT dose should be increased to 70 Gy
• Altered fractionation RT increases acute grade 3-4 mucositis and the need for a
feeding tube during RT
• There are no data to suggest that the total RT dose can be decreased in
p16-positive oropharyngeal tumours
• No data are available to guide treatment between minimally invasive surgery or
RT for node negative p16-positive T1 or T2 tumours
• Brachytherapy remains an option for selected stage I oral cavity and
oropharyngeal tumours, although its use is in decline
Locally advanced disease
• Standard options for locally advanced disease (stage III or IV oral cavity,
larynx, hypopharynx and p16-negative oropharyngeal cancer, or T3-4/N0-3 and
T0-4/N1-3 p16-positive oropharyngeal cancer) are surgery plus adjuvant (C)RT
or primary CRT alone
• The surgical option includes reconstruction plus risk-adapted postoperative RT
or CRT
• Primary combined concomitant CRT is the standard treatment in non-resectable
patients and for resectable patients when the anticipated functional outcome
and/or the prognosis is so poor that mutilating surgery is not justified
18
Surgery
• Primary surgical treatment is recommended for T3/T4 oral cavity and T4
laryngeal cancers and also for advanced hypopharyngeal cancers, especially with
laryngeal cartilage invasion (i.e. stage T4) or a non-functional larynx
• Surgery can be used for advanced HPV-positive and -negative oropharyngeal
lesions if RT is contraindicated
• For oral cavity cancers, wide surgical excision followed by appropriate
reconstruction needs to be employed
• During total laryngopharyngectomy, the pharyngeal mucosa may need reinforcing
or patching with a free soft tissue flap or a pedicled flap
• Smaller oropharyngeal lesions may be resected transorally but larger ones may
require a mandibular swing approach
• Surgically treated tumours will generally require postoperative RT or CRT
• When the patient has a relatively small primary tumour but a large neck mass,
the appropriate treatment must be decided by an MDT
• Except for oral cavity cancer, a primary non-surgical option will usually be
chosen, with surgery reserved for salvage treatment; occasionally, neck surgery
before CRT may be considered
Concomitant CRT
• For locally advanced disease, the use of concomitant CRT has resulted in greater
locoregional control and improved overall survival (OS) compared with RT alone,
irrespective of tumour location in the oral cavity, pharynx or larynx
• Cisplatin-based RT, with a total dose of ≥ 200 mg/m2 cisplatin, is recommended
• Standard fractionation and altered fractionation regimens both provide benefits
• With accelerated RT (i.e. 70 Gy in 6 weeks), two courses of cisplatin (100 mg/m2)
are equivalent to three delivered in a 7-week RT regimen, and there is the
advantage of improved ChT compliance
• For fit patients, 3-weekly cisplatin [at 100 mg/m2 given on days 1, 22 and 43
of concomitant RT (70 Gy)] is superior to weekly cisplatin (30 mg/m2) and is
preferred to weekly cisplatin at a dose of 40 mg/m2
• Platinum combined with 5-fluorouracil (5-FU) is a valid option in patients who
cannot tolerate high-dose cisplatin
• RT with concomitant cetuximab has demonstrated improved locoregional control,
progression-free survival (PFS) and OS compared with RT alone
• In patients with p16-positive oropharyngeal SCCHN, RT plus cetuximab was
associated with a shorter OS than RT plus cisplatin
19
• In patients with locally advanced, HPV-negative tumours, CRT is recommended,
with cetuximab reserved for patients considered unfit for platinum-based CRT
Altered fractionation RT should be considered since this improves survival
• Cetuximab did not improve OS or PFS when given with concomitant 3-weekly
cisplatin and RT in patients with locally advanced, stage III and IV SCCHN
• Induction ChT followed by concomitant CRT for non-laryngeal or hypopharyngeal
tumours has not been shown to be superior to concomitant CRT alone
• Omitting concomitant ChT or replacing ChT with cetuximab in patients with
p16-positive oropharyngeal SCC is not endorsed
Induction ChT
• Of the two validated approaches for larynx preservation, concomitant CRT is
associated with higher preservation rates than induction ChT (three courses)
followed by RT alone, but survival is similar
• The use of induction ChT with a platinum-based combination has been
associated with organ preservation in patients with locally advanced laryngeal
or hypopharyngeal SCCHN who would require a total laryngectomy or
pharyngolaryngectomy
• Taxane/platinum/5-FU (TPF) is superior to platinum/5-FU and is now the standard
induction ChT regimen
• Organ preservation with induction ChT does not improve OS compared with
surgery, although there tends to be a reduction in distant metastasis
• Induction ChT followed by concomitant CRT has not been shown to improve
outcome and can have substantial overall toxicity
• Not all patients with locally advanced laryngeal or hypopharyngeal cancer should
be offered induction ChT
Patients with massive larynx cartilage invasion (T4a), extra-laryngeal extension
(T4a) or with severely impaired laryngeal function should be excluded and
offered upfront surgery
• Induction ChT is not recommended outside of a laryngeal-preservation strategy
and the standard regimen is concomitant CRT with high-dose (100 mg/m2)
cisplatin when a non-surgical approach is preferred
Neck dissection after CRT
• In patients with nodal disease treated by RT or concomitant CRT, a surveillance
policy in cases of negative FDG–PET and normal size lymph nodes at 12 weeks
post-CRT has been validated
• The evaluation of FDG–PET response can be challenging, so the five-point scale
(Hopkins Criteria) to assess response is recommended
20
Postoperative (C)RT
• When a surgical option is preferred as the primary treatment modality,
postoperative RT may be required to decrease the risk of locoregional recurrence
• Locoregional recurrence risk factors include pT3-4, positive margin (tumour
≤ 1 mm from the margin), close resection margin (between 1 and 5 mm),
perineural infiltration, lymphovascular spread, > 1 invaded lymph node and the
presence of extracapsular nodal infiltration
These have been established mainly for oral cavity cancers; lesser distance to
the margin at other sites is often appropriate
• For patients with one or more of these risk factors, postoperative RT up to 58 Gy
(one risk factor only) or 63-64 Gy (several risk factors) has been validated
• For patients with only one lymph node invaded without other adverse features,
postoperative RT is optional provided at least 15 lymph nodes have been
analysed
• For patients with an R1 resection and extracapsular spread, concomitant CRT
(66 Gy) with high-dose cisplatin (100 mg/m2 every 3 weeks) improved OS
compared with the same dose of RT alone
• Weekly cisplatin (40 mg/m2) plus RT has been shown to be non-inferior to
high-dose cisplatin (100 mg/m2) plus RT for postoperative patients with high-risk
SCCHN
• Postoperative RT should be started within 6-7 weeks after surgery and/or the treatment
regimen of surgery and postoperative RT should be delivered within 11 weeks
Unknown primary
• The diagnostic work-up includes an FDG–PET, head and neck imaging (preferably
MRI), and a panendoscopy with bilateral tonsillectomy and a mucosectomy of the
base of the tongue in case of HPV-positive disease
• For p16-positive SCC, HPV status should be confirmed with a specific HPV (DNA,
RNA or ISH) test
• The treatment of HPV-positive and -negative disease is the same and comprises
primary surgery (neck dissection) alone or followed by RT or CRT (based on the
same postoperative risk factors as other SCCHN subsites) or primary RT or CRT
followed by neck dissection for residual disease
• Patients with pN1 disease and no other risk factors do not require postoperative
RT if ≥ 15 nodes have been analysed
• Total mucosal RT is associated with significant morbidity and is not
recommended
• Oropharynx RT can be considered as an option in some cases
21
Management of recurrent and/or metastatic disease
• Management strategies for recurrent and/or metastatic SCCHN are shown in the
figure on the next page
22
MANAGEMENT OF RECURRENT AND/OR METASTATIC DISEASE NOT AMENABLE TO CURATIVE RT OR SURGERY
Metastatic or recurrent/persistent disease not amenable to curative RT or surgery
Pretreated with platinum- Pretreated with platinum-

No platinum-based ChT No platinum-based ChT during No platinum-based ChT during
based ChT within the last based ChT within the last
during the last 6 months and the last 6 months and PD-L1 the last 6 months and
6 months and 6 months and with prior
PD-L1-positive tumour assessment not carried out PD-L1-negative tumour
immunotherapy-naive immunotherapy
Standard: Standard: Standard: Standard: Option:

• Pembrolizumab monotherapy • Pembrolizumab plus • Platinum/5-FU/cetuximab • Nivolumab or pembrolizumab • Taxane or methotrexate or
• Pembrolizumab plus platinum/5-FU cetuximab and/or BSC
Options: Option:
platinum/5-FU Options: • Pembrolizumab plus • Taxane or methotrexate
Options: • Platinum/5-FU/cetuximab platinum/5-FU or cetuximab and/or BSC
• Platinum/5-FU/cetuximab if contraindication to • TPeX if contraindication to
if contraindication to immunotherapy and fit for • Methotrexate or taxane or immunotherapy
immunotherapy and fit for platinum-based therapy cetuximab and/or BSC in
platinum-based therapy case of contraindication to
• Methotrexate or taxane immunotherapy and unfit for
• Methotrexate or taxane or cetuximab and/or BSC platinum-based therapy
or cetuximab and/or BSC if contraindication to
if contraindication to immunotherapy and unfit for
immunotherapy and unfit platinum-based therapy
for platinum-based therapy
5-FU, 5-fluorouracil; BSC, best supportive care; ChT, chemotherapy; CRT, chemoradiotherapy; M, metastasis; N, node; PD-L1, programmed death-ligand 1; RT, radiotherapy; T, tumour;
TPeX, cisplatin/docetaxel/cetuximab
23
• In selected patients with oligometastatic disease (OMD) at diagnosis, local
and/or regional treatment (with surgery or RT) can be considered for treatment
with curative intent, especially after a response to upfront systemic treatment
• For patients with a high burden of distant metastases (e.g. more than two distant
sites, mainly visceral involvement), starting systemic treatment is a priority and
locoregional treatment should be carried out only if symptoms occur
• Patients with local or locoregional recurrence should be referred to an MDT at a
reference tertiary centre
• For patients with a good PS and an early-stage laryngeal recurrence occurring
> 2 years after primary treatment, salvage surgery is associated with a reasonable
oncological outcome
Patients with a poor PS and a locally advanced oropharyngeal or
hypopharyngeal SCC can receive palliative local or systemic treatment
• Two different approaches are validated for patients with locoregional relapse not
amenable to locoregional salvage treatment and/or with distant metastases
A ‘chemo-free’ approach with pembrolizumab monotherapy in patients with
CPS ≥ 1 SCCHN, especially when a rapid tumour shrinkage is not needed
The combination of pembrolizumab and ChT (cisplatin or carboplatin plus
5-FU), independent of PD-L1 status, particularly in symptomatic patients or
when a rapid tumour shrinkage is needed
• It is not known if platinum/5-FU/pembrolizumab improves survival compared
with platinum (cisplatin or carboplatin)/5-FU/cetuximab (EXTREME regimen) in
patients with SCCHN not expressing PD-L1
• The Food and Drug Administration (FDA) has approved pembrolizumab in
combination with ChT as first-line treatment regardless of PD-L1 expression and
pembrolizumab alone for patients with PD-L1-expressing tumours (CPS ≥ 1)
• The European Medicines Agency (EMA) has approved pembrolizumab with or
without ChT only for patients with a CPS ≥ 1
• EXTREME is EMA-approved as a first-line treatment for patients with recurrent or
metastatic SCCHN and is the standard of care for patients with contraindications
to anti-programmed cell death protein 1 (PD-1) inhibitors and in patients with a
tumour not expressing PD-L1
Cisplatin/docetaxel/cetuximab (TPeX) can be considered an alternative to
EXTREME for some patients [e.g. in cases of dihydropyrimidine dehydrogenase
(DPD) deficiency]
• EXTREME can also be considered as a second-line treatment after progression
on an immune checkpoint inhibitor (ICI) in fit patients considered eligible for
platinum-based ChT
24
• DPD testing is recommended before initiating 5-FU
• For patients who progress within 6 months of platinum therapy
Nivolumab is both FDA- and EMA-approved
Pembrolizumab is also FDA-approved and has received EMA approval for use in
patients whose tumours express PD-L1 with a TPS of ≥ 50%
• After progression on platinum-based ChT and anti-PD-1 inhibitors, no standard
of care exists
• Cetuximab is approved by the FDA after platinum failure
• Taxanes, with or without cetuximab and/or methotrexate, are frequently used
after platinum failure, although no randomised trials have demonstrated their
benefit in this setting
PERSONALISED MEDICINE
• Opportunities for personalised medicine in SCCHN are shown in the table below
PERSONALISED MEDICINE IN SCCHN
BIOMARKER METHOD VALIDATED USE
1. Surrogate marker for HPV-induced oropharyngeal
p16 p16 IHC cancer
2. Prognostic factor for oropharyngeal cancer
First-line recurrent/metastatic disease to identify
PD-L1 PD-L1 IHC (FDA-approved test) patients that may benefit from pembrolizumab
monotherapy
FDA, Food and Drug Administration; HPV, human papillomavirus; IHC, immunohistochemistry; PD-L1, programmed death-ligand
1; SCCHN, squamous cell carcinoma of the head and neck
• HPV-induced oropharyngeal cancer has a better prognosis than HPV-negative

SCCHN, but current treatment strategies are the same
• The efficacy of pembrolizumab or nivolumab is higher in patients with
PD-L1-expressing tumours
• PD-L1 staining (CPS) for recurrent/metastatic SCCHN is recommended
FOLLOW-UP
• Follow-up should involve the whole MDT
• Clinical follow-up, including a head and neck examination by flexible endoscopy,
should be carried out every 2-3 months during the first 2 years, every 6 months
for years 3-5 and annually thereafter
• For locally advanced disease, head and neck imaging is recommended 3 months
after the primary treatment to assess the patient status and to have a baseline
post-treatment imaging assessment
25
• FDG–PET/CT is recommended 3 months after CRT for patients with node-positive
disease to assess the necessity of neck dissection; otherwise, imaging should
be carried out if symptoms occur or in case of abnormalities found at the clinical
examination
• For patients treated with RT, daily teeth fluorination, dental evaluation every
6 months and yearly TSH dosage are recommended
• Tobacco and alcohol withdrawal counselling and psychological support are
recommended
• Prevention and screening for other cancers sharing the same risk factors (i.e.
lung cancer in smokers, cervical cancer, etc.) should be carried out according to
their respective guidelines
26
Diagnosis
• Clinical evaluation should include a history of symptoms, complete physical
examination, including neck palpation and flexible head and neck fibreoptic
endoscopy, PS, nutritional status with weight assessment, dental examination,
speech and swallowing function and psychosocial evaluation
• A CBC, assessment of liver enzymes, serum creatinine, albumin, coagulation
parameters and TSH should be carried out routinely
• Pathological confirmation is mandatory
• Stomatological evaluation with tooth extraction when required is also usually
carried out
• CE-CT scan and/or MRI are mandatory to assess the primary tumour
and regional lymph nodes as well as cartilage invasion for laryngeal or
hypopharyngeal cancer
• As a minimum, a chest CT should be carried out
• FDG–PET is recommended for the work-up of a carcinoma of unknown primary
to direct specific mucosal biopsy and to evaluate response to RT or CRT or in
cases of suspected recurrence
Pathology assessment
• SCCHN should be classified according to the WHO 4th edition classification
• HPV evaluation using p16 IHC should be carried out on all patients with newly
diagnosed oropharyngeal SCC
• For neck metastases of unknown origin, where p16 status is positive, another
specific HPV test is required for confirmation
• Pathological assessment of surgical specimens should include the size of tumour,
growth pattern, DOI for oral cavity cancer, total number of lymph nodes removed,
number of invaded lymph nodes and their location, presence of extracapsular
nodal extension, perineural and lymphatic infiltration and the surgical margins
• For recurrent and/or metastatic SCCHN, tumour PD-L1 expression should be
evaluated by an approved PD-L1 test (TPS or CPS)
27
Molecular biology
• The current management of patients with SSCHN is not based on genomic
alterations or gene expression profiles
Staging
• SCCHN should be staged according to the UICC TNM Cancer Staging Manual
8th edition
Pre-treatment risk assessment
• Treatment proposals should integrate objective tumour parameters and patient
parameters
• The optimal treatment strategy must be discussed in an MDT, involving personnel
involved in diagnosis, treatment and treatment support
• Patients should be treated at high-volume facilities
TREATMENT
• In the case of RT, all patients should be treated with IMRT or VMAT
• Treatment delays should be avoided or compensated
Early-stage disease
• In early-stage disease, conservative surgery or RT (external beam or
brachytherapy for selected stage I oropharyngeal or oral cavity subsites)
give similar locoregional control
• Single-modality treatment should be used as much as possible
Surgery
• Minimally invasive treatments (i.e. TLM or TORS) offer the potential for organ
preservation with less functional morbidity than open surgery and often less
long-term toxicity than RT
• Transoral surgery is usually recommended as a single modality for oral cavity,
oropharyngeal and laryngeal lesions
• For oropharyngeal cancer, oncological outcomes with TORS, open surgery and
(C)RT are comparable
• The use of TORS does not obviate the need for postoperative RT in some cases
28
• TLM is a current standard of care for early glottic cancers
• With the exception of T1-2 glottic cancer, ipsilateral selective neck dissection or
sentinel node biopsy is recommended for cT1-2 SCCHN tumours treated with
primary surgery
RT
• Early-stage disease can be treated by RT alone without the use of concomitant or
induction ChT
• For stage I disease, a standard fractionation regimen of 66-70 Gy, depending on
the tumour volume and location, is recommended
• For stage II disease, either hyperfractionated higher-total dose RT (e.g. 80.5 Gy
delivered in 70 fractions of 1.15 Gy twice daily over 7 weeks) or moderately
accelerated similar-total dose RT (e.g. 66-70 Gy delivered in 33-35 fractions of 2 Gy
over 5.5-6 weeks) are recommended, and can also be offered to patients with T1
or T2 tumours and neck disease with a single positive lymph node of < 3 cm
• Except for T1 glottic laryngeal tumours, prophylactic nodal RT is required (up to
50 Gy in 2 Gy fractions; 70 Gy in case of a single positive lymph node of < 3 cm)
• Brachytherapy remains an option for selected stage I oral cavity and
oropharyngeal tumours
Locally advanced disease
• Standard options for locally advanced disease are surgery plus adjuvant (C)RT or
primary CRT alone
• Primary combined concomitant CRT is the standard treatment for non-resectable
patients and for resectable patients when the anticipated functional outcome
and/or the prognosis is so poor that mutilating surgery is not justified
Surgery
• Primary surgical treatment is recommended for T3/T4 oral cavity and T4
laryngeal cancers and also for advanced hypopharyngeal cancers, especially with
laryngeal cartilage invasion (i.e. stage T4) or a non-functional larynx
• Surgery can be used for advanced HPV-positive and -negative oropharyngeal
lesions if RT is contraindicated
• Surgically treated tumours will generally require postoperative RT or CRT
• Except for oral cavity cancer, a primary non-surgical option will usually be
chosen, with surgery reserved for salvage treatment; occasionally, neck surgery
before CRT may be considered
29
Concomitant CRT
• Concomitant CRT increases locoregional control and compared with RT alone in
tumours of the oral cavity, pharynx and larynx
• Cisplatin-based RT, with a total dose of ≥ 200 mg/m2 cisplatin, is recommended
• Standard fractionation and altered fractionation regimens both provide benefits
• With accelerated RT (i.e. 70 Gy in 6 weeks), two courses of cisplatin (100 mg/m2)
are equivalent to three delivered in a 7-week RT regimen
• For fit patients, the preferred ChT is 3-weekly cisplatin [at 100 mg/m2 given on
days 1, 22 and 43 of concomitant RT (70 Gy)]
• Platinum combined with 5-FU is a valid option in patients who cannot tolerate
high-dose cisplatin
• In patients with locally advanced, HPV-negative tumours, CRT is recommended,
with cetuximab reserved for patients considered unfit for platinum-based CRT
• Induction ChT followed by concomitant CRT for non-laryngeal or hypopharyngeal
tumours has not been shown to be superior to concomitant CRT alone
Induction ChT
• For larynx preservation, concomitant CRT is associated with higher preservation
rates than induction ChT (three courses) followed by RT alone, but survival is
similar
• Platinum-based induction ChT has been associated with organ preservation in
patients with locally advanced laryngeal or hypopharyngeal SCCHN who would
require a total laryngectomy or pharyngolaryngectomy
• TPF is the standard induction ChT regimen
• Organ preservation with induction ChT does not improve OS compared with
surgery
• Patients with massive larynx cartilage invasion (T4a), extra-laryngeal extension
(T4a) or with severely impaired laryngeal function should be offered upfront
surgery instead of induction ChT
• Induction ChT is not recommended outside of a laryngeal-preservation strategy
Neck dissection after CRT
• In patients with nodal disease treated by RT or concomitant CRT, a surveillance
policy in cases of negative FDG–PET and normal size lymph nodes at 12 weeks
post-CRT has been validated
30
Postoperative (C)RT
• For patients with one or more locoregional recurrence risk factors (including
pT3-4, positive margin, close resection margin, perineural infiltration,
lymphovascular spread, > 1 invaded lymph node and the presence of
extracapsular nodal infiltration), postoperative RT up to 58 Gy (one risk factor
only) or 63-64 Gy (several risk factors) has been validated
• For patients with only one lymph node invaded without other adverse features,
postoperative RT is optional provided ≥ 15 lymph nodes have been analysed
• For patients with an R1 resection and extracapsular spread, concomitant CRT
(66 Gy) with high-dose cisplatin (100 mg/m2 every 3 weeks) is recommended
• Postoperative RT should be started within 6-7 weeks after surgery and/or the
treatment regimen of surgery and postoperative RT should be delivered within
11 weeks
Unknown primary
• The diagnostic work-up includes an FDG–PET, head and neck imaging, and a
panendoscopy with bilateral tonsillectomy and a mucosectomy of the base of the
tongue in case of HPV-positive disease
• The treatment of HPV-positive and -negative disease is the same and comprises
primary surgery alone or followed by RT or CRT, or primary RT or CRT followed
by neck dissection for residual disease
• Patients with pN1 disease and no other risk factor do not require postoperative
RT if ≥ 15 nodes have been analysed
• Oropharynx RT can be considered as an option in some cases
Management of recurrent and/or metastatic disease
• In selected patients with OMD at diagnosis, local and/or regional treatment (with
surgery or RT) can be considered for treatment with curative intent
• For patients with a high burden of distant metastases, starting systemic treatment
is a priority
• Patients with local or locoregional recurrence should be referred to an MDT at a
reference tertiary centre
• For patients with a good PS and an early-stage laryngeal recurrence, salvage
surgery is associated with a reasonable oncological outcome
• Two different approaches validated for patients with locoregional relapse not
amenable to locoregional salvage treatment and/or with distant metastases
are pembrolizumab monotherapy (in patients with CPS ≥ 1 SCCHN) and
pembrolizumab plus ChT (cisplatin or carboplatin plus 5-FU), independent of
PD-L1 status, particularly when rapid tumour shrinkage is required
31
• The FDA has approved pembrolizumab plus ChT as first-line treatment regardless
of PD-L1 expression and pembrolizumab alone for patients with PD-L1-expressing
tumours (CPS ≥ 1)
• The EMA has approved pembrolizumab with or without ChT only for patients with
a CPS ≥ 1
• EXTREME remains the first-line standard of care for patients with
contraindications to anti-PD-1 inhibitors and in patients with a tumour not
expressing PD-L1, and can also be considered after progression on an ICI in fit
patients eligible for platinum-based ChT
• DPD deficiency testing is recommended before initiating 5-FU
• TPeX can be considered an alternative to EXTREME for some patients
• For patients who progress within 6 months of platinum therapy, nivolumab is both
FDA- and EMA-approved, and pembrolizumab is FDA-approved and has EMA
approval for use in patients whose tumours express PD-L1 with a TPS of ≥ 50%
• After progression on platinum-based ChT and anti-PD-1 inhibitors, no standard
of care exists
Treatment strategies for HPV-positive and HPV-negative SCCHN should be the same
The efficacy of pembrolizumab or nivolumab is higher in patients with
PD-L1-expressing tumours
PD-L1 staining (CPS) for recurrent/metastatic SCCHN is recommended
FOLLOW-UP
Clinical follow-up, including a head and neck examination by flexible endoscopy,
should be carried out every 2-3 months during the first 2 years, every 6 months for
years 3-5 and annually thereafter
For locally advanced disease, head and neck imaging is recommended 3 months
after the primary treatment
FDG–PET/CT is recommended 3 months after CRT for patients with node-positive
disease to assess the necessity of neck dissection; otherwise, imaging should
be carried out if symptoms occur or in case of abnormalities found at the clinical
examination
For patients treated with RT, daily teeth fluorination, dental evaluation every
6 months and yearly TSH dosage are recommended
32
NASOPHARYNGEAL CARCINOMA

Diagnosis
• Definitive diagnosis is made by endoscope-guided biopsy of the primary
nasopharyngeal tumour
• Where no clinical primary tumour is visible at endoscopy, biopsy of
nasopharyngeal tissue positive at magnetic resonance imaging (MRI) or
positron emission tomography (PET) is suggested
• Diagnostic neck biopsy and/or neck nodal dissection is not recommended; if
carried out, node surgical biopsy should be avoided
• Determination of Epstein-Barr virus (EBV) on the histological sample by in situ
hybridisation (ISH) is indicated
Pathology/molecular biology
• The histological type should be classified according to the World Health
Organization (WHO) 4th edition classification, as shown in the table below
WHO CLASSIFICATION OF NASOPHARYNGEAL CANCER
ICD-O CODE
Non-keratinising squamous cell carcinoma 8072/3
Keratinising squamous cell carcinoma 8071/3
Basaloid squamous cell carcinoma 8083/3
ICD-O, International Classification of Diseases for Oncology; WHO, World Health Organization
• Keratinising cancer is more frequent in non-endemic areas whereas non-keratinising

cancer comprises the majority of cases and is linked to EBV infection
EBV expression
• EBV is considered by the International Agency for Research on Cancer to be in
Group 1 for nasopharyngeal carcinoma (NPC), that is, a virus for which there is
sufficient evidence of carcinogenicity in humans
• Latent EBV has been found in high-grade dysplasia and NPC cells but not in
normal epithelium or low-grade dysplasia, and has been identified in a clonal
pattern in pre-invasive lesions of the nasopharynx that contain EBV RNAs
characteristic of latent infection
33
• The EBV latent-gene expression in NPC is predominantly restricted to the poorly
immunogenic Epstein-Barr Nuclear Antigen 1, Latent Membrane Protein 2A and
Latent Membrane Protein 2B
• EBV is almost always a necessary factor for non-keratinising NPC
Human papillomavirus expression
• In regions where NPC is endemic, p16 positivity and human papillomavirus
(HPV) expression is reported in up to 8% of non-keratinising undifferentiated
carcinoma and carries a better prognosis than its EBV counterpart
• In non-endemic areas, an association between HPV expression and prognosis is
unclear
• Whether HPV is involved in carcinogenesis and disease progression has yet to be
established
Molecular analysis
• Currently, no actionable mutations in NPC have been identified
• However, gene expression analysis may be useful in identifying patients at a
higher risk of developing distant metastases
• Mutational signatures relevant to DNA repair pathways show prognostic value
with potential clinical implications
Other risk factors
• Genetic susceptibility plays a clear role in the development of NPC
• Environmental factors are also causal agents, related mainly to the consumption
of salted fish
Screening
• The use of plasma EBV DNA, carried out in duplicate at least 4 weeks apart,
coupled with endoscopic examination and MRI, can only be recommended for
detecting early, asymptomatic NPC in endemic areas and is limited to individuals
considered to be at higher risk (i.e. males aged 40-62 years)
• However, there is poor standardisation between the different plasma EBV DNA
assays used
• NPC is staged according to the American Joint Committee on Cancer (AJCC)
staging classification 8th edition, as shown in the table on the next page
Compared with the previous edition, this classification better delineates the
tumour (T) stage and nodal extension
34
AJCC STAGING CLASSIFICATION 8TH EDITION FOR NPC
PRIMARY TUMOUR (T)

TX Primary tumour cannot be assessed
T0 No tumour identified, but EBV-positive cervical node(s) involvement
Tis Carcinoma in situ
Tumour confined to the nasopharynx or extension to oropharynx and/or nasal cavity without
T1
parapharyngeal involvement
Tumour with extension to parapharyngeal space and/or adjacent soft tissue involvement
T2
(medial pterygoid, lateral pterygoid, prevertebral muscles)
Tumour with infiltration of bony structures at skull base, cervical vertebra, pterygoid
T3
structures and/or paranasal sinuses
Tumour with intracranial extension, involvement of cranial nerves, hypopharynx, orbit,
T4 parotid gland and/or extensive soft tissue infiltration beyond the lateral surface of the lateral
pterygoid muscle
REGIONAL LYMPH NODES (N)

NX Regional nodes cannot be assessed
Unilateral metastasis in cervical lymph node(s) and/or unilateral or bilateral metastasis in

N1 retropharyngeal lymph node(s), ≤ 6 cm in greatest dimension, above the caudal border of
cricoid cartilage
Bilateral metastasis in cervical lymph node(s), ≤ 6 cm in greatest dimension, above the
N2
caudal border of cricoid cartilage
Unilateral or bilateral metastasis in cervical lymph node(s), > 6 cm in greatest dimension
N3
and/or extension below the caudal border of cricoid cartilage
DISTANT METASTASIS (M)

cM0 No distant metastasis
cM1 Distant metastasis
pM1 Distant metastasis, microscopically confirmed
35
STAGE GROUPING
Stage 0 Tis, N0, M0
Stage I T1, N0, M0
Stage II T0 or T1, N1, M0; T2, N0, M0; T2, N1, M0
Stage III T0, T1 or T2, N2, M0; T3, N0, N1 or N2, M0
Stage IVA T4, any N, M0; any T, N3, M0
Stage IVB Any T, any N, M1
AJCC, American Joint Committee on Cancer; EBV, Epstein-Barr virus; NPC, nasopharyngeal carcinoma
Amin MB, et al. AJCC cancer staging manual. 8th ed. New York: Springer International Publishing; 2017. Reprinted with
permission.
• As shown in the table below, routine staging procedures include a medical

history, physical examination with cranial nerve examination, complete blood
count (CBC), serum biochemistry [including liver and renal function tests and
lactate dehydrogenase (LDH)], nasopharyngoscopy and radiological imaging of
the nasopharynx and base of the skull and neck
DIAGNOSTIC WORK-UP
1. Medical history and physical examination

2. CBC, serum biochemistry
3. Nasopharyngoscopy
4. Tumour biopsy (EBER by ISH)
5. CT scan or MRI of the nasopharynx and base of the skull and neck (to the clavicle) (MRI preferred)
6. FDG–PET/CT imaging
7. Baseline audiometric testing, dental examination, nutritional status evaluation, ophthalmological and
endocrine evaluation
8. Plasma EBV DNA
9. QoL assessment (e.g. EORTC QLQ-C30)
FDG, [18F]2-fluoro-2-deoxy-D-glucose; CBC, complete blood count; CT, computed tomography; EBER, Epstein-Barr virus-encoded
RNA; EBV, Epstein-Barr virus; EORTC, European Organisation for Research and Treatment of Cancer; ISH, in situ hybridisation;
MRI, magnetic resonance imaging; PET, positron emission tomography; QLQ, quality of life questionnaire; QoL, quality of life
• MRI is the most accurate way of defining local tumour staging and is preferred
where available and according to the centre’s expertise
• [18F]2-fluoro-2-deoxy-D-glucose (FDG)–PET/computed tomography (CT) adds
further accuracy in nodal staging and is recommended for detecting distant
metastases in locally advanced disease
36
• Baseline audiometric testing, dental examination, nutritional status evaluation and
ophthalmological and endocrine evaluation should be carried out as appropriate
• The application of pre-treatment quality of life (QoL) scales may better delineate
individual risk and prompt medical or physical support before the start of
treatment
• Incorporation of plasma EBV DNA both in the pre- and post-treatment setting
may improve the prognostic capacity of the tumour-node-metastasis staging
system
Currently, plasma EBV DNA detection has no impact on treatment strategy
• Biomolecular signatures with gene expression and microRNA, together with
some nomograms using factors such as T and N stage, age, gender, body mass
index, haemoglobin, LDH, plasma EBV DNA and C-reactive protein, may help to
determine prognosis in patients in endemic areas
Data are limited to support their use in choosing a treatment strategy
TREATMENT
• Recommendations are based mainly on data from studies in the endemic setting,
where non-keratinising, EBV-related carcinomas constitute most cases
• The optimal treatment strategy for patients with locally advanced NPC should be
discussed within a multidisciplinary team (MDT)
• Treatment in a high-volume facility has been reported as an independent
prognostic factor for improved survival, at least in endemic regions, and so is
recommended
• Radiotherapy (RT) is the mainstay of therapy for local and locoregional NPC,
as shown in the figure on the next page, and is an essential component of
curative-intent treatment of non-disseminated NPC
37
38
TREATMENT ALGORITHM FOR STAGE I-IVA NPC
Stage I IMRT IMRT/ChT
IMRT T4, N0, M0 ICT + IMRT/ChT

Stage II
IMRT/ChT IMRT/ChT + AC
IMRT/ChT ICT + IMRT/ChT
T0-T2, N2, M0 ICT + IMRT/ChT Stage IVA T4, N1-N2, M0 IMRT/ChT
IMRT/ChT + AC IMRT/ChT + AC
T3, N0, M0 IMRT/ChT ICT + IMRT/ChT

Any T, N3, M0
Stage III
IMRT/ChT IMRT/ChT + AC
T3, N1, M0
ICT + IMRT/ChT
ICT + IMRT/ChT
T3, N2, M0 IMRT/ChT
IMRT/ChT + AC
AC, adjuvant chemotherapy; ChT, chemotherapy; ICT, induction chemotherapy; IMRT, intensity-modulated radiotherapy; M, metastasis; N, node; NPC, nasopharyngeal carcinoma; T, tumour
• Compared with previous RT techniques, intensity-modulated RT (IMRT) provides
enhanced outcomes; less severe late effects, such as xerostomia, trismus and
temporal lobe injury; and improved QoL for long-term survivors
• Proton therapy added as a boost is a promising approach for locally advanced
NPC and may reduce the incidence of severe mucositis and salivary dysfunctions
compared with a full course of IMRT only
• Target volume definition should include the primary tumour, pathological nodes,
adjacent regions considered at risk of microscopic spread from the tumour and
generally both sides of the neck (levels II-V and retropharyngeal nodes)
• A total dose of 70 Gy is needed for eradication of macroscopic disease and
50-60 Gy for the treatment of potential at-risk sites, usually by conventional or
moderately accelerated RT
• IMRT may be applied by simultaneous integrated boost (SIB), which is the
preferred choice due to its convenience, with sequential boost as an alternative
• In node-negative NPC, a reduced nodal volume may be feasible to reduce the
toxicity burden
• For induction chemotherapy (ICT), planning of IMRT gross tumour volume (GTV)
based on post-chemotherapy (ChT) MRI scans may be adopted if the pre-induction
tumour areas receive at least an intermediate dose (64 Gy)
• Planning optimisation in terms of prioritisation and dose constraints for target
and radiosensitive structures is fundamental
• Target volume definitions are shown in the table on the next page
39
CTV DELINEATION AND ANATOMIC BOUNDARIES ACCORDING TO
INTERNATIONAL GUIDELINES
CTV DELINEATION AND
CTV DEFINITION
ANATOMIC BOUNDARIES
High-risk volume GTVp + 5 mm (± whole NP)
Primary tumour (full therapeutic CTVp1 GTVp + 1 mm if tumour in close proximity to
dose) brainstem and spinal cord
High-risk volume
Node(s) (full therapeutic CTVn1 GTVn + 5 mm (consider 10 mm if nodal ECE)
dose)
GTVp + 10 mm + whole NP
GTVp + 2 mm if tumour in close proximity to
brainstem and spinal cord
Nasal cavity – posterior part: At least 5 mm
from choana
Posterior maxillary sinuses: At least 5 mm
from posterior wall (to ensure pterygopalatine
fossae) coverage
Intermediate-risk Posterior ethmoid sinus: Include vomer
Primary tumour volume CTVp2
(prophylactic dose) Base of skull: Cover foramina ovale,
rotundum, lacerum and petrous tip
Cavernous sinus: If T3/T4 (only involved
side)
Parapharyngeal spaces: Full coverage
Sphenoid sinus: Inferior 1/2 if T1-2; whole
if T3-4
Clivus: Anterior 1/3 if no invasion; whole
if invasion
Lymph nodes bilaterally: RP, II, III, VA, (IV,
VB) for all T and N categories plus at least
ipsilateral one level below the involved node
levels
Ipsilateral coverage of ipsilateral IB if:
• IB level positive (include whole level)
Intermediate-risk
• Structures that drain to level IB as the first
Node(s) volume CTVn2
echelon site (oral cavity, anterior half of
(prophylactic dose)
nasal cavity)
• Involvement of submandibular gland
• Ipsilateral level IIA LNs with ECE
• Consider if ipsilateral level IIA LNs with
maximum nodal axial diameter greater
than 2 cm
40
Levels IV and VB down to clavicle if VB:
Low-risk volume • If nodal involvement is confined to level II
Nodes (prophylactic dose) CTVn3 nodes only
– optional • Possible omission if N0 or N1 based solely
on RP positivity
CTV, clinical target volume; CTVn, nodal clinical target volume; CTVp, primary tumour clinical target volume; ECE, extracapsular
extension; GTVn, nodal gross target volume; GTVp, primary tumour gross target volume; LN, lymph node; NP, nasopharynx;
RP, retropharyngeal
Lee AW et al. Radiother Oncol 2018;126:25-36. Reproduced with permission.
• IMRT dose prescription to target volumes and fractionation schemes are shown
in the table below
SELECTED IMRT DOSE FRACTIONATION SCHEDULES
INTERMEDIATE-RISK LOW-RISK
HIGH-RISK CTV
CTV CTV-OPTIONAL
TD/DF/NF (GY)
TD/DF/NF (GY) TD/DF/NF (GY)
International 70/2/35 63-60/1.8-1.7/35 56/1.6/35
guidelines 69.96/2.12/33 63-59.4/1.9-1.8/33 54/1.63/33
54.12/1.64/33
RTOG 69.96/2.12/33 59.4/1.8/33
50/2/25
70/2.12/33 59.4/1.8/33
PYNEH 52.5/1.75/30
70/2/35 61.25/1.75/35
DAHANCA 66/2/33 60/1.82/33 50/1.52/33
PWH 70-76/2-2.17/35 60/2/35 NS
INT 69.96/2.12/33 59.4/1.8/33 56.1/1.7/33
CTV, clinical target volume; DAHANCA, Danish Head and Neck Cancer Group; df, dose per fraction; IMRT, intensity-modulated
radiotherapy; INT, National Cancer Institute, Milan; nf, number of fractions; NS, not specified; PWH, Prince of Wales Hospital;
PYNEH, Pamela Youde Nethersole Eastern Hospital; RTOG, Radiation Therapy Oncology Group; Td, total dose
• In most cases, conventional or moderate hypofractionation regimens are used to

a total dose of 70 Gy in 33-35 fractions
• Extreme caution should be exercised when increasing the total dose due to the
high risk of developing late toxicities
• Stage I disease is treated by RT alone
• Patients with stage II disease benefit from concurrent chemoradiotherapy (CRT)
with cisplatin 30 mg/m2/week when 2D-RT is used, with RT alone being suitable
only when IMRT is adopted
• Stage III and IVA disease are treated by CRT, the standard agent being cisplatin
The most commonly used regimen is cisplatin 100 mg/m2 every 3 weeks with
concomitant RT
41
Weekly cisplatin (40 mg/m2/week) has also been shown to improve OS
The optimal cumulative dose should be higher than 200 mg/m2
• Concurrent nedaplatin was found to be non-inferior to cisplatin in one
randomised trial
• Concurrent carboplatin is considered an available option but the evidence is
conflicting
• The addition of bevacizumab to platinum-based ChT concurrently with RT is not
recommended
• Intensification of the systemic treatment is needed for stage III-IVA
non-keratinising NPC
• ICT with cisplatin/gemcitabine followed by CRT showed a benefit in terms of
recurrence-free survival (RFS), overall survival (OS) and distant RFS, with more
acute, but not late, toxicities
• ICT added to CRT should not hinder the subsequent delivery of full-dose CRT,
and the time between the end of ICT and the start of RT should be kept as short
as possible
• Long-term data from a multicentre, randomised, factorial trial showed that,
compared with concurrent-adjuvant sequencing, induction-concurrent
sequencing led to improvements in progression-free survival and marginal
improvements in OS without an adverse impact on late toxicity
• The selection of patients to receive more ChT or immunotherapy, in the form
of ICT or adjuvant ChT, in addition to CRT, is a therapeutic area that is being
explored in ongoing randomised controlled trials
• Evaluating a patient’s risk profile is key and advanced nodal and primary stage,
as well as high basal EBV DNA, have been proposed as a means to select patients
for ICT
• In patients with persistent high EBV DNA after definitive treatment, adjuvant
cisplatin/gemcitabine did not improve outcome and is not recommended in
clinical practice
A personalised approach with non-cross-resistant drugs or participation in a
clinical trial is suggested
• In general, concurrent ChT is not tolerated as well in elderly patients compared
with younger patients and consequently dose intensity is reduced; thus, patient
selection is crucial
Management of advanced/metastatic disease
Treatment of locoregional recurrences
• The treatment of recurrent and metastatic disease is illustrated in the figure on
the following page
42
TREATMENT ALGORITHM FOR RECURRENT AND/OR METASTATIC NPC
Local or regional recurrence Metastatic disease
Amenable to salvage surgery

or re-irradiation? Newly diagnosed?
Yes No No Yes
Surgery ± IMRT or First line*: First line:

IMRT ± ChT Cisplatin + gemcitabine ChT followed by
RT on T and N sites
Second line*:
Nivolumab, pembrolizumab,
camrelizumab;
ChT (paclitaxel, docetaxel, 5-FU,
capecitabine, irinotecan, vinorelbine,
ifosfamide, doxorubicin, oxaliplatin,
cetuximab)
*Consider RT or surgery on metastatic sites

5-FU, 5-fluorouracil; ChT, chemotherapy; IMRT, intensity-modulated radiotherapy; N, node; NPC, nasopharyngeal carcinoma; RT, radiotherapy; T, tumour
43
• Small local recurrences are potentially curable, with the main therapeutic options
including nasopharyngectomy, brachytherapy, radiosurgery, stereotactic RT
(SRT), IMRT or a combination of surgery and RT, with or without concurrent ChT
• Treatment decisions are tailored to the individual case, considering the volume,
location/extent of the recurrent tumour, previous treatments, disease-free interval
(DFI), comorbidities and any pre-existing organ dysfunction
• For surgical salvage treatments, prognostic factors include T and N stage at
recurrence, surgical approach (with a better outcome reported for endoscopic
surgery) and feasibility of adjuvant re-irradiation
• Patients with local recurrences not invading the carotid artery and not extending
intracranially are candidates for nasopharyngectomy; local recurrence, stage
rT1-rT3, might benefit more from endoscopic nasopharyngectomy than from IMRT
• Lymphatic recurrences in the neck can be treated with neck dissection, the extent
(from selective to radical) depending on the nature of the recurrence
• Pre-treatment circulating EBV DNA has been shown to be a prognostic factor for
distant metastases in candidates for surgery
• Disease- and treatment-related prognostic factors for re-irradiated patients are:
T and N stage at recurrence, tumour volume, DFI, dosimetry calculations, dose
to target and fractionation schedule, window dose for organs at risk and RT
technique (IMRT, SRT)
• Preliminary results have shown activity and limited toxicity with proton and
carbon ion therapy for locally recurrent NPC
Treatment of metastatic disease or locoregional recurrences not amenable to
curative approaches
• In metastatic NPC, palliative ChT should be considered for patients with an
adequate performance status (PS); a combination of cisplatin/gemcitabine is
the first-line choice and improves OS
• In patients with newly diagnosed NPC, the addition of locoregional RT to
systemic therapy improves locoregional control and ultimately OS
• No standard second-line treatment exists
Active agents include paclitaxel, docetaxel, 5-fluorouracil (5-FU), capecitabine,
irinotecan, vinorelbine, ifosfamide, doxorubicin, oxaliplatin and cetuximab,
which can be used as single agents or in selected combinations
Poly-ChT is more active than mono-ChT but it is associated with increased and
cumulative toxicities
Treatment choice should be based on previous treatments, patient symptoms,
PS, patient preference and expected toxicity
44
• Immunotherapy represents a promising strategy in NPC, especially because
of the causative role of EBV, but the therapeutic positioning of the immune
checkpoint inhibitors, nivolumab, pembrolizumab and camrelizumab, is still to
be defined
• Cytotoxic T-cell lymphocyte (CTL) adoptive immunotherapy has demonstrated
activity in highly pre-treated patients
• Oligometastatic patients may achieve long-term survival after aggressive
treatment, including ChT, surgery or definitive RT to the metastases
• Pre-treatment plasma EBV DNA and clearance rates are prognostic factors in
metastatic patients treated with first-line ChT
• Plasma EBV DNA can be used to facilitate early diagnosis and recurrence
monitoring and also has prognostic value, both before and just after the end of
treatment, as shown in the table below
PERSONALISED MEDICINE SYNOPSIS
BIOMARKER METHODOLOGY USE

Prognostic before curative treatment
Prognostic role of clearance during ICT and CRT
Plasma EBV DNA PCR Prognostic 1-4 weeks after RT
Early diagnosis of recurrence during follow-up
Prognostic in recurrent and/or metastatic disease
CRT, chemoradiotherapy; EBV, Epstein-Barr virus; ICT, induction chemotherapy; PCR, polymerase chain reaction; RT, radiotherapy
• More research is needed to refine the role of plasma EBV DNA in the
management of NPC and to identify additional molecular markers that could lead
to advances in personalised medicine in NPC
FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP
• A proposed follow-up strategy after completion of curative treatment for NPC is
shown in the figure on the next page
• Documentation of complete remission in the nasopharynx and neck through
clinical and endoscopic examination and/or imaging studies is important and the
first radiological imaging is suggested 3 months after treatment completion
45
FOLLOW-UP ALGORITHM AFTER COMPLETION OF CURATIVE TREATMENT OF
NPC
Three months after IMRT, then every 6 months up to the

third year (for T2-T4 diseases)
Imaging
• MRI
• PET (higher specificity)
Endoscopic assessment every 3 months in the first

Nasal examination year, every 6 months in the second and third years and
annually thereafter for the first 5 years
Plasma EBV DNA 1-4 weeks after IMRT, then every year
Thyroid and pituitary Thyroid function assessment every year

assessment Pituitary function assessment in case of signs/symptoms
EBV, Epstein-Barr virus; IMRT, intensity-modulated radiotherapy; MRI, magnetic resonance imaging; NPC, nasopharyngeal
carcinoma; PET, positron emission tomography
• The sensitivity of PET is similar to that of MRI but its specificity is higher, helping
to differentiate between post-irradiation changes and recurrent tumours
The cost and availability of PET may limit its widespread use
• Risk of recurrence in the era of IMRT seems to have a bimodal behaviour: One
after approximately 1.5 years following the end of treatment (mainly in cases of
T3, T4 and N2, N3 diseases) and one after 3.5 years (for all T stages and N2, N3
diseases)
• Further follow-up for patients includes periodic (every 3 months in the first year,
every 6 months in the second and third year and annually thereafter for the first 5
years) examination of the nasopharynx and neck and cranial nerve function, and
evaluation of systemic complaints to identify distant metastases
46
• For T2-T4 tumours, MRI might be used on a 6-monthly basis to evaluate the
nasopharynx and the base of the skull, at least for the first 3 years after treatment
• Plasma EBV DNA should be evaluated at least every year
• Evaluation of thyroid function in patients who have received RT to the neck is
recommended annually and pituitary function should be evaluated periodically or
in case of signs and/or symptoms
• Attention should be paid to the recognition of late treatment-related effects,
mainly xerostomia, trismus, hearing impairment, temporal lobe necrosis,
cognitive impairment, cranial nerve injuries and second primary tumours
possibly related to RT
• In the future, adopting a risk-based follow-up could improve the early detection
of relapse and allow for optimisation of resources
47
Diagnosis
• Definitive diagnosis is made by endoscope-guided biopsy of the primary
nasopharyngeal tumour
• Diagnostic neck biopsy and/or neck nodal dissection is not recommended; if
carried out, node surgical biopsy should be avoided
• Determination of EBV on the histological sample by ISH is indicated
Pathology/molecular biology
• The histological type should be classified according to the WHO 4th edition
EBV expression
• EBV is almost always a necessary factor for non-keratinising NPC
HPV expression
• In regions where NPC is endemic, p16 positivity and HPV expression carries a
better prognosis than its EBV counterpart
• In non-endemic areas, an association between HPV expression and prognosis is
unclear
Molecular analysis
• Currently, no actionable mutations in NPC have been identified
• However, gene expression analysis may be useful in identifying patients at a
higher risk of developing distant metastases
• Mutational signatures relevant to DNA repair pathways show prognostic value
with potential clinical implications
Other risk factors
• Genetic susceptibility plays a clear role in the development of NPC
• Environmental factors are also causal agents, related mainly to the consumption
of salted fish
Screening
• The use of plasma EBV DNA, carried out in duplicate at least 4 weeks apart,
coupled with endoscopic examination and MRI, can only be recommended for
48
detecting early, asymptomatic NPC in endemic areas and is limited to individuals
considered to be at higher risk (i.e. males aged 40-62 years)
NPC is staged according to the AJCC staging classification 8th edition
Routine staging procedures, include a medical history, physical examination with
cranial nerve examination, CBC, serum biochemistry (including liver and renal
function tests and LDH), nasopharyngoscopy and radiological imaging of the
nasopharynx and base of the skull and neck
MRI is the most accurate way of defining local tumour staging and is preferred,
where available and according to the centre’s expertise
FDG–PET/CT is recommended for detecting distant metastases in locally advanced
disease
Baseline audiometric testing, dental examination, nutritional status evaluation and
ophthalmological and endocrine evaluation should be carried out as appropriate
The application of pre-treatment QoL scales may better delineate individual risk and
prompt medical or physical support before the start of treatment
Pre- and post-treatment plasma/serum load of EBV DNA has prognostic value
Biomolecular signatures with gene expression and microRNA, together with some
nomograms, may help to determine prognosis in patients in endemic areas
TREATMENT
• The optimal treatment strategy for patients with locally advanced NPC should be
discussed within an MDT
• IMRT is the mainstay of therapy for local and locoregional NPC and is an
essential component of curative-intent treatment of non-disseminated NPC
• Proton therapy added as a boost is a promising approach for locally advanced
NPC
• Target volume definition should include the primary tumour, pathological nodes,
adjacent regions considered at risk of microscopic spread from the tumour and
generally both sides of the neck (levels II-V and retropharyngeal nodes)
• A total dose of 70 Gy is needed for eradication of macroscopic disease and
50-60 Gy for the treatment of potential at-risk sites
• SIB is the preferred choice for IMRT
• In node-negative NPC, a reduced nodal volume may be feasible to reduce the
toxicity burden
49
• For ICT, planning of IMRT GTV based on post-ChT MRI scans may be adopted
• Planning optimisation in terms of prioritisation and dose constraints for target
and radiosensitive structures is fundamental
• In most cases, conventional or moderate hypofractionation regimens are used to
a total dose of 70 Gy in 33-35 fractions
• Extreme caution should be exercised when increasing the total dose due to the
high risk of developing late toxicities
• Stage I-II disease is treated by RT alone, although for stage II disease this is used
only when IMRT is adopted
• When 2D-RT is used, patients with stage II disease benefit from concurrent CRT
with cisplatin 30 mg/m2/week
• Stage III and IVA disease are treated by CRT
• The standard agent is cisplatin, which is commonly administered as
100 mg/m2 every 3 weeks with concomitant RT, although 40 mg/m2/week has
also been shown to improve OS
• The optimal cumulative dose of cisplatin should be higher than 200 mg/m2
• Concurrent nedaplatin was found to be non-inferior to cisplatin in one
randomised trial
• Concurrent carboplatin is an available option but the evidence is conflicting
• Intensification of the systemic treatment is needed for stage III-IVA
non-keratinising NPC
• ICT with cisplatin/gemcitabine followed by CRT showed outcomes benefits with
more acute, but not late, toxicities
• Advanced nodal and primary stage, as well as high basal EBV DNA, have been
proposed as a means to select patients for ICT
• In patients with persistent high EBV DNA after definitive treatment, a personalised
approach with non-cross-resistant drugs or participation in a clinical trial is
suggested
Management of advanced/metastatic disease
Treatment of locoregional recurrences
• Small local recurrences are potentially curable, with the main therapeutic options
including nasopharyngectomy, brachytherapy, radiosurgery, SRT, IMRT or a
combination of surgery and RT, with or without concurrent ChT
50
• Treatment decisions are tailored to the individual case
• Patients with local recurrences not invading the carotid artery and not extending
intracranially are candidates for nasopharyngectomy; local recurrence, stage
rT1-rT3, might benefit more from endoscopic nasopharyngectomy than from IMRT
• Lymphatic recurrences in the neck can be treated with neck dissection
• Pre-treatment circulating EBV DNA has been shown to be a prognostic factor for
distant metastases in candidates for surgery
Treatment of metastatic disease or locoregional recurrences not amenable to
curative approaches
• In metastatic NPC, palliative ChT should be considered for patients with an
adequate PS; a combination of cisplatin/gemcitabine is the first-line choice
• In patients with newly diagnosed NPC, the addition of locoregional RT to
systemic therapy improves locoregional control and ultimately OS
• No standard second-line treatment exists and active agents include paclitaxel,
docetaxel, 5-FU, capecitabine, irinotecan, vinorelbine, ifosfamide, doxorubicin,
oxaliplatin and cetuximab, which can be used as single agents or in selected
combinations
• Immunotherapy represents a promising strategy in NPC, especially because of
the causative role of EBV, but its therapeutic positioning is still to be defined
• CTL adoptive immunotherapy has demonstrated activity in highly pre-treated
patients
• Oligometastatic patients may achieve long-term survival after aggressive
treatment, including ChT, surgery or definitive RT to the metastases
Plasma EBV DNA can be used to facilitate early diagnosis and recurrence
monitoring and also has prognostic value, both before and just after the end of
treatment, although more research is needed to refine its role in management
FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP
The first radiological imaging is suggested 3 months after treatment completion
The sensitivity of PET is similar to that of MRI but its specificity is higher, helping
to differentiate between post-irradiation changes and recurrent tumours
Further follow-up includes periodic (every 3 months in the first year, every
6 months in the second and third year and annually thereafter for the first 5
years) examination of the nasopharynx and neck and cranial nerve function, and
evaluation of systemic complaints to identify distant metastases
51
For T2-T4 tumours, MRI might be used on a 6-monthly basis, at least for the first
3 years after treatment
Plasma EBV DNA should be evaluated at least every year
Evaluation of thyroid function in patients who have received RT to the neck is
recommended annually and pituitary function should be evaluated periodically or in
case of signs and/or symptoms
Attention should be paid to the recognition of late treatment-related effects
52
5-FU, 5-fluorouracil
AJCC, American Joint Committee on Cancer
CBC, complete blood count
CE, contrast-enhanced
ChT, chemotherapy
CPS, combined positive score
CRT, chemoradiotherapy
CT, computed tomography
DFI, disease-free interval
DFS, disease-free survival
DOI, depth of invasion
DPD, dihydropyrimidine dehydrogenase
EBV, Epstein-Barr virus
EHNS, European Head and Neck Society
EMA, European Medicines Agency
ESMO, European Society for Medical Oncology
ESTRO, European Society for Radiotherapy & Oncology
EURACAN, European reference network for rare adult solid cancers
EXTREME, platinum (cisplatin or carboplatin)/5-fluorouracil/cetuximab
FDA, Food and Drug Administration
FDG, [18F]2-fluoro-2-deoxy-D-glucose
GTV, gross tumour volume
HPV, human papillomavirus
ICI, immune checkpoint inhibitor
ICT, induction chemotherapy
IHC, immunohistochemistry
IMRT, intensity-modulated radiotherapy
ISH, in situ hybridisation
LDH, lactate dehydrogenase
MDT, multidisciplinary team
MRI, magnetic resonance imaging
NPC, nasopharyngeal carcinoma
OMD, oligometastatic disease
OS, overall survival
PD-1, programmed cell death protein 1
PD-L1, programmed death-ligand 1
PET, positron emission tomography
PFS, progression-free survival
PS, performance status
QoL, quality of life
R0, no residual tumour at the margin
R1, microscopic residual tumour at the margin
53
RFS, recurrence-free survival
RT, radiotherapy
SCC, squamous cell carcinoma
SCCHN, squamous cell carcinoma of the head and neck
SIB, simultaneous integrated boost
SRT, stereotactic radiotherapy
TLM, transoral laser microsurgery
TNM, tumour-node-metastasis
TORS, transoral robotic surgery
TPeX, cisplatin/docetaxel/cetuximab
TPF, taxane/platinum/5-FU
TPS, tumour proportion score
TSH, thyroid-stimulating hormone
UICC, Union for International Cancer Control
VMAT, volumetric modulated arc therapy
WHO, World Health Organization
54
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HEAD & NECK CANCERS 2021

ESMO POCKET GUIDELINES
HEAD & NECK

CANCERS
2021

HEAD & NECK CANCERS - ESMO POCKET GUIDELINE - 2021

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European Society for Medical Oncology (ESMO) tmc strategic communications

via Ginevra 4, 6900 Lugano, Switzerland www.wearetmc.co.uk

HEAD & NECK CANCERS 2021

HEAD & NECK

ESMO CLINICAL PRACTICE GUIDELINES

Distributed with support from F. Hoffmann-La Roche Ltd.

Please visit http://www.esmo.org or http://oncologypro.esmo.org to view the

SQUAMOUS CELL CARCINOMA OF THE ORAL CAVITY, LARYNX,

•Head and neck •Oesophagoscopy

PRIMARY TUMOUR (T)

T0 No evidence of primary tumour

Tis Carcinoma in situ

Lip and oral cavity

T3 Tumour > 4 cm in greatest dimension or > 10 mm DOI

Larynx cancer: Supraglottis

Larynx cancer: Glottis

Larynx cancer: Subglottis

T2 Tumour extends to vocal cord(s) with normal or impaired mobility

T3 Tumour limited to larynx with vocal cord fixation

p16-negative oropharyngeal cancer

T2 Tumour > 2 cm but ≤ 4 cm in greatest dimension

T3 Tumour > 4 cm in greatest dimension or extension to lingual surface of epiglottis

Tumour invades any of the following: Larynx‡, deep/extrinsic muscle of tongue

T2 Tumour > 2 cm but ≤ 4 cm in greatest dimension

T3 Tumour > 4 cm in greatest dimension or extension to lingual surface of epiglottis

Tumour invades any of the following: Larynx‡, deep/extrinsic muscle of tongue

REGIONAL LYMPH NODES (N)

N0 No regional lymph node metastasis

Metastasis in a single ipsilateral lymph node ≤ 3 cm in greatest dimension without

p16-positive oropharyngeal cancer

N0 No regional lymph node metastasis

N1 Unilateral metastasis in lymph node(s), all ≤ 6 cm in greatest dimension

N2 Controlateral or bilateral metastasis in lymph node(s), all ≤ 6 cm in greatest dimension

N3 Metastasis in lymph node(s) > 6 cm in dimension

DISTANT METASTASIS (M)

Oral cavity, lip, larynx, hypopharynx and p16-negative oropharyngeal cancer

IVC Any T Any N M1

p16-positive oropharyngeal cancer

Pre-treatment risk assessment

Oral cavity cancer (excluding lip carcinoma)

cT3-4a cN0-3 cM0

Standard: Standard: Options:

Standard: Standard: Standard: Options:

*Not requiring total laryngectomy

Oropharyngeal cancer p16-negative or p16-positive

cT1-2 cN0-N1 cM0 cT3-4 cN0 cM0, cT1-4 cN1-3 cM0

Standard: Standard: Standard: Options:

Metastatic or recurrent/persistent disease not amenable to curative RT or surgery

Pretreated with platinum- Pretreated with platinum-

Standard: Standard: Standard: Standard: Option:

• HPV-induced oropharyngeal cancer has a better prognosis than HPV-negative

DIAGNOSIS AND PATHOLOGY/MOLECULAR BIOLOGY

Keratinising squamous cell carcinoma 8071/3

Basaloid squamous cell carcinoma 8083/3

• Keratinising cancer is more frequent in non-endemic areas whereas non-keratinising

PRIMARY TUMOUR (T)

T0 No tumour identified, but EBV-positive cervical node(s) involvement

Tis Carcinoma in situ

REGIONAL LYMPH NODES (N)

N0 No regional lymph node metastasis

•Head and neck •Oesophagoscopy