SEOM clinical guidelines for the treatment of head and neck cancer (2017)

Head and neck cancer (HNC) is defined as malignant tumours located in the upper aerodigestive tract and represents 5% of oncologic cases in adults in Spain. More than 90% of these tumours have squamous histology.In an effort to incorporate evidence obtained since 2013 publication, Spanish Society of Medical Oncology (SEOM) presents an update of HNC diagnosis and treatment guideline. The eighth edition of TNM classification, published in January 2017, introduces important changes for p16-positive oropharyngeal tumours, for lip and oral cavity cancer and for N3 category. In addition, there are new data about induction chemotherapy and the role of immunotherapy in HNC.

# Introduction
Head and neck cancer (HNC) is defined as malignant tumours located in the upper aerodigestive tract (paranasal sinuses, nasopharynx, oropharynx, hypopharynx, larynx, oral cavity, nostrils and salivary glands).
It is necessary to emphasize that the most important risk factor continues to be tobacco along with alcohol, but the infection by human papillomavirus is key in the origin of some of these tumours and confers them special characteristics that possibly in the future condition its treatment.
It is a neoplasm with a high possibility of cure if it is diagnosed in early stages, but unfortunately two-thirds of the patients are diagnosed at an advanced locoregional stage (stages III and IV, without metastasis). More than 90% of these tumours have a squamous histology. In this guide we only talk about them.
In Spain, HNC represents 5% of all new cancer diagnoses in adults, being the sixth frequency neoplasia (fifth in men), with an incidence similar to the European median, and a mortality rate of three points below the European median.
A multidisciplinary team, bringing together all professionals who specialize in the diagnosis and treatment of these tumours, will make the decision to establish the best sequence of individualized treatment for each patient.
Within what is known as HNC, each location has a clinical presentation, staging, prognosis and different therapeutic approach. As this is a general guide, the particularities of each subsite will not be dealt with.

# Methodology
Methodology SEOM guidelines have been developed with the consensus of ten oncologists from the Spanish Group for the Treatment of Head and Neck Tumors (TTCC) and SEOM. To assign a level and quality of evidence and a grade of recommendation to the different statements of this treatment guideline, the Infectious Diseases Society of America-US Public Health Service Grading System for Ranking Recommendations in Clinical Guidelines was used [fig_ref] Table 1: Strength of recommendation and quality of evidence score [/fig_ref]. The final text has been reviewed and approved by all authors.

## Diagnosis and staging
Recording a good clinical history and following a methodology for the diagnosis of HNC should be inherent in all good clinical practice. We describe the essential points of any clinical history of a patient with HNC, not forgetting that a patient may have other symptoms or diseases.
Accurate staging is crucial for determining the appropriate approach and for tailoring therapy to each individual patient. In HNC, the following staging process is recommended:
(a) Complete history and physical examination. The TNM classification is the internationally accepted system for tumour staging. Stage at diagnosis predicts survival rates and guide management. The eighth edition of TNM classification was published in January, 2017 [bib_ref] Development and validation of a staging system for HPV-related oropharyngeal cancer by..., Sullivan [/bib_ref] ; however, its implementation is scheduled for January, 2018. The aim of this article is to be used for the managing of head and neck tumours in the next years. Therefore, the eighth classification is detailed.
[formula] (b) Complete [/formula]
The main change to the seventh edition is the separate classification for p16-positive oropharyngeal tumours. In the T category, T4a and T4b are pooled as T4 in p16positive oropharyngeal tumours. In addition, N category has been reclassified .
Other modifications in the eight edition are as follows: T category (T1-T3) of lip and oral cavity includes the extent of depth invasion (

## Early disease (clinical stage i-ii) treatment
Both surgery and radiotherapy (RT) (external or brachytherapy) provide similar locoregional control and survival outcomes, but they have not been compared in randomized trials [bib_ref] Head and neck cancer, Forastiere [/bib_ref] [bib_ref] Radiotherapy versus open surgery versus endolaryngeal surgery (with or without laser) for..., Dey [/bib_ref]. The choice of treatment modality depends on the functional outcome, the patient's wishes, the possibility of an adequate follow-up, the patient's general condition, and the likelihood of developing a second primary tumour (e.g., younger smoking patients use the surgical option not to jeopardize further treatment).
Curative surgery is the preferred option for cancer of the oral cavity and involves resection of tumour with an appropriate safety margin and subsequent reconstruction [II, B]. Elective neck dissection offers improved overall and disease-free survival compared with therapeutic neck dissection [I, A] [bib_ref] Elective versus therapeutic neck dissection in nondegenerative oral cancer, D&apos;cruz [/bib_ref]. Sentinel node lymph node biopsy may be indicated for small cancers to avoid morbidity [II, B] [bib_ref] Sentinel node biopsy for squamous cell carcinoma of the oral cavity and..., Govers [/bib_ref].
Oropharyngeal carcinoma should ideally be treated with single-modality therapy, either primary surgery or RT. Radical RT is a good option (a total dose equivalent of 70 Gy in 35 fractions is used) . Prophylactic RT should be given to the ipsilateral cervical lymph nodes for lateralized tumours and to both sides of the neck for nonlateralised tumours . Surgery should usually be carried out transorally, either by transoral laser microsurgery (TLM) or transoral robotic surgery (TORS). Oncologic results after transoral resection of the oropharynx appear to be comparable to open surgery [II, B] [bib_ref] Critical review: transoral laser microsurgery and roboticassisted surgery for oropharynx cancer including..., Moore [/bib_ref] , which is associated with increased morbidity and treatment complications. Patients having surgery to the primary should also undergo ipsilateral selective neck dissection. Dissection of the contralateral neck may also be considered in tumours arising at or very near the midline [II, B].
Radiotherapy or TLM are the two most commonly used treatment modalities in early laryngeal cancer . Individual treatment selection depends on patient and tumour factors and local expertise. Single-modality treatment is sufficient and combining surgery with RT should be avoided as functional outcomes (and perhaps survival in the context of incompletely resected tumour) may be compromised by combined modality therapy. Open surgical procedures are used less commonly today; however, they provide an option for the treatment of tumours which are not accessible to TLM. Elective treatment of the neck is not recommended because of the very low risk of occult nodal disease [III, C].
Early lesions of the hypopharynx can be treated with equal effectiveness with surgery or radiation [bib_ref] Organ preserving transoral laser microsurgery for cancer of the hypopharynx, Martin [/bib_ref]. Occult nodal disease is present in 30-40% of patients, so any treatment plan should include elective treatment of the cervical nodes [II, B].

## Locally advanced disease (clinical stages iii, iv-a, iv-b) treatment
In all cases there must be a multidisciplinary assessment to decide the best treatment option for each patient.
This type of tumours is divided into two groups: resectable and unresectable. There is no universally accepted definition of unresectability but some anatomical criteria are considered unequivocal (involvement of skull base, cervical vertebrae, prevertebral muscles, brachial plexus, mediastinal spread, involvement of the nasopharynx, fixed tumour to collarbone). Final decision depends on institution and surgeon abilities. Furthermore, if surgical team foresees the impossibility of achieving complete excision with adequate margins and/or functional and/or aesthetic sequelae of surgery are not acceptable and/or little expectation of surgical cure and/or high-risk surgery due to age or comorbidities, patient should be considered not able to be suitably operated.
The patient's nutritional status must be corrected and maintained. Dental rehabilitation is indicated before radiotherapy. Treatment depends on primary tumour location and extension.
A. Resectable locally advanced disease (III-IV-A) 1. Surgical resection followed by radiotherapy (IA) or chemoradiotherapy (IA). Adjuvant concurrent Tumour 2 cm or less in greatest dimension and more than 5 mm but not more than 10 mm depth invasion or Tumour more than 2 cm but not more than 4 cm in greatest dimension and depth if invasion no more than 10 mm T3 Tumour more than 4 cm in greatest dimension or more than 10 mm in depth invasion [bib_ref] The effect of induction chemotherapy using docetaxel, cisplatin, and fluorouracil on survival..., Kim [/bib_ref].
Evaluation of response after ICT:
- Complete response: disappearance of all clinically tumour burden. - Partial response: C 50% reduction of primary tumour without lymph node progression. - Stable disease: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progression disease.
- Progression disease: increase of tumour burden.
After locoregional treatment: salvage neck dissection should be considered in patients with residual lymph node disease and complete response of primary tumour.
Specific recommendations on locally advanced disease by anatomic site: 1. Hypopharynx: three options could be considered: -Surgical resection (total pharyngo-laryngectomy ? neck dissection) followed by radiotherapy (IA) or chemoradiotherapy (IA) if high-risk recurrence of pathological factors. Specially T4a.
-Concurrent chemoradiotherapy with three-weekly cisplatin is recommended if patient refuses surgery (IA). If cisplatin cannot be administered: cetuximab concurrent to radiotherapy (IA). -Induction chemotherapy with TPF schedule:
- If complete response ? radiotherapy (based on initial stage)  cisplatin/cetuximab (based on ICT toxicity). - If partial response ? surgery followed by radiotherapy or chemoradiotherapy. If the main objective is organ preservation, consider concomitant RT (with cisplatin or cetuximab) (IIB). - If stable disease or progression ? surgery (including neck dissection) followed by radiotherapy or chemoradiotherapy. N category for all locations A. Regional lymph nodes (except oropharynx pl6-positive) NX Regional lymph nodes cannot be assessed NO No regional lymph node metastasis N1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension without extranodal extension N2a Metastasis in a single ipsilateral lymph node more than 3 cm but no more than 5 cm in greatest dimension without extranodal extension N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension without extranodal extension N2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension without extranodal extension N3a Metastasis in a lymph node more than 6 cm in greatest dimension without extranodal extension M3b Metastasis in a single or multiple lymph nodes with clinical extranodal extension B. Regional lymph nodes in oropharynx p16-positive tumours nX Regional lymph nodes cannot be assessed -Surgical resection (total versus partial laryngectomy ? neck dissection) followed by radiotherapy (IA) or chemoradiotherapy (IA) if high-risk recurrence of pathological factors.
- Specially T4a.
- For the most part of subglottic tumours.
-Concurrent chemoradiotherapy with three-weekly cisplatin is recommended if patient refuses surgery (IA). If cisplatin cannot be administered: cetuximab concurrent to radiotherapy (IA). -Induction chemotherapy with TPF schedule (except for subglottic tumours) [bib_ref] Larynx preservation in pyriform sinus cancer: Preliminary Results of a European Organization..., Lefebvre [/bib_ref] :
- If complete response ? radiotherapy.
- If partial response ? concomitant RT (with cisplatin or cetuximab) (IIB) or consider surgery followed by radiotherapy. - If stable disease or progression ? surgery (including neck dissection) followed by radiotherapy or chemoradiotherapy. cisplatin. Several studies have demonstrated benefit in locoregional control and overall survival over radiotherapy alone with a significant increase in acute and chronic toxicity. 2. Concomitant radiotherapy and cetuximab have shown a benefit in locoregional control and overall survival compared to radiotherapy alone with a better toxicity profile compared to chemotherapy. It should be considered if the use of cisplatin is contraindicated such as neuropathy, nephropathy, heart disease and hearing loss. 3. Induction chemotherapy followed by locoregional treatment. This option has been reconsidered, especially in patients who require rapid response or are at increased risk of distant metastases.

## Recommendations for unresectable locally advanced disease (iv-b)
1. Induction chemotherapy followed by locoregional treatment TPF 9 3 cycles (IA) if ECOG 0-1 and good renal and liver function.
This strategy is recommended in greater volume (N3, N2c, important N2b, T4b), very symptomatic and fastgrowing locally advanced disease.
After induction chemotherapy: - If CR/PR: RT ? cisplatin (IIB) or RT ? cetuximab (IIB). TTCC group performed a trial which prelimimary results are inconclusive (because the required number of events have not yet been observed) but both arms show a good locoregional control of 50% at 3 years [bib_ref] A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus..., Hitt [/bib_ref]. The treatment's choice will be based on toxicities during induction chemotherapy and on prediction of tolerance to platinum-based sequential chemoradiotherapy. - If SD or PD: individualized treatment or best supportive care (includes palliative radiotherapy). In case of local complete response and persistent lymph node after locoregional treatment, lymph node salvage resection should be considered (IVD).

## Recurrent and metastatic disease treatment
The multidisciplinary team will assess the possibility of salvage surgery (operable tumour) or re-irradiation with or without chemotherapy/cetuximab. In the presence of oligometastatic disease, treatment with curative intent should also be discussed.
Once this option is discarded the treatment of choice is palliative chemotherapy:
First-line treatment 1. Chemotherapy-naive patients (a) In the patient with a performance status of 0/1 the first choice is the combination of cisplatin, 5-fluorouracil, and cetuximab (EXTREME protocol) [bib_ref] Platinum-based chemotherapy plus cetuximab in head and neck cancer, Vermorken [/bib_ref]. If the patient is medically unfit to receive cisplatin the use of carboplatin may be an option. Cetuximab should be maintained until progression or unacceptable toxicity. (b) If the patient cannot be treated with platinum (concomitant disease, previous treatment, etc.) or patients with PS 2, the treatment of choice is best supportive treatment of symptoms. In these patients, the combination ERBITAX (paclitaxel plus cetuximab) should be considered [bib_ref] Phase II study of the combination of cetuximab and weekly paclitaxel in..., Hitt [/bib_ref]. (c) The treatment of choice for patients with PS 3/4 is best supportive care of symptoms.
2. Patients who have received chemotherapy for locoregional disease (a) Patients with progressive disease more than 6 months after locoregional treatment can be treated like chemotherapy-naive patients. (b) Patients with progressive disease within 6 months after last cisplatin dose should not receive cisplatin or carboplatin. ERBITAX combination or second-line therapy should be considered.

## Second-line treatment
Inmunotherapy with nivolumab [bib_ref] Nivolumab for recurrent squamous-cell carcinoma of the head and neck, Ferris [/bib_ref] (Level of evidence I, A or pembrolizumab [bib_ref] Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/ or metastatic..., Chow [/bib_ref] [bib_ref] Pembrolizumab for platinum-and cetuximab-refractory head and neck cancer: results from a single-arm...., Bauml [/bib_ref] (Level II, B) has become the standard of care. PD-L1 positive tumours seem to benefit the most. If it is not possible to use immunotherapy, considering using agents such as taxanes, methotrexate, cetuximab or gemcitabine. If bad PS, only support treatment should be considered.
All patients should be recommended including in clinical trials if available.

## Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of interest.
Ethical Approval This article does not contain any studies with human participants or animals performed by any of the authors.
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[fig] Figure 2 -: Larynx Concurrent chemoradiotherapy with three-weekly cisplatin is recommended (IA). If cisplatin cannot be administered: cetuximab concurrent to radiotherapy (IA). -Consider induction chemotherapy with TPF schedule, only in those patients N bulky and fast tumour growth, individualizing benefit and toxicity. B. Unresectable locally advanced disease (IV-B) (Fig. 3) Different therapeutic strategies have been explored in this scenario 1. Concomitant chemoradiotherapy with three-weekly [/fig]
[fig] Figure 3: Treatment algorithm for unresectable locally advanced disease (IV- [/fig]
[table] Table 1: Strength of recommendation and quality of evidence score [/table]
[table] Table 2 T: category for the different locations A. Lip and oral cavity T1 Tumour 2 cm or less in greatest dimension and 5 mm or less depth of invasion T2 [/table]