Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS–ESMO–ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up

•This EHNS–ESMO–ESTRO Clinical Practice Guideline provides key recommendations for managing SCCHN.•It covers clinical and pathological diagnosis, staging and risk assessment, treatment and follow-up.•Opportunities for personalised medicine in SCCHN are also discussed.•All recommendations were compiled by a multidisciplinary group of experts from different institutions and countries.•Recommendations are based on available clinical evidence and the collective expert opinion of the authors. Squamous cell carcinoma of the head and neck (SCCHN) arises from epithelial cells and occurs in the oral cavity, pharynx and larynx. Nasopharyngeal carcinoma (NPC) is a disease with unique features and is therefore not covered in this Clinical Practice Guideline. Updated recommendations for the management of NPC are described in a separate Clinical Practice Guideline (submitted). SCCHN is the seventh most common cancer worldwide with an annual incidence of approximately 700 000 and a mortality rate estimated at 350 000 in 2018.1Bray F. Ferlay J. Soerjomataram I. et al.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2018; 68: 394-424Crossref PubMed Scopus (33702) Google Scholar In Europe, between 2000 and 2007, the annual crude incidence rates were 4.6/100 000 for laryngeal squamous cell carcinoma (SCC), 3.5/100 000 for oral cavity SCC, 3.3/100 000 for oropharyngeal SCC and 1.3/100 000 for hypopharyngeal SCC, corresponding to approximately 90 000 new cases per year.2Gatta G. Capocaccia R. Botta L. et al.Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study.Lancet Oncol. 2017; 18: 1022-1039Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar Five-year relative survival was 61%, 49%, 41% and 25% for laryngeal, oral cavity, oropharyngeal and hypopharyngeal SCC, respectively.2Gatta G. Capocaccia R. Botta L. et al.Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study.Lancet Oncol. 2017; 18: 1022-1039Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar Around 75%–85% of SCCHN is due to tobacco use and alcohol consumption, although human papillomavirus (HPV) infection as a cause of oropharyngeal cancer is increasing. The prevalence of oropharyngeal cancer attributable to HPV varies widely across the globe but is estimated at around 30%–35%.3Taberna M. Mena M. Pavón M.A. et al.Human papillomavirus-related oropharyngeal cancer.Ann Oncol. 2017; 28: 2386-2398Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar HPV-positive patients with oropharyngeal cancer have a significantly better outcome than patients diagnosed with HPV-negative disease.4Ang K.K. Harris J. Wheeler R. et al.Human papillomavirus and survival of patients with oropharyngeal cancer.N Engl J Med. 2010; 363: 24-35Crossref PubMed Scopus (4053) Google Scholar HPV-positive SCCHN outside of the oropharynx is rare (<6%). Other much weaker risk factors include radiation exposure, chronic infection, long-term immunosuppression, poor oral hygiene, poor nutrition, betel nut chewing and ill-fitting dentures. Fanconi anaemia, ataxia telangiectasia, Bloom's syndrome, Li-Fraumeni syndrome and dyskeratosis congenita are rare inherited causes of SCCHN. Genetic counselling should be considered in cases of cytopaenia, young age and history of several cancers in the family, particularly in the absence of the other risk factors. Specific polymorphisms in genes encoding for enzymes that metabolise carcinogens such as glutathione S-transferase (GSTM1), glutathione S-transferase (GSTT1) or human microsomal epoxide hydrolase (EPHX1) have been associated with SCCHN development.5Cadoni G. Boccia S. Petrelli L. et al.A review of genetic epidemiology of head and neck cancer related to polymorphisms in metabolic genes, cell cycle control and alcohol metabolism.Acta Otorhinolaryngol Ital. 2012; 32: 1-11PubMed Google Scholar The following symptoms should prompt clinicians to examine patients for an 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. A summary of clinical work-up recommendations for staging and diagnosis is shown in Table 1. 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 [IV, A]. A complete blood count, assessment of liver enzymes, serum creatinine, albumin, coagulation parameters and thyroid-stimulating hormone (TSH) should be routinely carried out. Pathological confirmation is mandatory [IV, A]. Examination and biopsy can be carried out transorally under local anaesthesia. For pharyngolaryngeal tumours, this is often best carried out using an endoscopic route under general anaesthesia [IV, A]. Stomatological evaluation with tooth extraction when required [especially if radiotherapy (RT) is being considered] is also usually carried out. Systematic bronchoscopy and oesophagoscopy are not advised but should be driven by symptoms and/or other diagnostic findings [IV, C].Table 1Work-up for staging and diagnosisStrongly recommendedAlternativeIf indicatedGeneral•Tumour biopsy•Medical history•Physical examination including head and neck examination•PS•Dental examination•Blood testaComplete blood count, assessment of liver enzymes, serum creatinine, albumin, coagulation parameters and TSH if RT is foreseen.•Speech and swallowing function•Nutritional status with weight assessment•Social and psychological evaluationLocal and regional assessment•Head and neck CE-CT and/or MRI•Rigid head and neck endoscopy under general anaesthesia•Teeth extractionbIdeally to be carried out during the head and neck endoscopy under general anaesthesia if indicated.Assessment of distant metastases•FDG-PET•Chest CTSecond primaries•Head and neck endoscopy•Oesophagoscopy•BronchoscopyCE, contrast-enhanced; CT, computed tomography; FDG-PET, 2′-deoxy-2′-[18F] fluoro-d-glucose positron emission tomography; MRI, magnetic resonance imaging; PS, performance status; RT, radiotherapy; TSH, thyroid-stimulating hormone.a Complete blood count, assessment of liver enzymes, serum creatinine, albumin, coagulation parameters and TSH if RT is foreseen.b Ideally to be carried out during the head and neck endoscopy under general anaesthesia if indicated. Open table in a new tab CE, contrast-enhanced; CT, computed tomography; FDG-PET, 2′-deoxy-2′-[18F] fluoro-d-glucose positron emission tomography; MRI, magnetic resonance imaging; PS, performance status; RT, radiotherapy; TSH, thyroid-stimulating hormone. 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 [III, A]. The two imaging techniques are complementary and their respective indications should be discussed with a radiologist specialised in head and neck cancer. CT and MRI have similar diagnostic value in the radiological evaluation of the neck. Chest imaging is important to assess the presence of distant metastases in high-risk tumours (i.e. presence of neck adenopathies) or a second lung primary in heavy smokers [III, A]. As a minimum, a chest CT should be carried out. The combination of 2′-deoxy-2′-[18F] fluoro-d-glucose (FDG) positron emission tomography (PET) and CE-CT of the chest have a higher sensitivity than chest CT or whole-body FDG-PET as separate modalities to detect tumours [II, B].6Senft A. de Bree R. Hoekstra O.S. et al.Screening for distant metastases in head and neck cancer patients by chest CT or whole body FDG-PET: a prospective multicenter trial.Radiother Oncol. 2008; 87: 221-229Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar FDG-PET is also recommended for the work-up of a carcinoma of unknown primary to direct specific mucosal biopsy.7Wong W.L. Sonoda L.I. Gharpurhy A. et al.18F-fluorodeoxyglucose positron emission tomography/computed tomography in the assessment of occult primary head and neck cancers–an audit and review of published studies.Clin Oncol (R Coll Radiol). 2012; 24: 190-195Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar Finally, FDG-PET is recommended to evaluate the neck response to RT or chemoradiotherapy (CRT) 10–12 weeks after completing treatment, or in cases of suspected recurrence.8Mehanna H. Wong W.L. McConkey C.C. et al.PET-CT surveillance versus neck dissection in advanced head and neck cancer.N Engl J Med. 2016; 374: 1444-1454Crossref PubMed Scopus (314) Google Scholar SCCHN should be classified according to the 4th edition of the World Health Organization (WHO) classification.9El-Naggar A.K. Chan J.K.C. Takata T. et al.The fourth edition of the head and neck World Health Organization blue book: editors' perspectives.Hum Pathol. 2017; 66: 10-12Crossref PubMed Scopus (56) Google Scholar This classification recognises the oropharynx as a distinctive subsite. HPV evaluation using p16 immunohistochemistry (IHC) should be carried out on all patients with newly diagnosed oropharyngeal SCC [I, A]. p16 IHC is a reliable surrogate marker for HPV positivity in the oropharynx, although 10%–15% of false-positive results occur.10Nauta I.H. Rietbergen M.M. van Bokhoven A. et al.Evaluation of the eighth TNM classification on p16-positive oropharyngeal squamous cell carcinomas in the Netherlands and the importance of additional HPV DNA testing.Ann Oncol. 2018; 29: 1273-1279Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar 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)] should be carried out in order to confirm the HPV status [III, A].11Fakhry C. Lacchetti C. Rooper L.M. et al.Human papillomavirus testing in head and neck carcinomas: ASCO Clinical Practice Guideline endorsement of the College of American Pathologists guideline.J Clin Oncol. 2018; 36: 3152-3161Crossref PubMed Scopus (79) Google Scholar,12Rassy E. Nicolai P. Pavlidis N. Comprehensive management of HPV-related squamous cell carcinoma of the head and neck of unknown primary.Head Neck. 2019; 41: 3700-3711Crossref PubMed Scopus (17) Google Scholar In case of neoplastic lymph node(s) with an unknown primary, the Epstein-Barr virus (EBV) status should also be determined by Epstein-Barr-encoded RNA (EBER) using ISH to exclude a nasopharyngeal cancer [III, A]. The prognostic value of p16 has only been observed in oropharyngeal SCC, and not in laryngeal, hypopharyngeal or oral cavity tumours. Thus, for non-oropharyngeal cancers of the head and neck, determination of p16 status is not mandatory. Pathological assessment of the 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. R0 and R1 resection) [I, A]. These features are important for pathological staging and prognosis, and to determine the postoperative adjuvant treatment. For recurrent and/or metastatic SCCHN, tumour programmed death-ligand 1 (PD-L1) expression should be evaluated by an approved PD-L1 test within the framework of quality assurance.13Cohen E.E.W. Bell R.B. Bifulco C.B. et al.The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC).J Immunother Cancer. 2019; 7: 184Crossref PubMed Scopus (153) Google Scholar PD-L1 expression is assessed either by the tumour proportion score (TPS), defined as the percentage of tumour cells with membranous PD-L1 staining, or by the combined positive score (CPS), defined as the number of PD-L1-positive cells (tumour cells, lymphocytes and macrophages) divided by the total number of tumour cells multiplied by 100. The CPS can help to define the first-line treatment strategy for recurrent/metastatic SCCHN [II, B]. Tobacco- and/or alcohol-induced SCCHN and HPV-positive oropharyngeal cancer are two distinct entities that differ significantly at both a clinical and molecular level.14Comprehensive genomic characterization of head and neck squamous cell carcinomas.Nature. 2015; 517: 576-582Crossref PubMed Scopus (1983) Google Scholar For HPV-negative SCCHN, the two most frequent genomic alterations are p53 (83%) and CDKN2A (57%) according to The Cancer Genome Atlas (TCGA) data.14Comprehensive genomic characterization of head and neck squamous cell carcinomas.Nature. 2015; 517: 576-582Crossref PubMed Scopus (1983) Google Scholar,15Leemans C.R. Snijders P.J.F. Brakenhoff R.H. The molecular landscape of head and neck cancer.Nat Rev Cancer. 2018; 18: 269-282Crossref PubMed Scopus (393) Google Scholar In HPV-positive oropharyngeal cancer, 56% harbour PI3KCA amplifications/mutations whereas other genetic alterations are rare. Different subgroups (mesenchymal, basal, classical and atypical) have also been defined based on gene expression profiles.16Chung C.H. Parker J.S. Karaca G. et al.Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression.Cancer Cell. 2004; 5: 489-500Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar, 17Keck M.K. Zuo Z. Khattri A. et al.Integrative analysis of head and neck cancer identifies two biologically distinct HPV and three non-HPV subtypes.Clin Cancer Res. 2015; 21: 870-881Crossref PubMed Scopus (213) Google Scholar, 18De Cecco L. Nicolau M. Giannoccaro M. et al.Head and neck cancer subtypes with biological and clinical relevance: meta-analysis of gene-expression data.Oncotarget. 2015; 6: 9627-9642Crossref PubMed Scopus (71) Google Scholar In addition, HPV-positive SCCHN can be subclassified into different gene profile groups, some of which are prognostic.19Zhang Y. Koneva L.A. Virani S. et al.Subtypes of HPV-positive head and neck cancers are associated with HPV characteristics, copy number alterations, PIK3CA mutation, and pathway signatures.Clin Cancer Res. 2016; 22: 4735-4745Crossref PubMed Scopus (60) Google Scholar However, despite a better understanding of the molecular biology of SCCHN, the current management of these patients is not based on genomic alterations or gene expression profiles. •Clinical examination and pathological confirmation are mandatory [IV, A].•Rigid head and neck endoscopy, head and neck CE-CT and/or MRI and chest imaging (with CT and/or FGD-PET) are strongly recommended [IV, A].•For oropharyngeal cancer, p16 IHC is strongly recommended [I, A].•For SCCHN of unknown primary, p16 and EBER are recommended. If p16 staining is positive, another specific HPV test should be carried out to confirm the HPV status [III, A].•On the surgical specimens, DOI of oral cavity cancer, assessment of the number of invaded lymph nodes as well as the presence extracapsular extension, perineural and lymphatic infiltration and the surgical margins must be evaluated [I, A].•For recurrent and/or metastatic SCCHN, tumour PD-L1 expression should be evaluated [II, B]. The Union for International Cancer Control (UICC) Tumour Node Metastasis (TNM) Cancer Staging Manual 8th edition head and neck chapters introduce significant changes from the 7th edition (supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2020.07.011).20O'Sullivan B. Head and neck tumours.in: Brierley J. Gospodarowicz M.K. Wittekind C. UICC TNM Classification of Malignant Tumours. 8 ed. Wiley, Chichester2017: 17-54Google Scholar The 8th edition takes new prognostic factors into account to better predict patient survival based on disease stage. In this context, it is important to outline that TNM staging is a prognostic factor and that current treatment strategies of SCCHN should not be modified based on any new classifications. The main modifications to the UICC TNM 8th edition are described in the supplementary text, available at https://doi.org/10.1016/j.annonc.2020.07.011. The objective of any treatment strategy for SCCHN is to achieve the highest possible cure rate with the lowest risk of morbidity. As such, treatment proposals should integrate both objective tumour parameters (e.g. tumour location, tumour histology, T stage, N stage) and patient parameters (e.g. physiological age, comorbidities, previous history of cancer, occupation, expected functional outcome, personal preference). In this framework, in addition to locoregional staging, every patient should undergo evaluation of their nutritional status, comorbidities, cardiopulmonary and renal function, frailty index (for geriatric patients), psychological and social status and dental status with rehabilitation in case of foreseen RT [III, A]. In case of significant malnutrition, defined as weight loss of more than 10% during the 6 months before diagnosis, nutritional improvement via enteral route through a feeding tube is highly recommended before starting treatment [II, A]. Percutaneous gastrostomy is generally preferred to a nasogastric feeding tube for long-term enteral support. The optimal treatment strategy must be discussed in a multidisciplinary team (MDT) including not only the main treatment disciplines (surgery, radiation oncology, medical oncology) but also the disciplines involved in diagnosis (radiology, nuclear medicine, pathology) and treatment support (e.g. nutritionist, research nurse, psychologist) [III, A]. Patients should also be treated at high-volume facilities as this has been reported as a strong and significant prognostic factor [II, A].21Torabi S.J. Benchetrit L. Kuo Yu P. et al.Prognostic case volume thresholds in patients with head and neck squamous cell carcinoma.JAMA Otolaryngol Head Neck Surg. 2019; 145: 708-715Crossref Scopus (9) Google Scholar •The UICC TNM 8th edition staging system should be used. A summary of therapeutic regimens for SCCHN is shown in supplementary Table S2, available at https://doi.org/10.1016/j.annonc.2020.07.011, and proposed management strategies for oral cavity, laryngeal, oropharyngeal and hypopharyngeal cancers are illustrated in Figure 1, Figure 2, Figure 3, Figure 4. All treatment recommendations are based on staging according to the UICC TNM 8th edition.Figure 2Management of laryngeal cancer (stage I–IVB).Show full captionBSC, best supportive care; ChT, chemotherapy; CRT, chemoradiotherapy; M, metastasis; N, node; RT, radiotherapy; T, tumour.a Not requiring total laryngectomy.b Requiring total laryngectomy.c cT1–2N0 glottic cancer does not require neck dissection or neck RT.d Altered fractionation (accelerated or hyperfractionated) RT is a valid option for selected T3 or T3N1.View Large Image Figure ViewerDownload (PPT)Figure 3Management of oropharyngeal cancer (p16-negative stage I–IVB; p16-positive stage I–III).Show full captionCRT, chemoradiotherapy; M, metastasis; N, node; RT, radiotherapy; T, tumour.a Altered fractionation (accelerated or hyperfractionated) RT is a valid option for T1–N1, T2–N0 or T2–N1.b Altered fractionation (accelerated or hyperfractionated) RT is a valid option for T1–N1 or T2–N1.View Large Image Figure ViewerDownload (PPT)Figure 4Management of hypopharyngeal cancer (stage I–IVB).Show full captionBSC, best supportive care; ChT, chemotherapy; CRT, chemoradiotherapy; M, metastasis; N, node; RT, radiotherapy; T, tumour.View Large Image Figure ViewerDownload (PPT) BSC, best supportive care; ChT, chemotherapy; CRT, chemoradiotherapy; M, metastasis; N, node; RT, radiotherapy; T, tumour. a Not requiring total laryngectomy. b Requiring total laryngectomy. c cT1–2N0 glottic cancer does not require neck dissection or neck RT. d Altered fractionation (accelerated or hyperfractionated) RT is a valid option for selected T3 or T3N1. CRT, chemoradiotherapy; M, metastasis; N, node; RT, radiotherapy; T, tumour. a Altered fractionation (accelerated or hyperfractionated) RT is a valid option for T1–N1, T2–N0 or T2–N1. b Altered fractionation (accelerated or hyperfractionated) RT is a valid option for T1–N1 or T2–N1. BSC, best supportive care; ChT, chemotherapy; CRT, chemoradiotherapy; M, metastasis; N, node; RT, radiotherapy; T, tumour. In case of RT, all patients should be treated by intensity-modulated RT (IMRT) or its variant volumetric-modulated arc therapy (VMAT) [I, A]. The overall treatment time of RT has been shown to influence the probability of local control, and any treatment delays should be avoided or compensated. International consensus guidelines have been published for the optimal selection of node levels as a function of tumour location as well as for the delineation of these levels in the neck.22Biau J. Lapeyre M. Troussier I. et al.Selection of lymph node target volumes for definitive head and neck radiation therapy: a 2019 update.Radiother Oncol. 2019; 134: 1-9Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar,23Grégoire V. Ang K. Budach W. et al.Delineation of the neck node levels for head and neck tumors: a 2013 update. DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG consensus guidelines.Radiother Oncol. 2014; 110: 172-181Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar Consensus guidelines have also been published for the delineation of the primary tumour target volumes.24Grégoire V. Evans M. Le Q.T. et al.Delineation of the primary tumour clinical target volumes (CTV-P) in laryngeal, hypopharyngeal, oropharyngeal and oral cavity squamous cell carcinoma: AIRO, CACA, DAHANCA, EORTC, GEORCC, GORTEC, HKNPCSG, HNCIG, IAG-KHT, LPRHHT, NCIC CTG, NCRI, NRG Oncology, PHNS, SBRT, SOMERA, SRO, SSHNO, TROG consensus guidelines.Radiother Oncol. 2018; 126: 3-24Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar Although promising data have been published favouring the use of proton therapy instead of megavoltage X-rays, there are no randomised clinical trial data available to recommend the routine use of intensity-modulated proton therapy (IMPT).25Moreno A.C. Frank S.J. Garden A.S. et al.Intensity modulated proton therapy (IMPT) - the future of IMRT for head and neck cancer.Oral Oncol. 2019; 88: 66-74Crossref PubMed Scopus (35) Google Scholar Early stage disease is defined as either T1–2N0 (stage I and II) oral cavity, laryngeal, hypopharyngeal and p16-negative oropharyngeal cancer or T1–2N0 p16-positive oropharyngeal cancer according to the UICC TNM 8th edition. In early-stage disease, conservative surgery or RT [external beam RT (EBRT) or brachytherapy for selected stage I oropharyngeal or oral cavity subsites] gives similar locoregional control [IV, A]. However, this is based on retrospective studies only and there are no randomised trials available for reference. In the absence of high-level evidence, the choice between these two modalities should be based on assessment of functional outcome and treatment morbidity for an individual patient as well as institutional and patient preferences and experience. Early disease should be treated as much as possible with a single-modality treatment (surgery or RT) [IV, A]. 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 the functional outcome (e.g. speech and swallowing) and is unlikely to require postoperative RT [V, B].26Huang S.H. Hahn E. Tsang R.K. et al.The interplay of IMRT and transoral surgery in HPV-mediated oropharyngeal cancer: getting the balance right.Oral Oncol. 2018; 86: 171-180Crossref PubMed Scopus (10) Google Scholar This is especially relevant given the increasing incidence of HPV-positive SCCHN as these patients tend to be younger and have a better long-term prognosis than those with HPV-negative SCCHN. This changing patient profile has strengthened interest in functional organ preservation surgery to improve functional outcomes and quality of life (QoL) in these patients. However, this issue is still not settled, as demonstrated by the randomised ORATOR trial which did not demonstrate any QoL advantage at 2 years when TORS (with or without postoperative RT) was compared with RT [with or without concomitant chemotherapy (ChT)] for the treatment of oropharyngeal SCC, although long-term outcomes with TORS have not yet been reported.27Nichols A.C. Theurer J. Prisman E. et al.Radiotherapy versus transoral robotic surgery and neck dissection for oropharyngeal squamous cell carcinoma (ORATOR): an open-label, phase 2, randomised trial.Lancet Oncol. 2019; 20: 1349-1359Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar In early-stage disease, transoral surgery is usually recommended as a single-modality treatment for oral cavity, oropharyngeal and laryngeal lesions [IV, A]. The surgical technique will depend on the location of the tumours and patient-related factors. Despite the lack of randomised trials, recent data suggest that the oncological outcomes of TORS for oropharyngeal cancer is comparable to open surgery and (C)RT [IV, A].28Golusiński W. Functional organ preservation surgery in head and neck cancer: transoral robotic surgery and beyond.Front Oncol. 2019; 9: 293Crossref PubMed Scopus (10) Google Scholar Despite the growing popularity of TORS in the treatment of oropharyngeal cancer, this approach has several potential drawbacks. Importantly, the use of TORS does not obviate the need for postoperative RT in some cases. Although the head and neck are relatively accessible, access and manoeuvrability are sometimes limited by anatomical restrictions. Although TLM is currently considered a standard of care for early glottic cancer, TORS has also been used to treat early-stage glottic carcinomas but data are currently limited.29Kayhan F.T. Koc A.K. Erdim I. Oncological outcomes of early glottic carcinoma treated with transoral robotic surgery.Auris Nasus Larynx. 2019; 46: 285-293Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar With the exception of T1–2 glottic cancer, ipsilateral selective neck dissection (bilateral in near-midline tumours) or sentinel node biopsy is recommended for cT1–2 SCCHN tumours that are treated with primary surgery [I, A].30Liao L.J. Hsu W.L. Wang C.T. et al.Analysis of sentinel node biopsy combined with other diagnostic tools in staging cN0 head and neck cancer: a diagnostic meta-analysis.Head Neck. 2016; 38: 628-634Crossref PubMed Scopus (24) Google Scholar, 31Schilling C. Stoeckli S.J. Haerle S.K. et al.Sentinel European Node Trial (SENT): 3-year results of sentinel node biopsy in oral cancer.Eur J Cancer. 2015; 51: 2777-2784Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, 32D'Cruz A.K. Vaish R. Kapre N. et al.Elective versus therapeutic neck dissection in node-negative oral cancer.N Engl J Med. 2015; 373: 521-529Crossref PubMed Scopus (517) Google Scholar Early-stage disease can be treated by RT alone without any use of concomitant or induction ChT [IV, A]. 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 [IV, A]. For stage II disease, a slightly more intense RT delivery is recommended with either hyperfractionation with 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) [I, A].33Lacas B. Bourhis J. Overgaard J. et al.Role of radiotherapy fractionation in head and neck cancers (MARCH): an updated meta-analysis.Lancet Oncol. 2017; 18: 1221-1237Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar It is beyond the scope of this publication to distinguish the respective merit of these regimens, and interested readers should refer to specialised publications on this topic. 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. Several randomised controlled trials and a meta-analysis have demonstrated that the use of hypoxic sensitisers improved locoregional control and disease-specific survival after RT [I, A].34Overgaard J. Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck--a systematic review and meta-analysis.Radiother Oncol. 2011; 100: 22-32Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar This radiosensitisation is achieved irrespective of the RT fractionation regimen and the modification of hypoxia used. 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 results in a significant increase in acute grade 3–4 mucositis to around 40% compared with 25% for standard RT, an increase in the need for a feeding tube during RT and a non-significant increase in late RT-induced morbidity.33Lacas B.